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Sheriff L, Copland A, Lecky DAJ, Done R, George LS, Jennings EK, Rouvray S, Elliot TAE, Jinks ES, Pallan L, Bending D. Lag3 and PD-1 pathways preferentially regulate NFAT-dependent TCR signalling programmes during early CD4 + T cell activation. IMMUNOTHERAPY ADVANCES 2025; 5:ltaf015. [PMID: 40351814 PMCID: PMC12066006 DOI: 10.1093/immadv/ltaf015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/25/2025] [Indexed: 05/14/2025] Open
Abstract
Introduction Lag3 and PD-1 are immune checkpoints that regulate T cell responses and are current immunotherapy targets. Yet how they function to control early stages of CD4+ T cell activation remains unclear. Methods Here, we show that the PD-1 and Lag3 pathways exhibit layered control of the early CD4+ T cell activation process, with the effects of Lag3 more pronounced in the presence of PD-1 pathway co-blockade (CB). RNA sequencing revealed that CB drove an early NFAT-dependent transcriptional profile, including promotion of ICOShi T follicular helper cell differentiation. Results NFAT pathway inhibition abolished CB-induced upregulation of NFAT-dependent co-receptors ICOS and OX40, whilst unaffecting the NFAT-independent gene Nr4a1. Mechanistically, Lag3 and PD-1 pathways functioned additively to regulate the duration of T cell receptor signals during CD4+ T cell re-activation. Phenotypic changes in peripheral blood CD4+ T cells in humans on anti-Lag3 and anti-PD-1 combination therapy revealed upregulation of genes encoding ICOS and OX40 on distinct CD4+ T cell subsets, highlighting the potential translational relevance of our findings. Conclusion Our data therefore reveal that PD-1 and Lag3 pathways converge to additively regulate TCR signal duration and may preferentially control NFAT-dependent transcriptional activity during early CD4+ T cell re-activation.
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Affiliation(s)
- Lozan Sheriff
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Alastair Copland
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - David A J Lecky
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Reygn Done
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Lorna S George
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Emma K Jennings
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Sophie Rouvray
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Thomas A E Elliot
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Elizabeth S Jinks
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Lalit Pallan
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - David Bending
- Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, United Kingdom
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Luo Y, Yuan Y, Liu D, Peng H, Shen L, Chen Y. Targeting novel immune checkpoints in the B7-H family: advancing cancer immunotherapy from bench to bedside. Trends Cancer 2025:S2405-8033(25)00055-X. [PMID: 40113530 DOI: 10.1016/j.trecan.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 03/22/2025]
Abstract
The B7-H family of immune checkpoint molecules is a crucial component of the immune regulatory network for tumors, offering new opportunities to modulate the tumor microenvironment (TME). The B7-H family - which includes B7-H2 (inducible T cell costimulatory ligand, ICOSL), B7-H3, B7-H4, B7-H5 (V-domain immunoglobulin suppressor of T cell activation, VISTA), B7-H6, and B7-H7 (HHLA2) - is known for its diverse roles in regulating innate and adaptive immunity. These molecules can exhibit co-stimulatory or co-inhibitory effects on T cells, influencing processes such as T cell activation, differentiation, and effector functions, and they are involved in the recruitment and polarization of various immune cells. This review explores the structural characteristics, receptor-ligand interactions, and signaling pathways associated with each B7-H family member. We also discuss the family's impact on tumor immunity and potential therapeutic strategies.
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Affiliation(s)
- Yiming Luo
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Ye Yuan
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Dan Liu
- Early Drug Development Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Haoxin Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
| | - Yang Chen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing, China; Department of Gastrointestinal Cancer, Beijing GoBroad Hospital, Beijing 102200, China.
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Ghaneialvar H, Jahani S, Hashemi E, Khalilzad MA, Falahi S, Rashidi MA, Majidpoor J, Najafi S. Combining anti-checkpoint immunotherapies and cancer vaccines as a novel strategy in oncological therapy: A review. Hum Immunol 2025; 86:111209. [PMID: 39662393 DOI: 10.1016/j.humimm.2024.111209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/17/2024] [Accepted: 11/26/2024] [Indexed: 12/13/2024]
Abstract
The field of cancer immunotherapy has experienced remarkable advancements in the treatment of human cancers over recent decades. Therapeutic cancer vaccines have been employed to elicit antitumor immune responses through the generation of specific reactions against tumor-associated antigens. Although preclinical studies have demonstrated hopeful results and at least one product is approved for clinical use, the overall efficacy of cancer vaccines remains restricted. The co-administration of anti-checkpoint antibodies alongside cancer vaccines is proposed as a potential strategy to enhance the clinical efficacy of immunotherapies. Among the various anti-checkpoint agents, monoclonal antibodies targeting CD127, OX40, and CD40 have been further investigated in combined administration with cancer vaccines, demonstrating a synergistic impact on disease outcomes in both animal models and human subjects. This combinational approach has been shown to suppress tumor regression, improve survival rates, and promote the efficacy of cancer vaccines via multiple mechanisms, including the augmentation of generation, activation, and expansion of CD8+ T cells, as well as the production of tumor-inhibitory cytokines. Importantly, the impact of the concurrent administration of anti-checkpoint agents and cancer vaccines surpass those observed with the sole vaccine, indicating that this strategy may offer significant advantages for clinical application in cancer patients. In this review, we aim to provide a comprehensive overview of the significance and therapeutic potential of the combined administration of checkpoint agonist/antagonist antibodies and cancer vaccines for human tumors.
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Affiliation(s)
- Hori Ghaneialvar
- Biotechnology and Medicinal Plants Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Saleheh Jahani
- Department of Pathology, School of Medicine, University of California, San Diego, USA
| | - Elham Hashemi
- Department of Anatomical Sciences, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Shahab Falahi
- Zoonotic Diseases Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Mohammad Amin Rashidi
- Department of Occupational Health and Safety, School of Public Health and Safety, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jamal Majidpoor
- Department of Anatomy, Faculty of Medicine, Infectious Disease Research Center, Gonabad University of Medical Sciences, Gonabad, Iran.
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Zhang Y, Chen A, Li D, Yuan Q, Zhu A, Deng J, Wang Y, Liu J, Liang C, Li W, Fang Q, Xie J, Zhang X, Zhang X, Zhang Y, Chen R, Pan T, Zhang H, He X. Development of T follicular helper cell-independent nanoparticle vaccines for SARS-CoV-2 or HIV-1 by targeting ICOSL. NPJ Vaccines 2024; 9:176. [PMID: 39341822 PMCID: PMC11438966 DOI: 10.1038/s41541-024-00971-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 09/19/2024] [Indexed: 10/01/2024] Open
Abstract
T helper cells, particularly T follicular helper (TFH) cells, are essential for the neutralizing antibody production elicited by pathogens or vaccines. However, in immunocompromised individuals, the inefficient support from TFH cells could lead to limited protection after vaccine inoculation. Here we showed that the conjugation of inducible T cell costimulatory (ICOS) onto the nanoparticle, together with immunogen, significantly enhanced the immune response of the vaccines specific for SARS-CoV-2 or human immunodeficiency virus type-1 (HIV-1) in TFH-deficient mice. Further studies indicated that ICOSL on B cells was triggered by ICOS binding, subsequently activated the PKCβ signaling pathway, and enhanced the survival and proliferation of B cells. Our findings revealed that the stimulation of ICOS-ICOSL interaction by adding ICOS on the nanoparticle vaccine significantly substitutes the function of TFH cells to support B cell response, which is significant for the immunocompromised people, such as the elderly or HIV-1-infected individuals.
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Affiliation(s)
- Yongli Zhang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Achun Chen
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Daiying Li
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Quyu Yuan
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Airu Zhu
- Guangzhou Laboratory, Bio-island, Guangzhou, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jieyi Deng
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yalin Wang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jie Liu
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Chaofeng Liang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Wenjie Li
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Qiannan Fang
- Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Jiatong Xie
- Shenzhen College of International Education, No. 3 Antuoshan 6th Road, Futian District, Shenzhen, China
| | - Xiantao Zhang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xu Zhang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yiwen Zhang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ran Chen
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ting Pan
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Center for Infection and Immunity Study, School of Medicine, Sun Yat-sen University, Shenzhen, China
| | - Hui Zhang
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Guangzhou Laboratory, Bio-island, Guangzhou, China
| | - Xin He
- Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
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Wang Y, Wang Q, He F, Qiao N, Li X, Wei L, Sun L, Dai W, Li Y, Pang X, Hu J, Huang C, Yang G, Pang C, Hu Z, Xing M, Wan C, Zhou D. Age-dependent decrease of circulating T follicular helper cells correlates with disease severity in elderly patients with COVID-19. Clin Immunol 2024; 266:110329. [PMID: 39067679 DOI: 10.1016/j.clim.2024.110329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/04/2024] [Accepted: 07/20/2024] [Indexed: 07/30/2024]
Abstract
Overwhelming evidence has shown that aging is a significant risk factor for COVID-19-related hospitalizations, death and other adverse health outcomes. Particular T cell subsets that susceptible to aging and associated with COVID-19 disease severity requires further elucidation. Our study recruited 57 elderly patients with acute COVID-19 and 27 convalescent donors. Adaptive immunity was assessed across the COVID-19 severity spectrum. Patients underwent age-dependent CD4+ T lymphopenia, preferential loss of circulating T follicular regulatory cells (cTfh) subsets including cTfh-em, cTfh-cm, cTfh1, cTfh2, cTfh17 and circulating T follicular regulatory cells (cTfr), which regulated antibody production through different pathways and correlated with COVID-19 severity, were observed. Moreover, vaccination improved cTfh-cm, cTfh2, cTfr proportion and promoted NAb production. In conclusion, the elderly had gone through age-dependent cTfh subsets deficiency, which impeded NAb production and enabled aggravation of COVID-19 to critical illness, whereas SARS-CoV-2 vaccine inoculation helped to rejuvenate cTfh, cTfr and intensify NAb responses.
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Affiliation(s)
- Yihan Wang
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Qiu Wang
- Department of Physical and Rehabilitation Medicine, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin 300052, China
| | - Furong He
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Nan Qiao
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Xuejun Li
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Liqun Wei
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Lingjin Sun
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Weiqian Dai
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Ying Li
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Xueyang Pang
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Jiayi Hu
- Department of Clinical Medicine, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China
| | - Chuan Huang
- Department of Physical and Rehabilitation Medicine, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin 300052, China
| | - Guangchen Yang
- Department of Physical and Rehabilitation Medicine, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin 300052, China
| | - Chongjie Pang
- Department of Infectious Diseases, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin 300052, China
| | - Zhidong Hu
- Department of Clinical Laboratory, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin 300052, China
| | - Man Xing
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China.
| | - Chunxiao Wan
- Department of Physical and Rehabilitation Medicine, Tianjin Medical University General Hospital, No. 154 Anshan Road, Tianjin 300052, China.
| | - Dongming Zhou
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qixiangtai Road, Tianjin 300070, China; Shanghai Public Health Clinical Center, Fudan University, No. 2901 Caolang Road, Shanghai 201508, China.
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Tili E, Otsu H, Commisso TL, Palamarchuk A, Balatti V, Michaille JJ, Nuovo GJ, Croce CM. MiR-155-targeted IcosL controls tumor rejection. Proc Natl Acad Sci U S A 2024; 121:e2408649121. [PMID: 38980909 PMCID: PMC11260163 DOI: 10.1073/pnas.2408649121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 06/08/2024] [Indexed: 07/11/2024] Open
Abstract
Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ-miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity.
