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Rueger S, Gruener E, Wang D, Abdool FS, Ober V, Vallée T, Stirner R, Conca R, Andrä I, Rogers L, Zahn R, Gersbacher E, Eger J, Pauli R, Postel N, Spinner CD, Vehreschild JJ, Stecher M, Nitschko H, Eberle J, Bogner JR, Seybold U, Draenert R, Leslie A, Kløverpris HN, Geldmacher C, Muenchhoff M, Held K, Roider J. Early treatment and PD1 inhibition enhance HIV-specific functionality of follicular CD8+ T cells. JCI Insight 2025; 10:e180309. [PMID: 40197363 PMCID: PMC11981630 DOI: 10.1172/jci.insight.180309] [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: 02/19/2024] [Accepted: 02/18/2025] [Indexed: 04/10/2025] Open
Abstract
People living with HIV treated during acute infection are the group for whom achieving functional cure appears most viable. Follicular CD8+ T cells could contribute to HIV reservoir clearance by accessing B cell follicles through CXCR5 expression. This study examines peripheral follicular CD8+ T cells using flow cytometry, transcriptome analyses, and functional assays in people treated during acute (n = 37) and chronic (n = 18) infection, as well as in individuals naturally controlling HIV (n = 20) and living without HIV (n = 10). Our results reveal that early, as opposed to late, treatment initiation preserves antiviral effector functions of follicular CD8+ T cells, which are further enhanced by PD1 inhibition. We also identify a correlation between follicular CD8+ T cells and intact proviral HIV DNA levels in acute, but not chronic, infection. Longitudinal transcriptomic analysis of peripheral effector cells after 48 weeks of suppressive therapy indicated traits of recent antigen exposure, suggesting potential recirculation into lymphoid tissue. These findings underscore the pivotal role of follicular CD8+ T cells in anti-HIV responses and support investigating targeted cure strategies, such as anti-PD1 therapy, especially in individuals initiating treatment during acute infection.
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Affiliation(s)
- Susanne Rueger
- Department of Infectious Diseases, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
- German Centre for Infection Research (DZIF), partner site Munich, Germany
| | - Eva Gruener
- Department of Infectious Diseases, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Danni Wang
- German Centre for Infection Research (DZIF), partner site Munich, Germany
- Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Faiaz Shaik Abdool
- Africa Health Research Institute (AHRI), and
- Department of Laboratory Medicine and Medical Science, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal (UKZN), Durban, South Africa
| | - Veronica Ober
- Department of Infectious Diseases, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Theresa Vallée
- German Centre for Infection Research (DZIF), partner site Munich, Germany
- Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, and
| | - Renate Stirner
- Department of Infectious Diseases, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Raffaele Conca
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, LMU University Hospital, LMU Munich, Munich, Germany
| | - Immanuel Andrä
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
| | - Lisa Rogers
- German Centre for Infection Research (DZIF), partner site Munich, Germany
- Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Munich, Germany
| | - Robert Zahn
- Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, LMU University Hospital, LMU Munich, Munich, Germany
| | | | - Joanna Eger
- Zentrum fuer Innere Medizin und Infektiologie, Munich, Germany
| | | | - Nils Postel
- prinzmed, Practice for Infectiology, Munich, Germany
| | - Christoph D. Spinner
- TUM School of Medicine and Health, Department of Clinical Medicine – Clinical Department for Internal Medicine II, University Medical Center, Technical University of Munich, Munich, Germany
| | - Jörg J. Vehreschild
- Medical Department 2, Hematology/Oncology and Infectious Diseases, University Hospital of Frankfurt, Frankfurt, Germany
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I for Internal Medicine, Cologne, Germany
- German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Germany
| | - Melanie Stecher
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I for Internal Medicine, Cologne, Germany
- German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Germany
| | - Hans Nitschko
- Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, and
| | - Josef Eberle
- German Centre for Infection Research (DZIF), partner site Munich, Germany
- Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, and
| | - Johannes R. Bogner
- Department of Infectious Diseases, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
- German Centre for Infection Research (DZIF), partner site Munich, Germany
| | - Ulrich Seybold
- Department of Infectious Diseases, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
| | - Rika Draenert
- Department of Infectious Diseases, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
- Antibiotic Stewardship Team, LMU University Hospital, LMU Munich, Munich, Germany
| | - Al Leslie
- Africa Health Research Institute (AHRI), and
- Department of Infection and Immunity, University College London (UCL), London, United Kingdom
| | - Henrik N. Kløverpris
- Africa Health Research Institute (AHRI), and
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Christof Geldmacher
- German Centre for Infection Research (DZIF), partner site Munich, Germany
- Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Munich, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection and Pandemic Research, Munich, Germany
| | - Maximilian Muenchhoff
- German Centre for Infection Research (DZIF), partner site Munich, Germany
- Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, and
| | - Kathrin Held
- German Centre for Infection Research (DZIF), partner site Munich, Germany
- Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Munich, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection and Pandemic Research, Munich, Germany
- Unit Global Health, Helmholtz Zentrum München, German Research Centre for Environmental Health (HMGU), Neuherberg, Germany
| | - Julia Roider
- Department of Infectious Diseases, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany
- German Centre for Infection Research (DZIF), partner site Munich, Germany