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Affiliation(s)
- Esmerina Tili
- Department of Anesthesiology, Wexner Medical Center, College of Medicine, The Ohio State University, Columbus, OH43210
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Hajime Otsu
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Teresa L. Commisso
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Alexey Palamarchuk
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Veronica Balatti
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | - Jean-Jacques Michaille
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
| | | | - Carlo M. Croce
- The Ohio State University, Comprehensive Cancer Center, Department of Cancer Biology and Genetics, Wexner Medical Center, Columbus, OH43210
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7
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Verma S, Dufort MJ, Olsen TM, Kimmel S, Labuda JC, Scharffenberger S, McGuire AT, Harrison OJ. Antigen-level resolution of commensal-specific B cell responses can be enabled by phage display screening coupled with B cell tetramers. Immunity 2024; 57:1428-1441.e8. [PMID: 38723638 PMCID: PMC11168869 DOI: 10.1016/j.immuni.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 02/07/2024] [Accepted: 04/16/2024] [Indexed: 06/14/2024]
Abstract
Induction of commensal-specific immunity contributes to tissue homeostasis, yet the mechanisms underlying induction of commensal-specific B cells remain poorly understood in part due to a lack of tools to identify these cells. Using phage display, we identified segmented filamentous bacteria (SFB) antigens targeted by serum and intestinal antibodies and generated B cell tetramers to track SFB-specific B cells in gut-associated lymphoid tissues. We revealed a compartmentalized response in SFB-specific B cell activation, with a gradient of immunoglobulin A (IgA), IgG1, and IgG2b isotype production along Peyer's patches contrasted by selective production of IgG2b within mesenteric lymph nodes. V(D)J sequencing and monoclonal antibody generation identified somatic hypermutation driven affinity maturation to SFB antigens under homeostatic conditions. Combining phage display and B cell tetramers will enable investigation of the ontogeny and function of commensal-specific B cell responses in tissue immunity, inflammation, and repair.
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Affiliation(s)
- Sheenam Verma
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Matthew J Dufort
- Center for Systems Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Tayla M Olsen
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA
| | - Samantha Kimmel
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Jasmine C Labuda
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Sam Scharffenberger
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Andrew T McGuire
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
| | - Oliver J Harrison
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA; Department of Immunology, University of Washington, Seattle, WA, USA.
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8
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Geels SN, Moshensky A, Sousa RS, Murat C, Bustos MA, Walker BL, Singh R, Harbour SN, Gutierrez G, Hwang M, Mempel TR, Weaver CT, Nie Q, Hoon DSB, Ganesan AK, Othy S, Marangoni F. Interruption of the intratumor CD8 + T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy. Cancer Cell 2024; 42:1051-1066.e7. [PMID: 38861924 PMCID: PMC11285091 DOI: 10.1016/j.ccell.2024.05.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 02/28/2024] [Accepted: 05/14/2024] [Indexed: 06/13/2024]
Abstract
PD-1 blockade unleashes potent antitumor activity in CD8+ T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells. CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8+ T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.
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Affiliation(s)
- Shannon N Geels
- Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA
| | - Alexander Moshensky
- Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA
| | - Rachel S Sousa
- Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA
| | - Claire Murat
- Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA
| | - Matias A Bustos
- Department of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, CA, USA
| | - Benjamin L Walker
- Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA
| | - Rima Singh
- Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA
| | - Stacey N Harbour
- Department of Pathology, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Giselle Gutierrez
- Institute for Immunology, University of California, Irvine, Irvine, CA, USA
| | - Michael Hwang
- Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA
| | - Thorsten R Mempel
- Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Casey T Weaver
- Department of Pathology, University of Alabama, Birmingham, Birmingham, AL, USA
| | - Qing Nie
- Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, USA; NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA
| | - Dave S B Hoon
- Department of Translational Molecular Medicine, Saint John's Cancer Institute, Santa Monica, CA, USA
| | - Anand K Ganesan
- Department of Dermatology, University of California, Irvine, Irvine, CA, USA
| | - Shivashankar Othy
- Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA
| | - Francesco Marangoni
- Institute for Immunology, University of California, Irvine, Irvine, CA, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
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9
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Raineri D, Abreu H, Vilardo B, Kustrimovic N, Venegoni C, Cappellano G, Chiocchetti A. Deep Flow Cytometry Unveils Distinct Immune Cell Subsets in Inducible T Cell Co-Stimulator Ligand (ICOSL)- and ICOS-Knockout Mice during Experimental Autoimmune Encephalomyelitis. Int J Mol Sci 2024; 25:2509. [PMID: 38473756 DOI: 10.3390/ijms25052509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/10/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
The inducible T cell co-stimulator ligand (ICOSL), expressed by antigen presenting cells, binds to the inducible T cell co-stimulator (ICOS) on activated T cells. Improper function of the ICOS/ICOSL pathway has been implicated in several autoimmune diseases, including multiple sclerosis (MS). Previous studies showed that ICOS-knockout (KO) mice exhibit severe experimental autoimmune encephalomyelitis (EAE), the animal model of MS, but data on ICOSL deficiency are not available. In our study, we explored the impact of both ICOS and ICOSL deficiencies on MOG35-55 -induced EAE and its associated immune cell dynamics by employing ICOSL-KO and ICOS-KO mice with a C57BL/6J background. During EAE resolution, MOG-driven cytokine levels and the immunophenotype of splenocytes were evaluated by ELISA and multiparametric flow cytometry, respectively. We found that both KO mice exhibited an overlapping and more severe EAE compared to C57BL/6J mice, corroborated by a reduction in memory/regulatory T cell subsets and interleukin (IL-)17 levels. It is noteworthy that an unsupervised analysis showed that ICOSL deficiency modifies the immune response in an original way, by affecting T central and effector memory (TCM, TEM), long-lived CD4+ TEM cells, and macrophages, compared to ICOS-KO and C57BL/6J mice, suggesting a role for other binding partners to ICOSL in EAE development, which deserves further study.
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Affiliation(s)
- Davide Raineri
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Hugo Abreu
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Beatrice Vilardo
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Natasa Kustrimovic
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Chiara Venegoni
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Giuseppe Cappellano
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Annalisa Chiocchetti
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
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10
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Akama-Garren EH, Yin X, Prestwood TR, Ma M, Utz PJ, Carroll MC. T cell help shapes B cell tolerance. Sci Immunol 2024; 9:eadj7029. [PMID: 38363829 PMCID: PMC11095409 DOI: 10.1126/sciimmunol.adj7029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 12/29/2023] [Indexed: 02/18/2024]
Abstract
T cell help is a crucial component of the normal humoral immune response, yet whether it promotes or restrains autoreactive B cell responses remains unclear. Here, we observe that autoreactive germinal centers require T cell help for their formation and persistence. Using retrogenic chimeras transduced with candidate TCRs, we demonstrate that a follicular T cell repertoire restricted to a single autoreactive TCR, but not a foreign antigen-specific TCR, is sufficient to initiate autoreactive germinal centers. Follicular T cell specificity influences the breadth of epitope spreading by regulating wild-type B cell entry into autoreactive germinal centers. These results demonstrate that TCR-dependent T cell help can promote loss of B cell tolerance and that epitope spreading is determined by TCR specificity.
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Affiliation(s)
- Elliot H. Akama-Garren
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA
| | - Xihui Yin
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tyler R. Prestwood
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Minghe Ma
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Paul J. Utz
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Michael C. Carroll
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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11
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Sahinoglu M, Sargin G, Yavasoglu I, Senturk T. The relationship between peripheral T follicular helper cells and disease severity in systemic sclerosis. Clin Exp Med 2024; 24:19. [PMID: 38280030 PMCID: PMC10822004 DOI: 10.1007/s10238-023-01286-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 11/04/2023] [Indexed: 01/29/2024]
Abstract
We aimed to investigate the association between follicular T helper cells (Tfh) and disease severity in systemic sclerosis (SSc), a chronic connective tissue disease characterized by progressive fibrosis. While Tfh cells have been extensively studied in other autoimmune diseases, their role in SSc remains poorly understood. A cohort of 50 SSc patients, diagnosed based on the ACR/EULAR 2013 classification criteria, was included in the study. Patient data, including demographic information, comorbidities, treatment history and organ involvement, were collected. Disease severity was assessed using the modified Rodnan skin score and Medsger disease severity index. Statistical analyses were performed, considering a p value of < 0.05 as statistically significant. 38% had SSc with limited skin involvement, while 62% had SSc with extensive skin involvement. However, there were no statistically significant differences observed in the levels of CD4+ CXCR5+ , CD4+ ICOS+ , CD4+ CD40L+ and CD4+ PD+ lymphocytes between the two groups. Notably, SSc patients with Raynaud's phenomenon, digital ulcer and lung involvement exhibited higher levels of CD4+ CXCR5+ lymphocytes compared to those without these manifestations. Furthermore, a significant positive correlation was observed between CD4+ CXCR5+ lymphocyte levels and the severity of lung disease according to the Medsger disease severity index. Based on these findings, we conclude that elevated levels of Tfh cells are associated with lung involvement in SSc and there is a significant correlation between Tfh cell levels and the severity of lung disease. These observations suggest a potential role for Tfh cells in the pathogenesis of lung involvement in SSc and may guide the development of targeted therapies for this aspect of the disease.
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Affiliation(s)
- Melek Sahinoglu
- Department of Internal Medicine, Aydin Adnan Menderes University, Aydin, Turkey
| | - Gokhan Sargin
- Department of Rheumatology, Aydin Adnan Menderes University, Aydin, Turkey.
| | - Irfan Yavasoglu
- Department of Hematology, Aydin Adnan Menderes University, Aydin, Turkey
| | - Taskin Senturk
- Department of Rheumatology, Aydin Adnan Menderes University, Aydin, Turkey
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12
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Thomas AL, Godarova A, Wayman JA, Miraldi ER, Hildeman DA, Chougnet CA. Accumulation of immune-suppressive CD4 + T cells in aging - tempering inflammaging at the expense of immunity. Semin Immunol 2023; 70:101836. [PMID: 37632992 PMCID: PMC10840872 DOI: 10.1016/j.smim.2023.101836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 08/21/2023] [Accepted: 08/21/2023] [Indexed: 08/28/2023]
Abstract
The 'immune risk profile' has been shown to predict mortality in the elderly, highlighting the need to better understand age-related immune dysfunction. While aging leads to many defects affecting all arms of the immune system, this review is focused on the accrual of immuno-suppressive CD4 + T cell populations, including FoxP3 + regulatory T cells, and subsets of IL-10-producing T follicular helper cells. New data suggest that such accumulations constitute feedback mechanisms to temper the ongoing progressive low-grade inflammation that develops with age, the so-called "inflammaging", and by doing so, how they have the potential to promote healthier aging. However, they also impair effector immune responses, notably to infections, or vaccines. These studies also reinforce the idea that the aged immune system should not be considered as a poorly functional version of the young one, but more as a dynamic system in which CD4 + T cells, and other immune/non-immune subsets, differentiate, interact with their milieu and function differently than in young hosts. A better understanding of these unique interactions is thus needed to improve effector immune responses in the elderly, while keeping inflammaging under control.
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Affiliation(s)
- Alyssa L Thomas
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45257, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Alzbeta Godarova
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45257, USA
| | - Joseph A Wayman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45257, USA
| | - Emily R Miraldi
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45257, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - David A Hildeman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45257, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Claire A Chougnet
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45257, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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13
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Thomas AL, Wayman JA, Almanan M, Bejjani AT, Miraldi ER, Chougnet CA, Hildeman DA. Elevated CD153 Expression on Aged T Follicular Helper Cells is Vital for B cell Responses. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.17.533214. [PMID: 36993647 PMCID: PMC10055293 DOI: 10.1101/2023.03.17.533214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Our recent data showed that an aberrant IL-10-producing T follicular helper population (Tfh10) accumulates dramatically with age and is associated with age-related declines in vaccine responsiveness. Through single cell gene expression and chromatin accessibility analysis of IL-10+ and IL-10- memory CD4+ T cells from young and aged mice, we identified increased expression of CD153 on aged Tfh and Tfh10 cells. Mechanistically, we linked inflammaging (increased IL-6 levels) to elevated CD153 expression of Tfh cells through c-Maf. Surprisingly, blockade of CD153 in aged mice significantly reduced their vaccine-driven antibody response, which was associated with decreased expression of ICOS on antigen-specific Tfh cells. Combined, these data show that an IL-6/c-Maf/CD153 circuit is critical for maintaining ICOS expression. Thus, although overall Tfh-mediated B cell responses are reduced in the context of vaccines and aging, our data suggest that elevated expression of CD153 on Tfh cells potentiates the remaining Tfh function in aged mice.
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Affiliation(s)
- Alyssa L Thomas
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology of Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Joseph A Wayman
- Division of Immunobiology of Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Maha Almanan
- Division of Immunobiology of Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Anthony T Bejjani
- Division of Immunobiology of Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Emily R Miraldi
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology of Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Claire A Chougnet
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology of Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - David A Hildeman
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology of Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
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14
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Wang L, Wu P, Shen Z, Yu Q, Zhang Y, Ye F, Chen K, Zhao J. An immune checkpoint-based signature predicts prognosis and chemotherapy response for patients with small cell lung cancer. Int Immunopharmacol 2023; 117:109827. [PMID: 36989973 DOI: 10.1016/j.intimp.2023.109827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 01/06/2023] [Accepted: 01/29/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Therapeutic options for small cell lung cancer (SCLC), a particularly lethal malignancy, remain limited. Members of the B7-CD28 family are compelling targets for immune checkpoint blockade strategies, which involve activating, inhibiting, and fine-tuning the T cell immune response. However, their clinical features and significance have not been explored comprehensively. METHOD We enrolled 228 patients with an initial diagnosis of SCLC, including 77 cases from Cbioportal and a validation cohort of 151 cases with qPCR data. Kaplan-Meier analysis and LASSO Cox model were used to identify a signature based on the B7-CD28 family, which was applied for accurate prediction of chemotherapy benefit and prognosis for SCLC patients. In addition, we applied bioinformatics analysis to explore potential signature-related molecular mechanisms and the immune landscape. RESULTS The mutation profiles of healthy tissues and SCLC tissues were distinct. A signature consisting of seven genes (CD86, ICOSLG, CD276, CD28, CTLA-4, PDCD1, and TMIGD2) was identified and applied to group patients based on risk level (high-risk and low-risk), producing two groups for which survival outcomes differed significantly (HR = 3.81, 95% CI: 2.16-6.74, P < 0.001). The immune checkpoint-based signature accurately predicted patient outcomes for the selected training and validation sets. Notably, low-risk patients were more likely to benefit from chemotherapy and showed greater immune activation. Additionally, time-dependent ROC curves and C-index analysis confirmed that the immune checkpoint-based signature has excellent predictive power for prognosis and chemotherapy benefit compared to clinically recognized parameters. Finally, multivariate analysis confirmed the identified signature as an independent risk factor for prognosis and chemotherapeutic response. CONCLUSION We systematically obtained a comprehensive molecular profile for B7-CD28 family members in SCLC patients, from which we produced a reliable and robust prognostic immune checkpoint-based signature with the potential to improve prognostic stratification and therapy strategies for SCLC patients.
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15
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Panneton V, Mindt BC, Bouklouch Y, Bouchard A, Mohammaei S, Chang J, Diamantopoulos N, Witalis M, Li J, Stancescu A, Bradley JE, Randall TD, Fritz JH, Suh WK. ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells. Life Sci Alliance 2023; 6:e202201615. [PMID: 36754569 PMCID: PMC9909462 DOI: 10.26508/lsa.202201615] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 01/24/2023] [Accepted: 01/25/2023] [Indexed: 02/10/2023] Open
Abstract
ICOS is a T-cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre-mediated ICOS knockout (ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3+ cells at an early stage of the GC reaction suggests that ICOS normally inhibits Klf2 expression to promote follicular features including Bcl6 up-regulation. Furthermore, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B-cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions.
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Affiliation(s)
- Vincent Panneton
- Institut de Recherches Cliniques de Montréal, Quebec, Canada
- Department of Microbiology, Infectiology and Immunology, University of Montreal, Quebec, Canada
| | - Barbara C Mindt
- Department of Microbiology and Immunology, McGill University, Quebec, Canada
- McGill University Research Centre on Complex Traits, McGill University, Quebec, Canada
| | | | - Antoine Bouchard
- Institut de Recherches Cliniques de Montréal, Quebec, Canada
- Molecular Biology Program, University of Montreal, Quebec, Canada
| | - Saba Mohammaei
- Institut de Recherches Cliniques de Montréal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Quebec, Canada
| | - Jinsam Chang
- Institut de Recherches Cliniques de Montréal, Quebec, Canada
- Molecular Biology Program, University of Montreal, Quebec, Canada
| | - Nikoletta Diamantopoulos
- Institut de Recherches Cliniques de Montréal, Quebec, Canada
- Department of Microbiology and Immunology, McGill University, Quebec, Canada
| | - Mariko Witalis
- Institut de Recherches Cliniques de Montréal, Quebec, Canada
- Molecular Biology Program, University of Montreal, Quebec, Canada
| | - Joanna Li
- Institut de Recherches Cliniques de Montréal, Quebec, Canada
- Department of Microbiology and Immunology, McGill University, Quebec, Canada
| | | | - John E Bradley
- Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Troy D Randall
- Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jörg H Fritz
- Department of Microbiology and Immunology, McGill University, Quebec, Canada
- McGill University Research Centre on Complex Traits, McGill University, Quebec, Canada
| | - Woong-Kyung Suh
- Institut de Recherches Cliniques de Montréal, Quebec, Canada
- Department of Microbiology, Infectiology and Immunology, University of Montreal, Quebec, Canada
- Department of Microbiology and Immunology, McGill University, Quebec, Canada
- Molecular Biology Program, University of Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Quebec, Canada
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16
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Zhang Y, Wang XL, Liu JJ, Qian ZY, Pan ZY, Song NP, Chen HY, Zhang W, Zhang X. ICOS/ICOSLG and PD-1 Co-Expression is Associated with the Progression of Colorectal Precancerous- Carcinoma Immune Microenvironment. J Inflamm Res 2023; 16:977-992. [PMID: 36915615 PMCID: PMC10008008 DOI: 10.2147/jir.s401123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 02/25/2023] [Indexed: 03/09/2023] Open
Abstract
Purpose This study aimed to investigate the expression of inducible T-cell co-stimulator (ICOS) and its ligand (ICOSLG), along with their association with clinicopathological features and influence on the immune profile in colorectal cancer (CRC). Patients and Methods The Cancer Genome Atlas Colorectal Adenocarcinoma cohorts were used. We also analyzed 131 clinical samples of colon lesions, including precancerous lesions (hyperplastic polyps, low-grade dysplasia, and high-grade dysplasia) and CRC tissues. We conducted immunohistochemical (IHC) assays and multiple IHC (mIHC) of CD4+, Foxp3+ tumor-infiltrating lymphocytes (TILs), and PD-1/PD-L1 immune checkpoints in precancerous lesions and CRC samples from our patient subsets to determine changes and correlations in ICOS and ICOSLG expression during progression through the adenoma-carcinoma pathway. Results High expression of ICOS and ICOSLG was a significant factor in CRC in multiple analyses and was positively correlated with CD4+/Foxp3+ TIL density and PD-1/PD-L1 expression, which increased with the sequential progression of lesions from precancerous tissues to carcinoma. Multivariable logistic regression analysis suggested that the location and expression level of ICOS/ICOSLG may be involved in precancerous-carcinoma progression. The co-expression status of PD-1 and ICOS/ ICOSLG could stratify patients with colorectal lesions into three groups of low, moderate, and high risk of progression. According to this classification and mIHC assays, we found a strong correlation between increased PD-1+ICOS+ or PD-1+ICOSLG+ co-expression and CRC, which might be deemed an independent factor in carcinogenesis. Conclusion Increased ICOS/ICOSLG expression may be associated with the progressive formation of Foxp3+ TILs in the immune microenvironment and may further promote the development of the abnormal cytology of colorectal lesions from precancerous neoplasia to CRC. Our findings support the interpretation that enhanced co-expression of PD-1+ICOS+ or PD-1+ICOSLG+ contributes to the immune-active microenvironment of the colorectal adenoma-carcinoma sequence.
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Affiliation(s)
- Yu Zhang
- Cancer Center, Department of Gastroenterology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People's Republic of China
| | - Xue-Li Wang
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, Zhejiang, People's Republic of China
| | - Jing-Jing Liu
- Bengbu Medical College, Bengbu, Anhui, People's Republic of China
| | - Zhen-Yuan Qian
- General Surgery, Cancer Center, Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People's Republic of China
| | - Zheng-Yang Pan
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Ni-Ping Song
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Hui-Yan Chen
- Clinical Laboratory, Tongxiang First People's Hospital, Tongxiang, Zhejiang, People's Republic of China
| | - Wei Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Xin Zhang
- Cancer Center, Department of Pathology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People's Republic of China
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17
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Kanannejad Z, Soleimanian S, Ghahramani Z, Sepahi N, Mohkam M, Alyasin S, Kheshtchin N. Immune checkpoint molecules in prevention and development of asthma. Front Immunol 2023; 14:1070779. [PMID: 36865540 PMCID: PMC9972681 DOI: 10.3389/fimmu.2023.1070779] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
Allergic asthma is a respiratory disease initiated by type-2 immune responses characterized by secretion of alarmins, interleukin-4 (IL-4), IL-5, and IL-13, eosinophilic inflammation, and airway hyperresponsiveness (AHR). Immune checkpoints (ICPs) are inhibitory or stimulatory molecules expressed on different immune cells, tumor cells, or other cell types that regulate immune system activation and maintain immune homeostasis. Compelling evidence indicates a key role for ICPs in both the progression and prevention of asthma. There is also evidence of asthma development or exacerbation in some cancer patients receiving ICP therapy. The aim of this review is to provide an updated overview of ICPs and their roles in asthma pathogenesis, and to assess their implications as therapeutic targets in asthma.
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Affiliation(s)
- Zahra Kanannejad
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeede Soleimanian
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Ghahramani
- Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Najmeh Sepahi
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Milad Mohkam
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheila Alyasin
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nasim Kheshtchin
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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18
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Wu H, Chen L, Zhou X, Wu Y, Yan Y, Zhu Y, Zhao C, Xue Q. Effect of tacrolimus on soluble costimulatory molecules in patients with refractory myasthenia gravis. J Neuroimmunol 2022; 372:577955. [PMID: 36054935 DOI: 10.1016/j.jneuroim.2022.577955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 08/07/2022] [Accepted: 08/21/2022] [Indexed: 12/31/2022]
Abstract
OBJECTIVES To investigate the expression and possible role of soluble costimulatory molecules in the treatment of refractory myasthenia gravis. METHODS Thirty-two patients with refractory myasthenia gravis were enrolled into this study and given tacrolimus 3 mg/day. At the beginning of treatment and 12 months follow-up period, clinical data were collected and recorded. The clinical classification of myasthenia gravis Foundation (MGFA) was performed. The MGFA-quantitative myasthenia gravis score (MGFA-QMGS), manual muscle test (MMT), MG activity of daily living (MG-ADL) and the activity of daily living (MG-ADL), the 15-item myasthenia gravis quality of life (MG QOL-15) and the dose change of prednisone were used to evaluate the efficacy. The expression levels of soluble costimulatory molecules and their ligands (sPD-1/sPD-L1, sICOS/sICOSL, sCD40/sCD40L), soluble CD25 and IL-2 in serum were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS We observed that oral administration of 3 mg tacrolimus daily for 1 year can significantly improve the clinical symptoms of patients with refractory myasthenia gravis, which is characterized by a significant reduction in clinical scores, such as QMG, MMT, ADL, MGQOL-15, and a reduction daily oral prednisolone (PSL) dose (P < 0.0001).We also found that the levels of plasma sPD-1, sCD40, IL-2 in refractory MG patients increased significantly, and those decreased significantly 12 months after tacrolimus treatment (P < 0.05). The level of sCD25 was negatively correlated with clinical severity scores (P < 0.05). After tacrolimus treatment, the level of sPD-L1 increased although there was no significant difference. CONCLUSION Tacrolimus could relieve the symptoms of refractory MG and significantly decrease the levels of plasma sPD-1, sICOSL, sCD40, sCD25 and IL-2. Soluble costimulatory molecules might be potential biomarkers for MG and tacrolimus treatment.