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Khanam A, Kottilil S. Reversal of immune exhaustion for functional cure of chronic hepatitis B: Is the time right? Hepatology 2025; 81:1129-1131. [PMID: 39141593 DOI: 10.1097/hep.0000000000001059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 07/25/2024] [Indexed: 08/16/2024]
Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Jiang D, Wu X, Chen C, Ju T, Du Y, Yang M, Cao K, Chen M, Zhou W, Qi J, Yan C, Cui D, Yan D, Yang S. Follicular cytotoxic T cells is dysfunctional in chronic hepatitis B patients with non-alcoholic fatty liver disease. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167646. [PMID: 39743024 DOI: 10.1016/j.bbadis.2024.167646] [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: 09/08/2024] [Accepted: 12/26/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND & AIMS Given the impact of nonalcoholic fatty liver disease (NAFLD) on T cell activation and proliferation functions, we aim to explore the heterogeneity of follicular cytotoxic T (Tfc) cells in chronic hepatitis B (CHB) patients with NAFLD. METHODS 32 healthy controls (HCs), 36 treatment-naïve CHB patients, and 19 treatment-naïve CHB + NAFLD patients were recruited. We employed multicolor flow cytometry to assess the exhausted phenotype and functionality of Tfc cells. CD8+ T cells were subjected to single-cell RNA sequencing. Furthermore, we co-cultured peripheral blood mononuclear cells from CHB patients with HepG2.2.15 cells under different treatment to investigate the underlying mechanism. RESULTS We observed an increased expression of inhibitory receptors in Tfc cells compared to their counterparts in CHB patients. In CHB + NAFLD patients the memory identity and functional properties of Tfc cells were impaired. Enhanced lipid oxidation and oxidative stress were found in the Tfc of CHB + NAFLD patients. Tfc cells were predominantly present within the exhausted effector T cells in CHB + NAFLD patients, while in CHB patients, Tfc cells were mainly distributed within the precursors of exhausted T cells and central memory T cells. The effector memory phenotype of Tfc cells was diminished but could be partially restored after antioxidant treatment. CONCLUSION We present the phenotype of Tfc cells in CHB patients, with or without NAFLD. Our findings provide evidence that the long-term memory identity and functionality of Tfc cells are impaired in CHB + NAFLD patients. Enhancing the characteristics of effector memory cells in Tfc through maintaining the redox balance may offer innovative therapeutic strategies for CHB + NAFLD patients.
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Affiliation(s)
- Daixi Jiang
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China; Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Xiaoyue Wu
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Can Chen
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Ju
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuxia Du
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengya Yang
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Kexin Cao
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengsha Chen
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenkai Zhou
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiaxing Qi
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China
| | - Cuilin Yan
- Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Dong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Shigui Yang
- Department of Emergency Medicine, Second Affiliated Hospital, Department of Epidemiology and Biostatistics, School of Public Health, The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China.
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Xu ZY, Dai ZS, Gong GZ, Zhang M. C-X-C chemokine receptor type 5 +CD8 + T cells as immune regulators in hepatitis Be antigen-positive chronic hepatitis B under interferon-alpha treatment. World J Gastroenterol 2025; 31:99833. [PMID: 39839901 PMCID: PMC11684170 DOI: 10.3748/wjg.v31.i3.99833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/30/2024] [Accepted: 11/15/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND C-X-C chemokine receptor type 5 (CXCR5)+CD8+ T cells represent a unique immune subset with dual roles, functioning as cytotoxic cells in persistent viral infections while promoting B cell responses. Despite their importance, the specific role of CXCR5+CD8+ T cells in chronic hepatitis B (CHB), particularly during interferon-alpha (IFN-α) treatment, is not fully understood. This study aims to elucidate the relationship between CXCR5+CD8+ T cells and sustained serologic response (SR) in patients undergoing 48 weeks of pegylated IFN-α (peg-IFN-α) treatment for CHB. AIM To elucidate the relationship between CXCR5+CD8+ T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-α treatment for CHB. METHODS This study enrolled 60 patients with hepatitis Be antigen (HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-α treatment. Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months, HBeAb-negative, hepatitis B virus DNA levels exceeding 2 × 104 copies/mL, and alanine aminotransferase (ALT) levels between 2 and 10 times the upper limit of normal. Blood samples were collected at baseline and at weeks 12, 24, 48, and a 24-week treatment-free follow-up (week 72) to measure serum interleukin (IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1 (PD-L1) expression on CD8+ T cells by flow cytometry, CXCR5 is a chemokine receptor that directs immune cells to specific tissues, while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity. RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5+CD8+ T cells compared to healthy controls (P < 0.01). Notably, CXCR5+CD8+ T cells were prominently expressed in patients who achieved sustained SR compared to non-SR (NSR). A significant correlation was observed between CXCR5 and PD-L1 expression (r = -0.189, P = 0.002). However, there was no significant correlation between serum IL-21 levels and CXCR5+CD8+ lymphocytes (r = -0.03, P = 0.625) or serum ALT levels (r = 0.026, P = 0.678). CONCLUSION The enhanced expression of CXCR5+CD8+ T cells in patients achieving HBeAg seroconversion during IFN-α treatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B. This study highlights the potential of CXCR5+CD8+ T cells as immune regulators in CHB, which may inform future therapeutic strategies to optimize antiviral treatments.
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Affiliation(s)
- Zhen-Yu Xu
- Department of Infectious Diseases, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Zhong-Shang Dai
- Department of Infectious Diseases, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Guo-Zhong Gong
- Department of Infectious Diseases, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Min Zhang
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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Cao L, Peng H, Chen Y, Xia B, Zeng T, Guo J, Yu F, Ye H, Zhang H, Chen X. ICOS-expressing CAR-T cells mediate durable eradication of triple-negative breast cancer and metastasis. J Immunother Cancer 2024; 12:e010028. [PMID: 39532433 PMCID: PMC11555110 DOI: 10.1136/jitc-2024-010028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The failure of conventional therapies and the propensity for recurrence and metastasis make triple-negative breast cancer (TNBC) a formidable challenge with grim prognoses and diminished survival rates. Immunotherapy, including immune checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapy, presents innovative and potentially more effective strategies for addressing TNBC. Within this context, the inducible costimulator (ICOS), a member of the CTLA4/CD28 family, plays a crucial role in regulating immune responses and T-cell differentiation by binding to its ligand ICOSL. However, the impact of the ICOS/ICOSL axis on cancer varies. METHODS In this study, immunohistochemistry was conducted to examine the expression level of ICOSL in TNBC tumor tissues. We developed ICOS-enhanced B7H3-CAR-T cells (ICOS-B7H3-CAR) using the third-generation CAR-T cell technology, which featured magnified ICOS expression and targeted the B7H3 antigen. Xenograft and metastasis models of TNBC were conducted to examine the cytotoxicity and durability of CAR-T cells in tumors. Overexpression and CRISPR/Cas9-mediated knockout (KO) techniques were employed to regulate the expression of ICOSL on TNBC cell lines. RESULTS Notably, we observed elevated ICOSL expression in TNBC tumor tissues, which correlated with poor survival prognosis in patients with TNBC. Compared with conventional B7H3-CAR-T cells, ICOS-B7H3-CAR-T cells significantly inhibited the tumor growth of TNBC cells both in vitro and in vivo, accompanied by increased secretion of cytokines such as interferon gamma and tumor necrosis factor alpha. Furthermore, the in vivo experiments illustrated that ICOS-B7H3-CAR-T cells exhibited prolonged antitumor activity and could effectively eradicate metastases in a TNBC metastasis model, consequently extending survival. Importantly, manipulating the expression of ICOSL on TNBC cells through overexpression or KO significantly influenced the function of ICOS-B7H3-CAR-T cells. This suggests that the level of ICOSL expression on TNBC cells is critical for enhancing the potent antitumor effects of ICOS-B7H3-CAR-T cells. CONCLUSION Overall, our study highlights the potential clinical application of ICOS as a promising strategy for combating TNBC recurrence and metastasis.