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Affiliation(s)
- Hui Wu
- Department of Neurology, Jing'an District Centre Hospital of Shanghai, Shanghai, China
| | - Lan Chen
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Department of Neurology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Xiaoling Zhou
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yanshi Wu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yu Yan
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yibei Zhu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Chongbo Zhao
- Huashan Rare Disease Center, Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Qun Xue
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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19
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Preddy I, Nandoliya K, Miska J, Ahmed AU. Checkpoint: Inspecting the barriers in glioblastoma immunotherapies. Semin Cancer Biol 2022; 86:473-481. [PMID: 35150865 PMCID: PMC9363531 DOI: 10.1016/j.semcancer.2022.02.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 02/05/2022] [Indexed: 01/27/2023]
Abstract
Despite an aggressive standard of care involving radiation therapy, temozolomide-based chemotherapy, and surgical resection, glioblastoma multiforme (GBM) continues to exhibit very high recurrence and mortality rates partly due to the highly plastic and heterogenous nature of the tumor. In recent years, activation of the immune system has emerged as a promising strategy in cancer therapies. However, despite recent successes in other fields, immunotherapeutic approaches continue to encounter challenges in GBM. In this review, we first discuss immunotherapies targeting the most well-studied immune checkpoint proteins, CTLA-4 and PD-1, followed by discussions on therapies targeting immune-stimulatory molecules and secreted metabolic enzymes. Finally, we address the major challenges with immunotherapy in GBM and the potential for combination and neoadjuvant immunotherapies to tip the scales in the fight against glioblastoma.
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Affiliation(s)
- Isabelle Preddy
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, United States
| | - Khizar Nandoliya
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, United States
| | - Jason Miska
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, United States; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, United States
| | - Atique U Ahmed
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, United States; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, United States.
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20
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Rapamycin-encapsulated costimulatory ICOS/CD40L-bispecific nanoparticles restrict pathogenic helper T-B-cell interactions while in situ suppressing mTOR for lupus treatment. Biomaterials 2022; 289:121766. [DOI: 10.1016/j.biomaterials.2022.121766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 08/16/2022] [Accepted: 08/25/2022] [Indexed: 11/23/2022]
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21
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Chang J, Bouchard A, Bouklouch Y, Panneton V, Li J, Diamantopoulos N, Mohammaei S, Istomine R, Alvarez F, Piccirillo CA, Suh WK. ICOS-Deficient Regulatory T Cells Can Prevent Spontaneous Autoimmunity but Are Impaired in Controlling Acute Inflammation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:301-309. [PMID: 35760518 DOI: 10.4049/jimmunol.2100897] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 05/02/2022] [Indexed: 12/12/2022]
Abstract
ICOS is induced in activated T cells and its main role is to boost differentiation and function of effector T cells. ICOS is also constitutively expressed in a subpopulation of Foxp3+ regulatory T cells under steady-state condition. Studies using ICOS germline knockout mice or ICOS-blocking reagents suggested that ICOS has supportive roles in regulatory T (Treg) cell homeostasis, migration, and function. To avoid any compounding effects that may arise from ICOS-deficient non-Treg cells, we generated a conditional knockout system in which ICOS expression is selectively abrogated in Foxp3-expressing cells (ICOS FC mice). Compared to Foxp3-Cre control mice, ICOS FC mice showed a minor numerical deficit of steady-state Treg cells but did not show any signs of spontaneous autoimmunity, indicating that tissue-protective Treg populations do not heavily rely on ICOS costimulation. However, ICOS FC mice showed more severe inflammation in oxazolone-induced contact hypersensitivity, a model of atopic dermatitis. This correlated with elevated numbers of inflammatory T cells expressing IFN-γ and/or TNF-α in ICOS FC mice compared with the control group. In contrast, elimination of ICOS in all T cell compartments negated the differences, confirming that ICOS has a dual positive role in effector and Treg cells. Single-cell transcriptome analysis suggested that ICOS-deficient Treg cells fail to mature into T-bet+CXCR3+ "Th1-Treg" cells in the draining lymph node. Our results suggest that regimens that preferentially stimulate ICOS pathways in Treg cells might be beneficial for the treatment of Th1-driven inflammation.
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Affiliation(s)
- Jinsam Chang
- Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada.,Molecular Biology Program, University of Montreal, Montreal, Quebec, Canada
| | - Antoine Bouchard
- Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada.,Molecular Biology Program, University of Montreal, Montreal, Quebec, Canada
| | - Yasser Bouklouch
- Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada
| | - Vincent Panneton
- Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada.,Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, Quebec, Canada
| | - Joanna Li
- Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada; and
| | - Nikoletta Diamantopoulos
- Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada; and
| | - Saba Mohammaei
- Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada.,Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Roman Istomine
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada; and
| | - Fernando Alvarez
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada; and
| | - Ciriaco A Piccirillo
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada; and
| | - Woong-Kyung Suh
- Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada; .,Molecular Biology Program, University of Montreal, Montreal, Quebec, Canada.,Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, Quebec, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada; and.,Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
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22
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Hodgson R, Christiansen D, Ierino F, Sandrin M. Inducible Co-Stimulator (ICOS) in transplantation: A review. Transplant Rev (Orlando) 2022; 36:100713. [PMID: 35878486 DOI: 10.1016/j.trre.2022.100713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/26/2022] [Accepted: 07/06/2022] [Indexed: 11/17/2022]
Abstract
Prevention of T cell activation is one of the goals of successful organ and tissue transplantation. Blockade of T cell co-stimulation, particularly of the CD28:B7 interaction, has been shown to prolong graft survival. Inducible Co-Stimulator (ICOS) is the third member of the B7 family and here we review the literature on ICOS, its receptor (B7RP-1), and blockade of this pathway in transplant models. ICOS:B7RP-1 are a single receptor:ligand pair with a loss of function of either being implicated in some autoimmune diseases. ICOS has multiple functions, related to its constitutive expression on B cells and activated T cells. In in vitro transplant models, ICOS:B7RP-1 blockade has produced mixed results as to its ability to modulate lymphocyte proliferation. Several in vivo transplant models demonstrate varying degrees of success in prolonging graft survival. Timing and dose of treatment appear important, and combination with other immunosuppressive treatments may also be of benefit. As ICOS has multiple functions, it may be that the observed variable results are due to inadvertent inactivation of graft protective functions. If these barriers can be overcome, ICOS:B7RP-1 blockade could provide an important target for future immunosuppression regimens.
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Affiliation(s)
- Russell Hodgson
- Department of Surgery, University of Melbourne, Heidelberg, Australia; Division of Surgery, Northern Health, Epping, Australia.
| | - Dale Christiansen
- Department of Surgery, University of Melbourne, Heidelberg, Australia
| | - Francesco Ierino
- Department of Surgery, University of Melbourne, Heidelberg, Australia; Department of Nephrology, St Vincent's Hospital, Fitzroy, Australia
| | - Mauro Sandrin
- Department of Surgery, University of Melbourne, Heidelberg, Australia
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23
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Ansari A, Sachan S, Jit BP, Sharma A, Coshic P, Sette A, Weiskopf D, Gupta N. An efficient immunoassay for the B cell help function of SARS-CoV-2-specific memory CD4 + T cells. CELL REPORTS METHODS 2022; 2:100224. [PMID: 35571764 PMCID: PMC9085463 DOI: 10.1016/j.crmeth.2022.100224] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/27/2021] [Accepted: 04/28/2022] [Indexed: 04/30/2023]
Abstract
The B cell "help" function of CD4+ T cells is an important mechanism of adaptive immunity. Here, we describe improved antigen-specific T-B cocultures for quantitative measurement of T cell-dependent B cell responses, with as few as ∼90 T cells. Utilizing M. tuberculosis (Mtb), we show that early priming and activation of CD4+ T cells is important for productive interaction between T and B cells and that similar effects are achieved by supplementing cocultures with monocytes. We find that monocytes promote survivability of B cells via BAFF and stem cell growth factor (SCGF)/C-type lectin domain family 11 member A (CLEC11A), but this alone does not fully recapitulate the effects of monocyte supplementation. Importantly, we demonstrate improved activation and immunological output of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific memory CD4+ T-B cell cocultures with the inclusion of monocytes. This method may therefore provide a more sensitive assay to evaluate the B cell help quality of memory CD4+ T cells, for example, after vaccination or natural infection.
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Affiliation(s)
- Asgar Ansari
- Vaccine Immunology Laboratory, National Institute of Immunology, New Delhi 110067, India
| | - Shilpa Sachan
- Vaccine Immunology Laboratory, National Institute of Immunology, New Delhi 110067, India
| | - Bimal Prasad Jit
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Ashok Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Poonam Coshic
- Department of Transfusion Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Alessandro Sette
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA 92037, USA
| | - Daniela Weiskopf
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Nimesh Gupta
- Vaccine Immunology Laboratory, National Institute of Immunology, New Delhi 110067, India
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24
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Labib D, Wang Z, Prakash P, Zimmer M, Smith MD, Frazel PW, Barbar L, Sapar ML, Calabresi PA, Peng J, Liddelow SA, Fossati V. Proteomic Alterations and Novel Markers of Neurotoxic Reactive Astrocytes in Human Induced Pluripotent Stem Cell Models. Front Mol Neurosci 2022; 15:870085. [PMID: 35592112 PMCID: PMC9113221 DOI: 10.3389/fnmol.2022.870085] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 03/29/2022] [Indexed: 12/20/2022] Open
Abstract
Astrocytes respond to injury, infection, and inflammation in the central nervous system by acquiring reactive states in which they may become dysfunctional and contribute to disease pathology. A sub-state of reactive astrocytes induced by proinflammatory factors TNF, IL-1α, and C1q ("TIC") has been implicated in many neurodegenerative diseases as a source of neurotoxicity. Here, we used an established human induced pluripotent stem cell (hiPSC) model to investigate the surface marker profile and proteome of TIC-induced reactive astrocytes. We propose VCAM1, BST2, ICOSL, HLA-E, PD-L1, and PDPN as putative, novel markers of this reactive sub-state. We found that several of these markers colocalize with GFAP+ cells in post-mortem samples from people with Alzheimer's disease. Moreover, our whole-cells proteomic analysis of TIC-induced reactive astrocytes identified proteins and related pathways primarily linked to potential engagement with peripheral immune cells. Taken together, our findings will serve as new tools to purify reactive astrocyte subtypes and to further explore their involvement in immune responses associated with injury and disease.
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Affiliation(s)
- David Labib
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
| | - Zhen Wang
- Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - Priya Prakash
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, United States
| | - Matthew Zimmer
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
| | - Matthew D. Smith
- Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
| | - Paul W. Frazel
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, United States
| | - Lilianne Barbar
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
| | - Maria L. Sapar
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
| | - Peter A. Calabresi
- Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, United States
| | - Junmin Peng
- Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United States
- Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - Shane A. Liddelow
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, United States
- Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY, United States
- Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, United States
- Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, United States
| | - Valentina Fossati
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
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25
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Ray MK, Fenton CG, Paulssen RH. Novel long non-coding RNAs of relevance for ulcerative colitis pathogenesis. Noncoding RNA Res 2022; 7:40-47. [PMID: 35224318 PMCID: PMC8844606 DOI: 10.1016/j.ncrna.2022.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/01/2022] [Accepted: 02/01/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND AIMS The study aimed to identify yet unknown and uncharacterized long non-coding RNAs (lncRNAs) in treatment-naïve ulcerative colitis (UC), and to define their possible roles in UC pathogenesis. For that purpose, accurate quantification methods for lncRNA transcript detection, multiple and "stringent" strategies were applied. New insights in the regulation of functional genes and pathways of relevance for UC through expression of lncRNAs are expected. METHODS The study was based on sequencing data derived from a data set consisting of treatment-naïve UC patients (n = 14) and control subjects (n = 16). Two complementary aligners were used to identify lncRNAs. Several different steps were used to validate differential expression including plotting the reads over the annotation for manual inspection. To help determine potential lncRNA involvement in biological processes, KEGG pathway enrichment was done on protein-coding genes which co-expressed with the lncRNAs. RESULTS A total of 99 lncRNAs were identified in UC. The lncRNAs which were not previously characterized (n = 15) in UC or other autoimmune diseases were selected for down-stream analysis. In total, 602 protein-coding genes correlated with the uncharacterized lncRNAs. KEGG pathway enrichment analysis revealed involvement of lncRNAs in two significantly enriched pathways, lipid and atherosclerosis, and T-cell receptor signaling. CONCLUSION This study identified a set of 15 yet uncharacterized lncRNAs which may be of importance for UC pathogenesis. These lncRNAs may serve as potential diagnostic biomarkers and might be of use for the development of UC treatment strategies in the future.
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Affiliation(s)
- Mithlesh Kumar Ray
- Clinical Bioinformatics Research Group, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Christopher G. Fenton
- Genomic Support Centre Tromsø (GSCT), Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Ruth H. Paulssen
- Clinical Bioinformatics Research Group, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
- Genomic Support Centre Tromsø (GSCT), Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
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26
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Jensen O, Trivedi S, Meier JD, Fairfax KC, Hale JS, Leung DT. A subset of follicular helper-like MAIT cells can provide B cell help and support antibody production in the mucosa. Sci Immunol 2022; 7:eabe8931. [PMID: 35030034 DOI: 10.1126/sciimmunol.abe8931] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Owen Jensen
- Division of Infectious Diseases, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.,Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT ,USA
| | - Shubhanshi Trivedi
- Division of Infectious Diseases, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Jeremy D Meier
- Division of Otolaryngology-Head and Neck Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.,Primary Children's Hospital, Salt Lake City, UT, USA
| | - Keke C Fairfax
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT ,USA
| | - J Scott Hale
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT ,USA
| | - Daniel T Leung
- Division of Infectious Diseases, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.,Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT ,USA
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27
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The Implementation of TNFRSF Co-Stimulatory Domains in CAR-T Cells for Optimal Functional Activity. Cancers (Basel) 2022; 14:cancers14020299. [PMID: 35053463 PMCID: PMC8773791 DOI: 10.3390/cancers14020299] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 01/31/2023] Open
Abstract
The Tumor Necrosis Factor Receptor Superfamily (TNFRSF) is a large and important immunoregulatory family that provides crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFRSF member has a distinct expression profile and a unique functional impact on various types of cells and at different stages of the immune response. Correspondingly, exploiting TNFRSF-mediated signaling for cancer immunotherapy has been a major field of interest, with various therapeutic TNFRSF-exploiting anti-cancer approaches such as 4-1BB and CD27 agonistic antibodies being evaluated (pre)clinically. A further application of TNFRSF signaling is the incorporation of the intracellular co-stimulatory domain of a TNFRSF into so-called Chimeric Antigen Receptor (CAR) constructs for CAR-T cell therapy, the most prominent example of which is the 4-1BB co-stimulatory domain included in the clinically approved product Kymriah. In fact, CAR-T cell function can be clearly influenced by the unique co-stimulatory features of members of the TNFRSF. Here, we review a select group of TNFRSF members (4-1BB, OX40, CD27, CD40, HVEM, and GITR) that have gained prominence as co-stimulatory domains in CAR-T cell therapy and illustrate the unique features that each confers to CAR-T cells.
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28
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Dong M, Chang J, Lebel MÈ, Gervais N, Fournier M, Mallet Gauthier È, Suh WK, Melichar HJ. The ICOS-ICOSL pathway tunes thymic selection. Immunol Cell Biol 2021; 100:205-217. [PMID: 34962663 PMCID: PMC9304562 DOI: 10.1111/imcb.12520] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 12/11/2021] [Accepted: 12/27/2021] [Indexed: 11/30/2022]
Abstract
Negative selection of developing T cells plays a significant role in T cell tolerance to self-antigen. This process relies on thymic antigen presenting cells which express both self-antigens as well as co-signaling molecules. Inducible T cell costimulator (ICOS) belongs to the CD28 family of co-signaling molecules and binds to ICOS ligand (ICOSL). The ICOS signaling pathway plays important roles in shaping the immune response to infections, but its role in central tolerance is less well understood. Here we show that ICOSL is expressed by subsets of thymic dendritic cells and medullary thymic epithelial cells as well as thymic B cells. ICOS expression is upregulated as T cells mature in the thymus and correlates with T cell receptor signal strength during thymic selection. We also provide evidence of a role for ICOS signaling in mediating negative selection. Our findings suggest that ICOS may fine-tune T cell receptor signals during thymic selection contributing to the generation of a tolerant T cell population.
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Affiliation(s)
- Mengqi Dong
- Département de microbiologie, Université de Montréal, infectiologie et immunologie, Montréal, Québec, H3T 1J4, Canada.,Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, H1T 2M4, Canada
| | - Jinsam Chang
- Institut de recherches cliniques de Montréal, Montréal, Québec, H2W 1R7, Canada.,Programme de biologie moléculaire, Université de Montréal, Montréal, Québec, H3T 1J4, Canada
| | - Marie-Ève Lebel
- Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, H1T 2M4, Canada
| | - Noémie Gervais
- Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, H1T 2M4, Canada
| | - Marilaine Fournier
- Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, H1T 2M4, Canada
| | - Ève Mallet Gauthier
- Département de microbiologie, Université de Montréal, infectiologie et immunologie, Montréal, Québec, H3T 1J4, Canada.,Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, H1T 2M4, Canada
| | - Woong-Kyung Suh
- Département de microbiologie, Université de Montréal, infectiologie et immunologie, Montréal, Québec, H3T 1J4, Canada.,Institut de recherches cliniques de Montréal, Montréal, Québec, H2W 1R7, Canada.,Programme de biologie moléculaire, Université de Montréal, Montréal, Québec, H3T 1J4, Canada
| | - Heather J Melichar
- Immunology-Oncology Unit, Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, H1T 2M4, Canada.,Département de médecine, Université de Montréal, Montréal, Québec, H3T 1J4, Canada
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29
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Boggio E, Gigliotti CL, Moia R, Scotta A, Crespi I, Boggione P, De Paoli L, Deambrogi C, Garzaro M, Vidali M, Chiocchetti A, Stoppa I, Rolla R, Dianzani C, Monge C, Clemente N, Gaidano G, Dianzani U. Inducible T-cell co-stimulator (ICOS) and ICOS ligand are novel players in the multiple-myeloma microenvironment. Br J Haematol 2021; 196:1369-1380. [PMID: 34954822 DOI: 10.1111/bjh.17968] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/03/2021] [Accepted: 11/09/2021] [Indexed: 12/19/2022]
Abstract
The inducible T-cell co-stimulator (ICOS) is a T-cell receptor that, once bound to ICOS ligand (ICOSL) expressed on several cell types including the B-cell lineage, plays a decisive role in adaptive immunity by regulating the interplay between B and T cells. In addition to its immunomodulatory functions, we have shown that ICOS/ICOSL signalling can inhibit the activity of osteoclasts, unveiling a novel mechanism of lymphocyte-bone cells interactions. ICOS and ICOSL can also be found as soluble forms, namely sICOS and sICOSL. Here we show that: (i) levels of sICOS and sICOSL are increased in multiple myeloma (MM) compared to monoclonal gammopathy of undetermined significance and smouldering MM; (ii) levels of sICOS and sICOSL variably correlate with several markers of tumour burden; and (iii) sICOS levels tend to be higher in Durie-Salmon stage II/III versus stage I MM and correlate with overall survival as an independent variable. Moreover, surface ICOS and ICOSL are expressed in both myeloma cells and normal plasma cells, where they probably regulate different functional stages. Finally, ICOSL triggering inhibits the migration of myeloma cell lines in vitro and the growth of ICOSL+ MOPC-21 myeloma cells in vivo. These results suggest that ICOS and ICOSL represent novel markers and therapeutic targets for MM.
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Affiliation(s)
- Elena Boggio
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Casimiro Luca Gigliotti
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Riccardo Moia
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | | | - Ilaria Crespi
- Maggiore della Carità University Hospital, Novara, Italy
| | - Paola Boggione
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Lorenzo De Paoli
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Clara Deambrogi
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Massimiliano Garzaro
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Matteo Vidali
- Maggiore della Carità University Hospital, Novara, Italy
| | - Annalisa Chiocchetti
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Ian Stoppa
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Roberta Rolla
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Chiara Dianzani
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Turin, Italy
| | - Chiara Monge
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Turin, Italy
| | - Nausicaa Clemente
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy
| | - Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
| | - Umberto Dianzani
- Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Università del Piemonte Orientale, Novara, Italy.,Maggiore della Carità University Hospital, Novara, Italy
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30
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Liu J, Xu K, Xing M, Zhuo Y, Guo J, Du M, Wang Q, An Y, Li J, Gao P, Wang Y, He F, Guo Y, Li M, Zhang Y, Zhang L, Gao GF, Dai L, Zhou D. Heterologous prime-boost immunizations with chimpanzee adenoviral vectors elicit potent and protective immunity against SARS-CoV-2 infection. Cell Discov 2021; 7:123. [PMID: 34923570 PMCID: PMC8684349 DOI: 10.1038/s41421-021-00360-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 12/04/2021] [Indexed: 02/04/2023] Open
Abstract
A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is urgently needed to tackle the COVID-19 global pandemic. Here, we describe the development of chimpanzee adenovirus serotypes 6 and 68 (AdC6 and AdC68) vector-based vaccine candidates expressing the full-length transmembrane spike glycoprotein. We assessed the vaccine immunogenicity, protective efficacy, and immune cell profiles using single-cell RNA sequencing in mice. Mice were vaccinated via the intramuscular route with the two vaccine candidates using prime-only regimens or heterologous prime-boost regimens. Both chimpanzee adenovirus-based vaccines elicited strong and long-term antibody and T cell responses, balanced Th1/Th2 cell responses, robust germinal center responses, and provided effective protection against SARS-CoV-2 infection in mouse lungs. Strikingly, we found that heterologous prime-boost immunization induced higher titers of protective antibodies, and more spike-specific memory CD8+ T cells in mice. Potent neutralizing antibodies produced against the highly transmissible SARS-CoV-2 variants B.1.1.7 lineage (also known as N501Y.V1) and B.1.351 lineage (also known as N501Y.V2) were detectable in mouse sera over 6 months after prime immunization. Our results demonstrate that the heterologous prime-boost strategy with chimpanzee adenovirus-based vaccines is promising for further development to prevent SARS-CoV-2 infection.
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Affiliation(s)
- Jiaojiao Liu
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Kun Xu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Tropical Medicine and Laboratory Medicine, The First Affiliated Hospital, Hainan Medical University, Hainan, China
- Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
| | - Man Xing
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yue Zhuo
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Jingao Guo
- University of Chinese Academy of Sciences, Beijing, China
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Meng Du
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Qi Wang
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yaling An
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Jinhe Li
- Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ping Gao
- Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yihan Wang
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Furong He
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yingying Guo
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Mingxi Li
- Comprehensive AIDS Research Center, Beijing Advanced Innovation Center for Structural Biology, School of Medicine and Vanke School of Public Health, Tsinghua University, Beijing, China
| | - Yuchao Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
- School of Life Science, Fudan University, Shanghai, China
| | - Linqi Zhang
- Comprehensive AIDS Research Center, Beijing Advanced Innovation Center for Structural Biology, School of Medicine and Vanke School of Public Health, Tsinghua University, Beijing, China
| | - George F Gao
- Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
- Chinese Center for Disease Control and Prevention (China CDC), Beijing, China.
| | - Lianpan Dai
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Tropical Medicine and Laboratory Medicine, The First Affiliated Hospital, Hainan Medical University, Hainan, China.
- University of Chinese Academy of Sciences, Beijing, China.
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
| | - Dongming Zhou
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
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31
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Zhang X, Hu X, Tian T, Pang W. The role of ICOS in allergic disease: Positive or Negative? Int Immunopharmacol 2021; 103:108394. [PMID: 34922247 DOI: 10.1016/j.intimp.2021.108394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/15/2021] [Accepted: 11/19/2021] [Indexed: 01/09/2023]
Abstract
With the rapid increase in the incidence of allergic diseases, the mechanisms underlying the development of these diseases have received a great deal of attention, and this is particularly true in regard to the role of ICOS in allergic diseases. Current studies have revealed that ICOS affects the functional activity of multiple immune cells that modulate the adaptive immune system. Additionally, ICOS also plays a crucial role in mediating cellular immunity and coordinating the response of the entire immune system, and thus, it plays a role in allergic reactions. However, the ICOS/ICOS-ligand (ICOS-L) axis functions in a dual role during the development of multiple allergic diseases. In this review, we explore the role of ICOS/ICOSL in the context of different immune cells that function in allergic diseases, and we summarize recent advances in their contribution to these diseases.