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Affiliation(s)
- Lixue Cao
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Haojie Peng
- Department of Breast Surgery, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong, China
| | - Yanzhen Chen
- Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Baijin Xia
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, Guangdong, China
| | - Tao Zeng
- Department of Breast Surgery, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jialing Guo
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Fei Yu
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Haiyan Ye
- Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Hui Zhang
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xinxin Chen
- Department of Breast Surgery, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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Khan MN, Mao B, Hu J, Shi M, Wang S, Rehman AU, Li X. Tumor-associated macrophages and CD8+ T cells: dual players in the pathogenesis of HBV-related HCC. Front Immunol 2024; 15:1472430. [PMID: 39450177 PMCID: PMC11499146 DOI: 10.3389/fimmu.2024.1472430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 09/16/2024] [Indexed: 10/26/2024] Open
Abstract
HBV infection is a key risk factor for the development and progression of hepatocellular carcinoma (HCC), a highly invasive tumor, and is characterized by its persistent immunosuppressive microenvironment. This review provides an in-depth analysis of HBV-related HCC and explores the interactions between neutrophils, natural killer cells, and dendritic cells, examining their roles in regulating tumor-associated macrophages and CD8+ T cells and shaping the tumor microenvironment. Two critical players in the immunosuppressive milieu of HBV-related HCC are CD8+ T cells and tumor-associated macrophages (TAMs). The study explores how TAMs, initially recruited to combat infection, transform, adopting a tumor-promoting phenotype, turning against the body, promoting tumor cell proliferation, suppressing anti-tumor immunity, and assisting in the spread of cancer. Meanwhile, CD8+ T cells, crucial for controlling HBV infection, become dysfunctional and exhausted in response to persistent chronic viral inflammation. The review then dissects how TAMs manipulate this immune response, further depleting CD8+ T cell functions through mechanisms like arginine deprivation and creating hypoxic environments that lead to exhaustion. Finally, it explores the challenges and promising therapeutic avenues that target TAMs and CD8+ T cells, either separately or in combination with antiviral therapy and personalized medicine approaches, offering hope for improved outcomes in HBV-related HCC.
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Affiliation(s)
- Muhammad Naveed Khan
- Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Western (Chongqing) Collaborative Innovation Center for Intelligent Diagnostics and Digital Medicine, Chongqing, China
| | - Binli Mao
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Juan Hu
- Department of Clinical Laboratory Medicine, Suining Central Hospital, Suining, Sichuan, China
| | - Mengjia Shi
- Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shunyao Wang
- Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Adeel Ur Rehman
- Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaosong Li
- Clinical Molecular Medicine Testing Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Western (Chongqing) Collaborative Innovation Center for Intelligent Diagnostics and Digital Medicine, Chongqing, China
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Peng Y, Yang H, Chen Q, Jin H, Xue YH, Du MQ, Liu S, Yao SY. An angel or a devil? Current view on the role of CD8 + T cells in the pathogenesis of myasthenia gravis. J Transl Med 2024; 22:183. [PMID: 38378668 PMCID: PMC10877804 DOI: 10.1186/s12967-024-04965-7] [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: 12/13/2023] [Accepted: 02/07/2024] [Indexed: 02/22/2024] Open
Abstract
BACKGROUND Myasthenia gravis (MG) and the experimental autoimmune MG (EAMG) animal model are characterized by T-cell-induced and B-cell-dominated autoimmune diseases that affect the neuromuscular junction. Several subtypes of CD4+ T cells, including T helper (Th) 17 cells, follicular Th cells, and regulatory T cells (Tregs), contribute to the pathogenesis of MG. However, increasing evidence suggests that CD8+ T cells also play a critical role in the pathogenesis and treatment of MG. MAIN BODY Herein, we review the literature on CD8+ T cells in MG, focusing on their potential effector and regulatory roles, as well as on relevant evidence (peripheral, in situ, cerebrospinal fluid, and under different treatments), T-cell receptor usage, cytokine and chemokine expression, cell marker expression, and Treg, Tc17, CD3+CD8+CD20+ T, and CXCR5+ CD8+ T cells. CONCLUSIONS Further studies on CD8+ T cells in MG are necessary to determine, among others, the real pattern of the Vβ gene usage of autoantigen-specific CD8+ cells in patients with MG, real images of the physiology and function of autoantigen-specific CD8+ cells from MG/EAMG, and the subset of autoantigen-specific CD8+ cells (Tc1, Tc17, and IL-17+IFN-γ+CD8+ T cells). There are many reports of CD20-expressing T (or CD20 + T) and CXCR5+ CD8 T cells on autoimmune diseases, especially on multiple sclerosis and rheumatoid arthritis. Unfortunately, up to now, there has been no report on these T cells on MG, which might be a good direction for future studies.
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Affiliation(s)
- Yong Peng
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, 412000, Hunan, China.
- Department of Neurology, The Third Affiliated Hospital of Hunan University of Chinese Medicine, Zhuzhou, 412000, Hunan, China.