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Affiliation(s)
- Xueyan Zhang
- Department of Otorhinolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xianyang Hu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Tengfei Tian
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, China
| | - Wenhui Pang
- Department of Otorhinolaryngology-Head and Neck Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
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32
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Robson A, Bakr F, Rashidghamat E, Willsmore ZN, Ally M, Greenblatt D, Barlow R, Wain EM, Child F, Esdaile B, Kempf W. Follicular T-Helper Cells in Marginal Zone Lymphoma: Evidence of an Organoid Immune Response. Am J Dermatopathol 2021; 43:e197-e203. [PMID: 34231493 DOI: 10.1097/dad.0000000000002017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Primary cutaneous marginal zone B-cell lymphoma (MZL) follows an indolent clinical course. Histopathologically, there is a polymorphous infiltrate that includes small lymphocyte-like and centrocyte-like B cells and plasma cells usually with a substantial T-cell fraction. Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, in which the signature cells have a follicular T-helper (TFH) phenotype and are admixed with numerous B cells. Thus, both present histologies of combined B-cell and T-cell infiltrates and represent differential diagnoses. The presence of TFH in MZL has yet to be elucidated. METHODS Forty-one biopsies from 40 cases of MZL and 7 cases of lymphoid hyperplasia cutis (LCH) were stained with antibodies to follicular T-helper cells, including Bcl-6, PD-1, ICOS, and CD10, as part of their diagnostic workup, were reviewed, and the stained slides were evaluated semiquantitively. Five reactive lymph nodes were also evaluated as controls. RESULTS All cases of MZL and LCH contained TFH, albeit usually in low proportions. There were repeated differences in levels of expression between TFH markers, with PD1 and Bcl-6 being the most prevalent. The pattern of involvement in MZL and LCH closely mirrored that observed in the reactive lymph nodes. CONCLUSION MZL includes TFH cells, similar to reactive lymph nodes, and a complexity of cell types. This provides evidence of an organoid immune response challenging its simple categorization as a malignancy.
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Affiliation(s)
- Alistair Robson
- London Digital Pathology, UK, and IPOLFG, Serviço de Anatomia Patológica, Lisboa, Portugal
| | - Farrah Bakr
- London Digital Pathology, UK, and IPOLFG, Serviço de Anatomia Patológica, Lisboa, Portugal
- Department of Dermatology, St John's Institute of Dermatology, London, United Kingdom
- Department of Dermatology, Stanford University, Stanford, CA
- Department of Dermatology, Whittington Health National Health Service Foundation Trust, London, United Kingdom ; and
- Department of Dermatology, University Hospital Zurich, Zürich, Switzerland
| | - Ellie Rashidghamat
- Department of Dermatology, St John's Institute of Dermatology, London, United Kingdom
| | - Zena N Willsmore
- Department of Dermatology, St John's Institute of Dermatology, London, United Kingdom
| | - Mina Ally
- Department of Dermatology, Stanford University, Stanford, CA
| | - Danielle Greenblatt
- London Digital Pathology, UK, and IPOLFG, Serviço de Anatomia Patológica, Lisboa, Portugal
- Department of Dermatology, St John's Institute of Dermatology, London, United Kingdom
- Department of Dermatology, Stanford University, Stanford, CA
- Department of Dermatology, Whittington Health National Health Service Foundation Trust, London, United Kingdom ; and
- Department of Dermatology, University Hospital Zurich, Zürich, Switzerland
| | - Richard Barlow
- London Digital Pathology, UK, and IPOLFG, Serviço de Anatomia Patológica, Lisboa, Portugal
- Department of Dermatology, St John's Institute of Dermatology, London, United Kingdom
- Department of Dermatology, Stanford University, Stanford, CA
- Department of Dermatology, Whittington Health National Health Service Foundation Trust, London, United Kingdom ; and
- Department of Dermatology, University Hospital Zurich, Zürich, Switzerland
| | - E Mary Wain
- London Digital Pathology, UK, and IPOLFG, Serviço de Anatomia Patológica, Lisboa, Portugal
- Department of Dermatology, St John's Institute of Dermatology, London, United Kingdom
- Department of Dermatology, Stanford University, Stanford, CA
- Department of Dermatology, Whittington Health National Health Service Foundation Trust, London, United Kingdom ; and
- Department of Dermatology, University Hospital Zurich, Zürich, Switzerland
| | - Fiona Child
- Department of Dermatology, St John's Institute of Dermatology, London, United Kingdom
| | - Ben Esdaile
- Department of Dermatology, Whittington Health National Health Service Foundation Trust, London, United Kingdom ; and
| | - Werner Kempf
- Department of Dermatology, University Hospital Zurich, Zürich, Switzerland
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33
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Varela AA, Cheng S, Werren JH. Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations. PeerJ 2021; 9:e12159. [PMID: 34616619 PMCID: PMC8449537 DOI: 10.7717/peerj.12159] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/24/2021] [Indexed: 12/13/2022] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) is the cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken an approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that “coevolve” with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact with ACE2, while additional predicted novel ACE2 interactors are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as Coagulation Factor V and fibrinogen components FGA, FGB, and FGG, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). ACE2 also connects to proteins involved in cytokine signaling and immune response (e.g. XCR1, IFNAR2 and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has elucidated possible functions for relatively uncharacterized proteins and possible new functions for well-characterized ones. Suggestions are made for the validation of ERC-predicted ACE2 protein interactions. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.
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Affiliation(s)
- Austin A Varela
- Department of Biology, University of Rochester, Rochester, New York, United States
| | - Sammy Cheng
- Department of Biology, University of Rochester, Rochester, New York, United States
| | - John H Werren
- Department of Biology, University of Rochester, Rochester, New York, United States
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34
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Wan S, Ni L, Zhao X, Liu X, Xu W, Jin W, Wang X, Dong C. Costimulation molecules differentially regulate the ERK-Zfp831 axis to shape T follicular helper cell differentiation. Immunity 2021; 54:2740-2755.e6. [PMID: 34644536 DOI: 10.1016/j.immuni.2021.09.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 06/22/2021] [Accepted: 09/20/2021] [Indexed: 01/21/2023]
Abstract
T follicular helper (Tfh) cells play essential roles in regulating humoral immunity, especially germinal center reactions. However, how CD4+ T cells integrate the antigenic and costimulatory signals in Tfh cell development is still poorly understood. Here, we found that phorbol 12-myristate 13-acetate (PMA) + ionomycin (P+I) stimulation, together with interleukin-6 (IL-6), potently induce Tfh cell-like transcriptomic programs in vitro. The ERK kinase pathway was attenuated under P+I stimulation; ERK2 inhibition enhanced Tfh cell development in vitro and in vivo. We observed that inducible T cell costimulator (ICOS), but not CD28, lacked the ability to activate ERK, which was important in sustaining Tfh cell development. The transcription factor Zfp831, whose expression was repressed by ERK, promoted Tfh cell differentiation by directly upregulating the expression of the transcription factors Bcl6 and Tcf7. We have hence identified an ERK-Zfp831 axis, regulated by costimulation signaling, in critical regulation of Tfh cell development.
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Affiliation(s)
- Siyuan Wan
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Lu Ni
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Xiaohong Zhao
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Xindong Liu
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Wei Xu
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Wei Jin
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Xiaohu Wang
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Chen Dong
- Institute of Immunology and School of Medicine, Tsinghua University, Beijing, China; Shanghai Immune Therapy Institute, Shanghai Jiaotong University School of Medicine-affiliated Renji Hospital, Shanghai, China.
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35
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Talebi M, Nozad Charoudeh H, Movassaghpour Akbari AA, Baradaran B, Kazemi T. Effect of Cellular-Based Artificial Antigen Presenting Cells Expressing ICOSL, in T-cell Subtypes Differentiation and Activation. Adv Pharm Bull 2021; 11:537-542. [PMID: 34513629 PMCID: PMC8421621 DOI: 10.34172/apb.2021.062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 06/16/2020] [Accepted: 08/05/2020] [Indexed: 12/17/2022] Open
Abstract
Purposes: Effective and selective T-cell activation and proliferation during the T-cell expansion phase of a cellular adoptive immunotherapy method, challenging because recent studies revealed the importance of each subtype of T-cells in different immunologic strategies against tumors, like CAR-T cell therapies. Artificial antigen presenting cells (aAPCs) regarded as a natural way to manipulate T-cell subtypes activation and specific proliferation. In the current study, we utilized K562 cells based aAPC method expressing the ICOSL molecule, to evaluate T-cell subtypes differentiation rate and functional status. Methods: CD3+T-cells isolated and, co-cultured with ICOSL expressing K562 cells. After 4, 6, and 10 days selective CD markers of T-cell subtypes and each subtype's activity-related genes levels evaluated by qPCR methods. Results: During the culture period, CD4+ Th related phenotype reduced continuously, and in day 10th of culture CD4+ T-cell's population significantly reduced (P =0.029). In contrast, the CD8+ population ratio was ascending during the study period but was not statistically significant. FoxP3+CD25-, Treg population ratio was significantly increased during the time in comparison with the control group, as well as memory T-cell phenotypic marker, CD127+, expressing cells ratio. T-cell subpopulations activity-related genes expression levels evaluated too, and the Th1 related IL-2 and INF-γ reductions observed alongside regulatory T-cells gene (IL-10) and Cytotoxic T-cell's related gene (Geranzym-A) elevations. Conclusion: We concluded that the K562-ICOSL based aAPC system is working and effective in T-cell short to medium culture periods, and this approach preparing relatively selective milieu for CD8+ T-Cell differentiation and much less Treg differentiation.
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Affiliation(s)
- Mehdi Talebi
- Department of Applied Cell Sciences, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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36
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Hoefig KP, Reim A, Gallus C, Wong EH, Behrens G, Conrad C, Xu M, Kifinger L, Ito-Kureha T, Defourny KAY, Geerlof A, Mautner J, Hauck SM, Baumjohann D, Feederle R, Mann M, Wierer M, Glasmacher E, Heissmeyer V. Defining the RBPome of primary T helper cells to elucidate higher-order Roquin-mediated mRNA regulation. Nat Commun 2021; 12:5208. [PMID: 34471108 PMCID: PMC8410761 DOI: 10.1038/s41467-021-25345-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 07/28/2021] [Indexed: 01/01/2023] Open
Abstract
Post-transcriptional gene regulation in T cells is dynamic and complex as targeted transcripts respond to various factors. This is evident for the Icos mRNA encoding an essential costimulatory receptor that is regulated by several RNA-binding proteins (RBP), including Roquin-1 and Roquin-2. Here, we identify a core RBPome of 798 mouse and 801 human T cell proteins by utilizing global RNA interactome capture (RNA-IC) and orthogonal organic phase separation (OOPS). The RBPome includes Stat1, Stat4 and Vav1 proteins suggesting unexpected functions for these transcription factors and signal transducers. Based on proximity to Roquin-1, we select ~50 RBPs for testing coregulation of Roquin-1/2 targets by induced expression in wild-type or Roquin-1/2-deficient T cells. Besides Roquin-independent contributions from Rbms1 and Cpeb4 we also show Roquin-1/2-dependent and target-specific coregulation of Icos by Celf1 and Igf2bp3. Connecting the cellular RBPome in a post-transcriptional context, we find contributions from multiple RBPs to the prototypic regulation of mRNA targets by individual trans-acting factors. An extensive RNA binding protein atlas (RBPome) for primary T cells would be a useful resource. Here the authors use two different methods to characterise the mouse and human T cell RBPome and show regulation of Roquin-1/2 dependent and independent pathways.
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Affiliation(s)
- Kai P Hoefig
- Research Unit Molecular Immune Regulation, Helmholtz Center Munich, Munich, Germany
| | - Alexander Reim
- Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Munich, Germany
| | - Christian Gallus
- Institute of Diabetes and Obesity, Helmholtz Center Munich, Munich, Germany
| | - Elaine H Wong
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
| | - Gesine Behrens
- Research Unit Molecular Immune Regulation, Helmholtz Center Munich, Munich, Germany
| | - Christine Conrad
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
| | - Meng Xu
- Research Unit Molecular Immune Regulation, Helmholtz Center Munich, Munich, Germany
| | - Lisa Kifinger
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
| | - Taku Ito-Kureha
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany
| | - Kyra A Y Defourny
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany.,Department of Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands
| | - Arie Geerlof
- Institute of Structural Biology, Helmholtz Center Munich, Neuherberg, Germany
| | - Josef Mautner
- Research Unit Gene Vectors, Helmholtz Center Munich & Children's Hospital, TU Munich, Munich, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Center Munich, Munich, Germany
| | - Dirk Baumjohann
- Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany.,Medical Clinic III for Oncology, Immuno-Oncology and Rheumatology University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Regina Feederle
- Monoclonal Antibody Core Facility and Research Group, Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany
| | - Matthias Mann
- Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Munich, Germany
| | - Michael Wierer
- Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Munich, Germany. .,Proteomics Research Infrastructure, University of Copenhagen, Copenhagen, Denmark.
| | - Elke Glasmacher
- Institute of Diabetes and Obesity, Helmholtz Center Munich, Munich, Germany. .,Roche Pharma Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany.
| | - Vigo Heissmeyer
- Research Unit Molecular Immune Regulation, Helmholtz Center Munich, Munich, Germany. .,Institute for Immunology, Biomedical Center, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany.
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Matsuda Y, Watanabe T, Li XK. Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells. Front Immunol 2021; 12:682334. [PMID: 34276669 PMCID: PMC8282180 DOI: 10.3389/fimmu.2021.682334] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/17/2021] [Indexed: 01/14/2023] Open
Abstract
Both acute and chronic antibody-mediated allograft rejection (AMR), which are directly mediated by B cells, remain difficult to treat. Long-lived plasma cells (LLPCs) in bone marrow (BM) play a crucial role in the production of the antibodies that induce AMR. However, LLPCs survive through a T cell-independent mechanism and resist conventional immunosuppressive therapy. Desensitization therapy is therefore performed, although it is accompanied by severe side effects and the pathological condition may be at an irreversible stage when these antibodies, which induce AMR development, are detected in the serum. In other words, AMR control requires the development of a diagnostic method that predicts its onset before LLPC differentiation and enables therapeutic intervention and the establishment of humoral immune monitoring methods providing more detailed information, including individual differences in the susceptibility to immunosuppressive agents and the pathological conditions. In this study, we reviewed recent studies related to the direct or indirect involvement of immunocompetent cells in the differentiation of naïve-B cells into LLPCs, the limitations of conventional methods, and the possible development of novel control methods in the context of AMR. This information will significantly contribute to the development of clinical applications for AMR and improve the prognosis of patients who undergo organ transplantation.
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Affiliation(s)
- Yoshiko Matsuda
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Takeshi Watanabe
- Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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38
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McKinski K, McNulty D, Zappacosta F, Birchler M, Szapacs M, Evans C. Orthogonal quantification of soluble inducible T-cell costimulator (ICOS) in healthy and diseased human serum. J Pharm Anal 2021; 12:317-323. [PMID: 35582393 PMCID: PMC9091914 DOI: 10.1016/j.jpha.2021.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/02/2021] [Accepted: 06/24/2021] [Indexed: 12/04/2022] Open
Abstract
Inducible T-cell costimulator (ICOS), a homodimeric protein expressed on the surface of activated T-cells, is being investigated as a potential therapeutic target to treat various cancers. Recent studies have reported aberrant increases in the soluble form of ICOS (sICOS) in human serum in disease-state patients, primarily using commercial ELISA kits. However, results from our in-house immunoassay did not show these aberrant increases, leading us to speculate that commercial sICOS ELISAs may be prone to interference. We directly tested that hypothesis and found that one widely used commercial kit yields false-positives and is prone to human anti-mouse antibody interference. We then analyzed a panel of healthy, cancer, chronic hepatitis C virus, systemic lupus erythematosus, and diffuse cutaneous systemic sclerosis human serum using our in-house immunoassay and reported the measured sICOS concentrations in these populations. Since even well characterized immunoassay methods are prone to non-specific interference, we also developed a novel sICOS LC-MS/MS method to confirm the results. Using these orthogonal approaches, we show that sICOS is a low abundance soluble protein that cannot be measured above approximately 20 pg/mL in human serum.
Soluble ICOS is a low-abundance protein that is not detectable above approximately 20 pg/mL in human serum. Commercial soluble ICOS kits may be prone to HAMA interference and thus false-positives. Off-the-shelf assay kits should be well characterized in order to minimize non-specific interferences.
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Roussel L, Vinh DC. ICOSL in host defense at epithelial barriers: lessons from ICOSLG deficiency. Curr Opin Immunol 2021; 72:21-26. [PMID: 33756276 DOI: 10.1016/j.coi.2021.03.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/28/2021] [Accepted: 03/01/2021] [Indexed: 01/31/2023]
Abstract
Autosomal recessive mutations in Inducible T Cell Costimulator Ligand (ICOSLG) result in a combined immunodeficiency syndrome of humans, saliently marked by recurrent respiratory tract infections and significant disease with DNA-based viruses at epithelial barriers, including human papillomavirus (HPV). These features are also seen in persons with loss of function of the complementary gene, ICOS. The infection phenotypes associated with these natural experiments disclose a critical role of the corresponding proteins, ICOSL and ICOS, in human immunity at mucocutaneous barriers. Here, we review the syndromes of ICOSL and ICOS deficiency and explore the mechanisms by which the ICOSL:ICOS axis mediates epithelial host defenses.
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Affiliation(s)
- Lucie Roussel
- Host-directed Immunotherapy to Fight Infectious Diseases (HI-FI) Program, Research Institute - McGill University Health Centre, Montreal, Quebec, Canada
| | - Donald C Vinh
- Host-directed Immunotherapy to Fight Infectious Diseases (HI-FI) Program, Research Institute - McGill University Health Centre, Montreal, Quebec, Canada; Division of Infectious Diseases, McGill University Health Centre, Montreal, Quebec, Canada; Division of Medical Microbiology, Department of Pathology & Laboratory Medicine, McGill University Health Centre, Montreal, Quebec, Canada; Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
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40
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The ubiquitin ligase Peli1 inhibits ICOS and thereby Tfh-mediated immunity. Cell Mol Immunol 2021; 18:969-978. [PMID: 33707688 PMCID: PMC8115645 DOI: 10.1038/s41423-021-00660-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 02/13/2021] [Indexed: 11/11/2022] Open
Abstract
T follicular helper (Tfh) cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection. However, the molecular mechanism controlling Tfh cell differentiation is poorly understood. Here, through two mixed bone marrow chimeric experiments, we identified Peli1, a T cell-enriched E3 ubiquitin ligase, as an intrinsic regulator that inhibits Tfh cell differentiation. Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator (ICOS) expression, and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4+ T cells. Mechanistically, increased ICOS expression on Peli1-KO CD4+ T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2, a transcription factor that inhibits Tfh differentiation. Therefore, reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells. As a consequence, Peli1-deficient CD4+ T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models. Collectively, our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfh-related autoimmunity or infectious diseases.
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Abstract
Among antibodies, IgA is unique because it has evolved to be secreted onto mucosal surfaces. The structure of IgA and the associated secretory component allow IgA to survive the highly proteolytic environment of mucosal surfaces but also substantially limit IgA's ability to activate effector functions on immune cells. Despite these characteristics, IgA is critical for both preventing enteric infections and shaping the local microbiome. IgA's function is determined by a distinct antigen-binding repertoire, composed of antibodies with a variety of specificities, from permissive polyspecificity to cross-reactivity to exquisite specificity to a single epitope, which act together to regulate intestinal bacteria. Development of the unique function and specificities of IgA is shaped by local cues provided by the gut-associated lymphoid tissue, driven by the constantly changing environment of the intestine and microbiota.
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Affiliation(s)
- Timothy W Hand
- R.K. Mellon Institute for Pediatric Research, Department of Pediatrics, Division of Infectious Diseases, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania 15224, USA;
| | - Andrea Reboldi
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA;
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Sun K, Ma S, Tian S, Zhang M, Liu Y, Li B, Zhou X, Zheng X, Zhou X, Wang L, Han Y. An enhanced level of LAMP-2A participates in CD4 +T cell hyperactivity in patients with primary biliary cholangitis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:101. [PMID: 33569403 PMCID: PMC7867869 DOI: 10.21037/atm-20-2427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background Primary biliary cholangitis (PBC) is an immune-mediated chronic cholestasis, in which T cell homeostasis plays an important role. Lysosomal-associated membrane protein 2 isoform A (LAMP-2A) has been implicated in the regulation of CD4+T cell responses. Methods We comprehensively evaluated the immunobiology of CD4+T cells in patients with PBC (PBC, n=42), chronic hepatitis B (CHB, n=20), and healthy control subjects (HC, n=20) by flow cytometry including activation status and LAMP-2A expression. Additionally, we investigated the activation responses of PBC-naïve CD4+T cells by stimulation in vitro and tested the changes caused by deleting the gene encoding LAMP-2A. Results Firstly, we found an increased activation status of circulating CD4+T cells from PBC patients compared to the HC subjects, and PBC-naïve CD4+T cells showed enhanced responses after stimulation in vitro. Secondly, PBC-naïve CD4+T cells expressed a significantly higher level of LAMP-2A compared to the HC and CHB groups [PBC vs. HC, 1,954.74 (1,254.28-3,057.14) vs. 1,542.12 (961.18-2,277.98), P=0.03; vs. CHB, 1,153.59 (726.87-1,275.48), P=0.02], and the overreactions of PBC-naïve CD4+T cells could be reversed by interfering with LAMP-2A expression in vitro. Thirdly, the LAMP-2A expression level of PBC-naïve CD4+T cells was related to disease severity and drug response. Conclusions An abnormally increased LAMP-2A expression of PBC-naïve CD4+T cells might be related to excessive activation responses. LAMP-2A could be a novel therapeutic target for the treatment of PBC by reversing excessive responses and consequently reducing biliary injury.
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Affiliation(s)
- Keshuai Sun
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Shuoyi Ma
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Siyuan Tian
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Miao Zhang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Yansheng Liu
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Bo Li
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Xia Zhou
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Xiaohong Zheng
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Xinmin Zhou
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Lu Wang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
| | - Ying Han
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China
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Xiao ZX, Hu X, Jarjour W, Zheng SG. The role of B7 family members in the generation of Immunoglobulin. J Leukoc Biol 2020; 109:377-382. [PMID: 33118237 DOI: 10.1002/jlb.1mr0420-003rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 04/08/2020] [Accepted: 04/15/2020] [Indexed: 10/23/2022] Open
Abstract
Ig is a Y-shaped protein produced by plasma cells and exerts multiple functions in humoral immunity. There are five groups of Igs including IgA, IgD, IgE, IgG, and IgM, which differ in their heavy chain class. The primary function of Igs includes the neutralization of extrinsic pathogens, agglutination of foreign cells for phagocytosis, precipitation of soluble antigens in serum, and complement fixation. The B cells activated by antigen(s) can differentiate into antibody-producing cells that are called plasma cells and usually matured in the germinal center (GC). Follicular T helper (Tfh) cells crosstalk with antigen-presenting cells and play a crucial role in the development of the GC. Moreover, Tfh cells regulate trafficking through the GC to allow formative interaction with GC B cells that ultimately results in affinity maturation, B-cell memory, and Ig class switching. The B7 family is a series of number of structurally related membrane proteins that bind with a specific receptor to deliver costimulatory or co-inhibitory signals that regulate the activation of T cells in GC. Here, we review and summarize the recent advance of the effects of B7 family members on Ig production and relative diseases.
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Affiliation(s)
- Ze Xiu Xiao
- Institute of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xiaojiang Hu
- Institute of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Wael Jarjour
- Department of Internal Medicine, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
| | - Song Guo Zheng
- Department of Internal Medicine, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, USA
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Rujas E, Cui H, Sicard T, Semesi A, Julien JP. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. Nat Commun 2020; 11:5066. [PMID: 33033255 PMCID: PMC7545189 DOI: 10.1038/s41467-020-18828-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/15/2020] [Indexed: 12/20/2022] Open
Abstract
The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Å resolution. A central FDPPPF motif and residues within the CC' loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors.