| | - Huan Yang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Quan Chen
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, 412000, Hunan, China
- Department of Neurology, The Third Affiliated Hospital of Hunan University of Chinese Medicine, Zhuzhou, 412000, Hunan, China
| | - Hong Jin
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, 412000, Hunan, China
- Department of Neurology, The Third Affiliated Hospital of Hunan University of Chinese Medicine, Zhuzhou, 412000, Hunan, China
| | - Ya-Hui Xue
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, 412000, Hunan, China
- Department of Neurology, The Third Affiliated Hospital of Hunan University of Chinese Medicine, Zhuzhou, 412000, Hunan, China
| | - Miao-Qiao Du
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, 412000, Hunan, China
- Department of Neurology, The Third Affiliated Hospital of Hunan University of Chinese Medicine, Zhuzhou, 412000, Hunan, China
| | - Shu Liu
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, 412000, Hunan, China
- Department of Neurology, The Third Affiliated Hospital of Hunan University of Chinese Medicine, Zhuzhou, 412000, Hunan, China
| | - Shun-Yu Yao
- Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, 412000, Hunan, China
- Department of Neurology, The Third Affiliated Hospital of Hunan University of Chinese Medicine, Zhuzhou, 412000, Hunan, China
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Cai Y, Ji H, Zhou X, Zhao K, Zhang X, Pan L, Shi R. Interleukin-21 modulates balance between regulatory T cells and T-helper 17 cells in chronic hepatitis B virus infection. BMC Infect Dis 2023; 23:719. [PMID: 37875903 PMCID: PMC10594809 DOI: 10.1186/s12879-023-08723-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 10/17/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND Chronic HBV infection is always accompanied by differences in the balance between regulatory T cells (Tregs) and T-helper 17 (Th17) cells in infection phases. IL-21 plays an important role in the progression of chronic HBV infection. Thus, the aim of our study was to investigate the role of the regulatory function of IL-21 in maintaining the balance between Tregs and Th17 cells in chronic HBV infection. METHODS Twenty-five chronic HBV-infected patients in the immune-tolerant (IT) phase and 23 chronic hepatitis B (CHB) patients were recruited in this study. Cytokines production was measured by ELISA. The mRNA expression levels were determined by qPCR. CD4+T cells were stimulated with or without IL-21. Tregs and Th17 cells were measured by flow cytometry. pSTAT3 and STAT3 expression was assessed by Western blotting. RESULTS The concentration of IL-21 in the serum of CHB were significantly higher than that in the serum from IT patients, and IL-21 and IL-21R levels in the PBMCs from CHB were higher than those from IT patients. IL-21 promoted Th17 cells differentiation and function but inhibited Treg cells differentiation and function by activating STAT3 signaling pathways, upregulating RORγt expression, downregulating Foxp3 expression, by increasing IL-17and IL-22 secretion, and decreasing TGF-β secretion in chronic HBV infection. The proportion of Tregs and TGF-β concentrations in CHB was significantly lower than that in IT patients. Furthermore, the percentage of Th17 cells and the IL-17 concentration in CHB was markedly higher than that in IT patients, causing a reduction in the Tregs/Th17 ratio in CHB patients. CONCLUSIONS Our results suggest that IL-21 may contribute to inflammation in chronic HBV infection by modulating the balance between Treg and Th17 cells.
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Affiliation(s)
- Yun Cai
- Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China
- Department of Gastroenterology Disease, The First People's Hospital of Jintan District, Changzhou, 213200, China
| | - Hailei Ji
- Department of Infections Disease, The Third People's Hospital of Zhenjiang, Zhenjiang, 212000, China
| | - Xin Zhou
- Department of Gastroenterology Disease, The First People's Hospital of Jintan District, Changzhou, 213200, China
| | - Kai Zhao
- Department of Gastroenterology Disease, The First People's Hospital of Jintan District, Changzhou, 213200, China
| | - Xiaoping Zhang
- Department of Gastroenterology Disease, The First People's Hospital of Jintan District, Changzhou, 213200, China
| | - Liang Pan
- Department of Gastroenterology Disease, The First People's Hospital of Jintan District, Changzhou, 213200, China
| | - Ruihua Shi
- Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, China.
- Department of Gastroenterology Disease, The Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China.
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9
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Zhou J, He X, Ou Y, Peng S, Li D, Zhou Q, Fu J, Long Y, Tan Y. Role of CXCR5 + CD8 + T cells in human hepatitis B virus infection. J Viral Hepat 2023; 30:638-645. [PMID: 37129474 DOI: 10.1111/jvh.13840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/05/2023] [Accepted: 04/15/2023] [Indexed: 05/03/2023]
Abstract
The replication of HBV in hepatocytes can be effectively inhibited by lifelong antiviral therapy. Because of the long-term presence of HBV reservoirs, the virus rebound frequently occurs once the treatment is stopped, which poses a considerable obstacle to the complete removal of the virus. In terms of gene composition, regulation of B cell action and function, CXCR5+ CD8+ T cells are similar to CXCR5+ CD4+ T follicular helper cells, while these cells are characterized by elevated programmed cell death 1 and cytotoxic-related proteins. CXCR5+ CD8+ T cells are strongly associated with progression in inflammatory and autoimmune diseases. In addition, CXCR5 expression on the surface of CD8+ T cells is mostly an indicator of memory stem cell-like failure in progenitor cells in cancer that are more responsive to immune checkpoint blocking therapy. Furthermore, the phenomena have also been demonstrated in some viral infections, highlighting the duality of the cellular immune response of CXCR5+ CD8+ T cells. This mini-review will focus on the function of CXCR5+ CD8+ T cells in HBV infection and discuss the function of these CD8+ T cells and the potential of associated co-stimulators or cytokines in HBV therapeutic strategies.