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Affiliation(s)
- Edurne Rujas
- Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, M5G 0A4, Canada.,Biofisika Institute (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080, Bilbao, Spain
| | - Hong Cui
- Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, M5G 0A4, Canada
| | - Taylor Sicard
- Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, M5G 0A4, Canada.,Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Anthony Semesi
- Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, M5G 0A4, Canada
| | - Jean-Philippe Julien
- Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, M5G 0A4, Canada. .,Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada. .,Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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Varricchi G, Bencivenga L, Poto R, Pecoraro A, Shamji MH, Rengo G. The emerging role of T follicular helper (T FH) cells in aging: Influence on the immune frailty. Ageing Res Rev 2020; 61:101071. [PMID: 32344191 DOI: 10.1016/j.arr.2020.101071] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 04/03/2020] [Accepted: 04/08/2020] [Indexed: 01/10/2023]
Abstract
The world population is undergoing a rapid expansion of older adults. Aging is associated with numerous changes that affect all organs and systems, including every component of the immune system. Immunosenescence is a multifaceted process characterized by poor response to vaccine and higher incidence of bacterial and viral infections, cancer, cardiovascular and autoimmune diseases. Immunosenescence has been associated with chronic low-grade inflammation referred to as inflammaging, whose underlying mechanisms remain incompletely elucidated, including age-related changes affecting components of the innate and adaptive immune system. T follicular helper (TFH) cells, present in lymphoid organs and in peripheral blood, are specialized in providing cognate help to B cells and are required for the production of immunoglobulins. Several subsets of TFH cells have been identified in humans and mice and modifications in TFH cell phenotype and function progressively occur with age. Dysfunctional TFH cells play a role in cancer, autoimmune and cardiovascular diseases, all conditions particularly prevalent in elderly subjects. A specialized population of Treg cells, named T follicular regulatory (TFR) cells, present in lymphoid organs and in peripheral blood, exerts opposing roles to TFH cells in regulating immunity. Indeed, changes in TFH/TFR cell ratio constitute a relevant feature of aging. Herein we discuss the cellular and molecular changes in both TFH cells and TFR cells that occur in aging and recent findings suggesting that TFH cells and/or their subsets could be involved in atherosclerosis, cancer, and autoimmunity.
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Fastrès A, Pirottin D, Fievez L, Marichal T, Desmet CJ, Bureau F, Clercx C. Characterization of the Bronchoalveolar Lavage Fluid by Single Cell Gene Expression Analysis in Healthy Dogs: A Promising Technique. Front Immunol 2020; 11:1707. [PMID: 32849601 PMCID: PMC7406785 DOI: 10.3389/fimmu.2020.01707] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/26/2020] [Indexed: 12/14/2022] Open
Abstract
Single-cell mRNA-sequencing (scRNA-seq) is a technique which enables unbiased, high throughput and high-resolution transcriptomic analysis of the heterogeneity of cells within a population. This recent technique has been described in humans, mice and other species in various conditions to cluster cells in populations and identify new subpopulations, as well as to study the gene expression of cells in various tissues, conditions and origins. In dogs, a species for which markers of cell populations are often limiting, scRNA-seq presents with elevated yet untested potential for the study of tissue composition. As a proof of principle, we used scRNA-seq to identify cellular populations of the bronchoalveolar lavage fluid (BALF) in healthy dogs (n = 4). A total of 5,710 cells were obtained and analyzed by scRNA-seq. Fourteen distinct clusters of cells were identified, further identified as macrophages/monocytes (4 clusters), T cells (2 clusters) and B cells (1 cluster), neutrophils (1 cluster), mast cells (1 cluster), mature or immature dendritic cells (1 cluster each), ciliated or non-ciliated epithelial cells (1 cluster each) and cycling cells (1 cluster). We used for the first time in dogs the scRNA-seq to investigate cellular subpopulations of the BALF of dog. This study hence expands our knowledge on dog lung immune cell populations, paves the way for the investigation at single-cell level of lower respiratory diseases in dogs, and establishes that scRNA-seq is a powerful tool for the study of dog tissue composition.
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Affiliation(s)
- Aline Fastrès
- Department of Clinical Sciences, Faculty of Veterinary Medicine, FARAH, University of Liège, Liège, Belgium
| | - Dimitri Pirottin
- Laboratory of Cellular and Molecular Immunology, Department of Functional Sciences and GIGA-Inflammation, Infection and Immunity, University of Liège, Liège, Belgium
| | - Laurence Fievez
- Laboratory of Cellular and Molecular Immunology, Department of Functional Sciences and GIGA-Inflammation, Infection and Immunity, University of Liège, Liège, Belgium
| | - Thomas Marichal
- Laboratory of Cellular and Molecular Immunology, Department of Functional Sciences and GIGA-Inflammation, Infection and Immunity, University of Liège, Liège, Belgium
| | - Christophe J Desmet
- Laboratory of Cellular and Molecular Immunology, Department of Functional Sciences and GIGA-Inflammation, Infection and Immunity, University of Liège, Liège, Belgium
| | - Fabrice Bureau
- Laboratory of Cellular and Molecular Immunology, Department of Functional Sciences and GIGA-Inflammation, Infection and Immunity, University of Liège, Liège, Belgium
| | - Cécile Clercx
- Department of Clinical Sciences, Faculty of Veterinary Medicine, FARAH, University of Liège, Liège, Belgium
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de Vos L, Grünwald I, Bawden EG, Dietrich J, Scheckenbach K, Wiek C, Zarbl R, Bootz F, Landsberg J, Dietrich D. The landscape of CD28, CD80, CD86, CTLA4, and ICOS DNA methylation in head and neck squamous cell carcinomas. Epigenetics 2020; 15:1195-1212. [PMID: 32281488 DOI: 10.1080/15592294.2020.1754675] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
CTLA-4 blocking therapeutic antibodies are currently under investigation in head and neck squamous cell carcinoma (HNSCC). A better understanding of the epigenetic regulation of the CD28 superfamily members CD28, CTLA-4, and ICOS and their B7 ligands, CD80 and CD86, could support the development of biomarkers for response prediction to anti-CTLA-4 immunotherapy. We investigated methylation of the encoding genes CD28, CTLA4, ICOS, CD80, and CD86 at single CpG resolution (51 CpG sites) in a cohort of HNSCC (N = 528) and normal adjacent tissue samples (N = 50) provided by The Cancer Genome Research Atlas, in isolated blood leukocytes from healthy individuals (N = 28), and HNSCC cell lines (N = 39). We analysed methylation levels with regard to mRNA expression, overall survival, mutational load, interferon-γ signature, and signatures of immune cell infiltrates. Depending on the location of the CpG sites (promoter, promoter flank, gene body, and intergenic sites), we found significant differences in methylation levels among isolated leukocytes, between leukocytes and HNSCC cell lines, and among HNSCCs. Methylation of all analysed genes correlated inversely or positively with mRNA expression, depending on the CpG site. CD28, CTLA4, and ICOS revealed almost identical correlation patterns. Furthermore, we found significant correlations with survival and features of response to immunotherapy, i.e. interferon-γ signature, signatures of tumour infiltrating immune cells, and mutational load. Our results suggest CD28, CTLA4, ICOS, CD80, and CD86 expression levels are epigenetically co-regulated by DNA methylation. This study provides rationale to test their DNA methylation as potential biomarker for prediction of response to CTLA-4 immune checkpoint inhibitors.
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Affiliation(s)
- Luka de Vos
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn , Bonn, Germany
| | - Ingela Grünwald
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn , Bonn, Germany
| | - Emma Grace Bawden
- Department of Microbiology & Immunology, The University of Melbourne at the Peter Doherty Institute for Infection & Immunity , Melbourne, Australia
| | - Jörn Dietrich
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn , Bonn, Germany
| | - Kathrin Scheckenbach
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Düsseldorf , Düsseldorf, Germany
| | - Constanze Wiek
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Düsseldorf , Düsseldorf, Germany
| | - Romina Zarbl
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn , Bonn, Germany
| | - Friedrich Bootz
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn , Bonn, Germany
| | - Jennifer Landsberg
- Department of Dermatology and Allergy, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn , Bonn, Germany
| | - Dimo Dietrich
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn , Bonn, Germany
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Carballido JM, Regairaz C, Rauld C, Raad L, Picard D, Kammüller M. The Emerging Jamboree of Transformative Therapies for Autoimmune Diseases. Front Immunol 2020; 11:472. [PMID: 32296421 PMCID: PMC7137386 DOI: 10.3389/fimmu.2020.00472] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 02/28/2020] [Indexed: 12/12/2022] Open
Abstract
Standard treatments for autoimmune and autoinflammatory disorders rely mainly on immunosuppression. These are predominantly symptomatic remedies that do not affect the root cause of the disease and are associated with multiple side effects. Immunotherapies are being developed during the last decades as more specific and safer alternatives to small molecules with broad immunosuppressive activity, but they still do not distinguish between disease-causing and protective cell targets and thus, they still have considerable risks of increasing susceptibility to infections and/or malignancy. Antigen-specific approaches inducing immune tolerance represent an emerging trend carrying the potential to be curative without inducing broad immunosuppression. These therapies are based on antigenic epitopes derived from the same proteins that are targeted by the autoreactive T and B cells, and which are administered to patients together with precise instructions to induce regulatory responses capable to restore homeostasis. They are not personalized medicines, and they do not need to be. They are precision therapies exquisitely targeting the disease-causing cells that drive pathology in defined patient populations. Immune tolerance approaches are truly transformative options for people suffering from autoimmune diseases.
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Affiliation(s)
- José M. Carballido
- Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland
- Autoimmunity Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Camille Regairaz
- Autoimmunity Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Celine Rauld
- Autoimmunity Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Layla Raad
- Autoimmunity Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Damien Picard
- Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Michael Kammüller
- Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland
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Preite S, Gomez-Rodriguez J, Cannons JL, Schwartzberg PL. T and B-cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity. Immunol Rev 2020; 291:154-173. [PMID: 31402502 DOI: 10.1111/imr.12790] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 05/30/2019] [Indexed: 12/15/2022]
Abstract
Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in lymphocyte signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3Kδ, p110δ, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder "Activated PI3K-delta syndrome" and mouse models of this disease (Pik3cdE1020K/+ mice) have provided fundamental insight into pathways regulated by PI3Kδ in T and B cells and their contribution to lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3Kδ in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8+ T-cell function. We further present data demonstrating the ability of the AKT-resistant FOXO1AAA mutant to rescue IgG1 class switching defects in Pik3cdE1020K/+ B cells, as well as data supporting a role for PI3Kδ in promoting multiple T-helper effector cell lineages.
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Affiliation(s)
- Silvia Preite
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.,National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Julio Gomez-Rodriguez
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.,National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Jennifer L Cannons
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.,National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Pamela L Schwartzberg
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.,National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
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Jeong S, Park SH. Co-Stimulatory Receptors in Cancers and Their Implications for Cancer Immunotherapy. Immune Netw 2020; 20:e3. [PMID: 32158591 PMCID: PMC7049585 DOI: 10.4110/in.2020.20.e3] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 01/27/2020] [Accepted: 01/27/2020] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs), including anti-PD-1 and anti-CTLA-4 therapeutic agents, are now approved by the Food and Drug Administration for treatment of various types of cancer. However, the therapeutic efficacy of ICIs varies among patients and cancer types. Moreover, most patients do not develop durable antitumor responses after ICI therapy due to an ephemeral reversal of T-cell dysfunction. As co-stimulatory receptors play key roles in regulating the effector functions of T cells, activating co-stimulatory pathways may improve checkpoint inhibition efficacy, and lead to durable antitumor responses. Here, we review recent advances in our understating of co-stimulatory receptors in cancers, providing the necessary groundwork for the rational design of cancer immunotherapy.
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Affiliation(s)
- Seongju Jeong
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Korea
| | - Su-Hyung Park
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Korea.,Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea
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