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Affiliation(s)
- Juan Zhou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Xiaojing He
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yangjing Ou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Shuang Peng
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Dan Li
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Qing Zhou
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Jingli Fu
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yunzhu Long
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Yingzheng Tan
- Department of Infectious Diseases, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
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10
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Khanam A, Ghosh A, Chua JV, Kottilil S. Blockade of CCR4 breaks immune tolerance in chronic hepatitis B patients by modulating regulatory pathways. J Transl Med 2023; 21:271. [PMID: 37081509 PMCID: PMC10120209 DOI: 10.1186/s12967-023-04104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/04/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Immunotargets including checkpoint inhibitors and toll-like receptor 8 agonists have recently gained attention for the recovery of hepatitis B virus (HBV)-specific T cell exhaustion in chronic hepatitis B(CHB). Chemokine receptors have a similar significant role during viral infections; however, their role in CHB remains poorly understood. Therefore, in this study we evaluated the role of chemokine receptor 4 (CCR4) in deriving immunosuppression during CHB. METHODS We characterized CCR4+CD8+ T cells in CHB and identified their involvement in immunosuppression. Further, we examined if CCR4 blockade with mogamulizumab antibody can recover the functional exhaustion in HBsAg-specific T cells. RESULTS CHB patients exhibit higher frequency of CCR4+CD8+ T cells that increase with higher HBsAg levels and fibrosis scores. In vitro, HBs antigen triggers CCR4 expression. These cells express multiple inhibitory receptors and exhibit immunosuppressive functions by producing excessive immunoregulatory cytokines IL-4, IL-5, IL-10 and TGF-β1. CCR4 Blockade significantly boosted HBsAg-specific antiviral-cytokine production(IFN-γ, TNF-α and IL-21) in T cells through enhancing their proliferation capacity and polarizing these cells towards T helper 1(Th1) and T follicular helper cells(TFH) in case of CD4 cells, and cytotoxic T cell 1(TC1) and cytotoxic T follicular(TCF) cells in case of CD8. Cytotoxic potential was improved, while no induction of immunosuppressive-cytokines was seen after anti-CCR4 treatment thereby eliminating the risk of treatment-induced immunosuppression. CCR4 blockade inhibited the development and effector function of Tregs by controlling their expansion and TGF-β1 production preventing Tregs-induced immunotolearance. CONCLUSIONS CCR4 blockade reconstitutes antiviral immune response in T cells and limits the immunosuppressive functions of Tregs, representing them as a promising immunotherapeutic target for functional cure of CHB.
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Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Alip Ghosh
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Joel V Chua
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
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11
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Dumolard L, Aspord C, Marche PN, Macek Jilkova Z. Immune checkpoints on T and NK cells in the context of HBV infection: Landscape, pathophysiology and therapeutic exploitation. Front Immunol 2023; 14:1148111. [PMID: 37056774 PMCID: PMC10086248 DOI: 10.3389/fimmu.2023.1148111] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
In hepatitis B virus (HBV) infection, the interplay between the virus and the host immune system is crucial in determining the pathogenesis of the disease. Patients who fail to mount a sufficient and sustained anti-viral immune response develop chronic hepatitis B (CHB). T cells and natural killer (NK) cells play decisive role in viral clearance, but they are defective in chronic HBV infection. The activation of immune cells is tightly controlled by a combination of activating and inhibitory receptors, called immune checkpoints (ICs), allowing the maintenance of immune homeostasis. Chronic exposure to viral antigens and the subsequent dysregulation of ICs actively contribute to the exhaustion of effector cells and viral persistence. The present review aims to summarize the function of various ICs and their expression in T lymphocytes and NK cells in the course of HBV infection as well as the use of immunotherapeutic strategies targeting ICs in chronic HBV infection.
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Affiliation(s)
- Lucile Dumolard
- University Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Team Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Institute for Advanced Biosciences, Grenoble, France
| | - Caroline Aspord
- University Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Team Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Institute for Advanced Biosciences, Grenoble, France
- R&D Laboratory, Etablissement Français du Sang Auvergne-Rhone-Alpes, Grenoble, France
| | - Patrice N. Marche
- University Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Team Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Institute for Advanced Biosciences, Grenoble, France
| | - Zuzana Macek Jilkova
- University Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Team Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Institute for Advanced Biosciences, Grenoble, France
- Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, Grenoble, France
- *Correspondence: Zuzana Macek Jilkova,
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12
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Murayama K, Ikegami I, Kamekura R, Sakamoto H, Yanagi M, Kamiya S, Sato T, Sato A, Shigehara K, Yamamoto M, Takahashi H, Takano KI, Ichimiya S. CD4+CD8+ T follicular helper cells regulate humoral immunity in chronic inflammatory lesions. Front Immunol 2022; 13:941385. [PMID: 36091071 PMCID: PMC9452889 DOI: 10.3389/fimmu.2022.941385] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/26/2022] [Indexed: 11/29/2022] Open
Abstract
T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses at the initial and recall phases. Recent studies have indicated the possible involvement of Tfh cells in the process of chronic inflammation. However, the functional role of Tfh cells in persistent immune settings remains unclear. Here, we report that CD4+CD8+ (double-positive, DP; CD3+CD4+CD8+CXCR5hiPD-1hi) Tfh cells, a subset of germinal-center-type Tfh cells, were abundantly present in the fibroinflammatory lesions of patients with immunoglobulin G4-related disease (IgG4-RD). Transcriptome analyses showed that these DP-Tfh cells in the lesions of IgG4-RD preferentially expressed signature genes characteristic of cytotoxic CD8+ T cells, such as Eomes, CRTAM, GPR56, and granzymes, in addition to CD70. Scatter diagram analyses to examine the relationships between tissue-resident lymphocytes and various clinical parameters revealed that the levels of DP-Tfh cells were inversely correlated to the levels of serum IgG4 and local IgG4-expressing (IgG4+) memory B cells (CD19+CD27+IgD-) in patients with IgG4-RD. Cell culture experiments using autologous tonsillar lymphocytes further suggested that DP-Tfh cells possess a poor B-cell helper function and instead regulate memory B cells. Since CD4+ (single positive, SP; CD3+CD4+CD8-CXCR5hiPD-1hi) Tfh cells differentiated into DP-Tfh cells under stimulation with IL-2 and IL-7 as assessed by in vitro experiments, these data imply that SP-Tfh cells are a possible origin of DP-Tfh cells under persistent inflammation. These findings highlight the potential feedback loop mechanism of Tfh cells in immune tolerance under chronic inflammatory conditions. Further studies on DP-Tfh cells may facilitate control of unresolved humoral responses in IgG4-RD pathological inflammation.
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Affiliation(s)
- Kosuke Murayama
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Otolaryngology and Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ippei Ikegami
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ryuta Kamekura
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Otolaryngology and Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Sakamoto
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Otolaryngology and Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiro Yanagi
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shiori Kamiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Taiki Sato
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akinori Sato
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Katsunori Shigehara
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Motohisa Yamamoto
- Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroki Takahashi
- Department of Clinical Immunology and Rheumatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ken-ichi Takano
- Department of Otolaryngology and Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shingo Ichimiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
- *Correspondence: Shingo Ichimiya,
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13
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Kramer KJ, Wilfong EM, Voss K, Barone SM, Shiakolas AR, Raju N, Roe CE, Suryadevara N, Walker LM, Wall SC, Paulo A, Schaefer S, Dahunsi D, Westlake CS, Crowe JE, Carnahan RH, Rathmell JC, Bonami RH, Georgiev IS, Irish JM. Single-cell profiling of the antigen-specific response to BNT162b2 SARS-CoV-2 RNA vaccine. Nat Commun 2022; 13:3466. [PMID: 35710908 PMCID: PMC9201272 DOI: 10.1038/s41467-022-31142-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 05/26/2022] [Indexed: 12/15/2022] Open
Abstract
RNA-based vaccines against SARS-CoV-2 have proven critical to limiting COVID-19 disease severity and spread. Cellular mechanisms driving antigen-specific responses to these vaccines, however, remain uncertain. Here we identify and characterize antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 using multiple single-cell technologies for in depth analysis of longitudinal samples from a cohort of healthy participants. Mass cytometry and unbiased machine learning pinpoint an expanding, population of antigen-specific memory CD4+ and CD8+ T cells with characteristics of follicular or peripheral helper cells. B cell receptor sequencing suggest progression from IgM, with apparent cross-reactivity to endemic coronaviruses, to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts. Responding lymphocyte populations correlate with eventual SARS-CoV-2 IgG, and a participant lacking these cell populations failed to sustain SARS-CoV-2-specific antibodies and experienced breakthrough infection. These integrated proteomic and genomic platforms identify an antigen-specific cellular basis of RNA vaccine-based immunity.
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Affiliation(s)
- Kevin J Kramer
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Vanderbilt Vaccine Center, Nashville, TN, 37232, USA
| | - Erin M Wilfong
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Human Immunology Discovery Initiative of the Vanderbilt Center for Immunobiology, Nashville, TN, 37232, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
| | - Kelsey Voss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Sierra M Barone
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Andrea R Shiakolas
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Vanderbilt Vaccine Center, Nashville, TN, 37232, USA
| | - Nagarajan Raju
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Vanderbilt Vaccine Center, Nashville, TN, 37232, USA
| | - Caroline E Roe
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | | | - Lauren M Walker
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Vanderbilt Vaccine Center, Nashville, TN, 37232, USA
| | - Steven C Wall
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Vanderbilt Vaccine Center, Nashville, TN, 37232, USA
| | - Ariana Paulo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Vanderbilt Vaccine Center, Nashville, TN, 37232, USA
| | - Samuel Schaefer
- Human Immunology Discovery Initiative of the Vanderbilt Center for Immunobiology, Nashville, TN, 37232, USA
| | - Debolanle Dahunsi
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Human Immunology Discovery Initiative of the Vanderbilt Center for Immunobiology, Nashville, TN, 37232, USA
| | - Camille S Westlake
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - James E Crowe
- Vanderbilt Vaccine Center, Nashville, TN, 37232, USA
- Human Immunology Discovery Initiative of the Vanderbilt Center for Immunobiology, Nashville, TN, 37232, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Vanderbilt Program in Computational Microbiology and Immunology, Nashville, TN, 37232, USA
| | | | - Jeffrey C Rathmell
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Human Immunology Discovery Initiative of the Vanderbilt Center for Immunobiology, Nashville, TN, 37232, USA.
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Vanderbilt Program in Computational Microbiology and Immunology, Nashville, TN, 37232, USA.
| | - Rachel H Bonami
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Human Immunology Discovery Initiative of the Vanderbilt Center for Immunobiology, Nashville, TN, 37232, USA.
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA.
- Vanderbilt Program in Computational Microbiology and Immunology, Nashville, TN, 37232, USA.
| | - Ivelin S Georgiev
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Vanderbilt Vaccine Center, Nashville, TN, 37232, USA.
- Human Immunology Discovery Initiative of the Vanderbilt Center for Immunobiology, Nashville, TN, 37232, USA.
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA.
- Vanderbilt Program in Computational Microbiology and Immunology, Nashville, TN, 37232, USA.
| | - Jonathan M Irish
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Human Immunology Discovery Initiative of the Vanderbilt Center for Immunobiology, Nashville, TN, 37232, USA.
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN, 37232, USA.
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Vanderbilt Program in Computational Microbiology and Immunology, Nashville, TN, 37232, USA.
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14
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Yan Y, Qiu Y, Davgadorj C, Zheng C. Novel Molecular Therapeutics Targeting Signaling Pathway to Control Hepatitis B Viral Infection. Front Cell Infect Microbiol 2022; 12:847539. [PMID: 35252042 PMCID: PMC8894711 DOI: 10.3389/fcimb.2022.847539] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
Numerous canonical cellular signaling pathways modulate hepatitis B virus (HBV) replication. HBV genome products are known to play a significant role in regulating these cellular pathways for the liver’s viral-related pathology and physiology and have been identified as the main factor in hepatocarcinogenesis. Signaling changes during viral replication ultimately affect cellular persistence, multiplication, migration, genome instability, and genome damage, leading to proliferation, evasion of apoptosis, block of differentiation, and immortality. Recent studies have documented that numerous signaling pathway agonists or inhibitors play an important role in reducing HBV replication in vitro and in vivo, and some have been used in phase I or phase II clinical trials. These optional agents as molecular therapeutics target cellular pathways that could limit the replication and transcription of HBV or inhibit the secretion of the small surface antigen of HBV in a signaling-independent manner. As principle-based available information, a combined strategy including antiviral therapy and immunomodulation will be needed to control HBV infection effectively. In this review, we summarize recent findings on interventions of molecular regulators in viral replication and the interactions of HBV proteins with the components of the various targeting cellular pathways, which may assist in designing novel agents to modulate signaling pathways to prevent HBV replication or carcinogenesis.
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Affiliation(s)
- Yan Yan
- Laboratory for Infection and Immunity, Hepatology Institute of Wuxi, The Fifth People’s Hospital of Wuxi, Affiliated Hospital of Jiangnan University, Wuxi, China
- *Correspondence: Yan Yan, ; Chunfu Zheng,
| | - Yuanwang Qiu
- Laboratory for Infection and Immunity, Hepatology Institute of Wuxi, The Fifth People’s Hospital of Wuxi, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Chantsalmaa Davgadorj
- Laboratory for Infection and Immunity, Hepatology Institute of Wuxi, The Fifth People’s Hospital of Wuxi, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Chunfu Zheng
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada
- *Correspondence: Yan Yan, ; Chunfu Zheng,
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