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1
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Martín P, Sánchez-Madrid F. T cells in cardiac health and disease. J Clin Invest 2025; 135:e185218. [PMID: 39817455 PMCID: PMC11735099 DOI: 10.1172/jci185218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025] Open
Abstract
Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. T lymphocytes are crucial components of the adaptive immune system that have emerged as key mediators in both cardiac health and the development and progression of CVD. This Review explores the diverse roles of T cell subsets, including Th1, Th17, γδ T cells, and Tregs, in myocardial inflammatory processes such as autoimmune myocarditis and myocardial infarction. We discuss the contribution of T cells to myocardial injury and remodeling, with emphasis on specific immune receptors, e.g., CD69, that have a critical role in regulating immune tolerance and maintaining the balance between T cell subsets in the heart. Additionally, we offer a perspective on recent advances in T cell-targeted therapies and their potential to modulate immune responses and improve clinical outcomes in patients with CVD and in heart transplant recipients. Understanding the intricate interplay between T cells and cardiovascular pathology is essential for developing novel immunotherapeutic strategies against CVD.
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Affiliation(s)
- Pilar Martín
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain
| | - Francisco Sánchez-Madrid
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain
- Department of Immunology, IIS Princesa, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain
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2
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Jin C, Li X, Zhang C. Expression of senescence-related CD161 promotes extranodal NK/T cell lymphoma by affecting T cell phenotype and cell cycle. Mol Med 2024; 30:230. [PMID: 39580409 PMCID: PMC11585959 DOI: 10.1186/s10020-024-00969-7] [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: 05/27/2024] [Accepted: 10/18/2024] [Indexed: 11/25/2024] Open
Abstract
PURPOSE The intention of this work is to probe the role of senescence-related gene CD161 in extranodal NK/T cell lymphoma (ENKTL). METHODS This study used H2O2 to establish three distinct in vitro oxidative stress aging models (NKL, SNT-8, and YT). Western blotting was employed to assess the levels of two iconic aging proteins, MMP1 and P53, and flow cytometry was utilized to investigate cell cycle and the expressions of CD4, CD8, and CD161. Cell viability was evaluated via the CCK-8 assay. The transcriptome analysis assessed the differential gene expression between the control and aging group of NKL. In vivo, we established a BALB/c mice aging tumor model. After 15 days, the mice were euthanized to harvest tumors. ELISA was employed to measure aging indicators in the mouse tissues. Flow cytometry was utilized to assess the levels of CD4, CD8, and CD161 in tumor samples. Hematoxylin-eosin (HE) staining was performed to evaluate the structure and cellular morphology of the tumor tissue. RESULTS In the NKL, SNT-8 and YT aging models, the levels of MMP1 and P53 proteins were significantly increased. Flow cytometry results indicated that all three cell types exhibited marked arrest in the G1 phase. Compared with the control group, the expressions of CD4 and CD161 in the aging group were significantly increased, while the expression of CD8 was decreased. Transcriptome analysis revealed 2,843 differentially expressed genes (DEGs) between the control and aging groups, with 2,060 up-regulated and 783 down-regulated genes identified. Following CD161 knockdown, cell viability of three cell types in the aging group was significantly reduced compared to the control group. The G1 phase of the cells was significantly interrupted. The expressions of CD4 and CD161 were significantly increased, and the expression of CD8 was decreased. However, in the aging + si-CD161 group, a partial alleviation of oxidative stress was observed with a reduction in CD161 expression levels. Animal experiments demonstrated that knockout of CD161 can inhibit tumor progression and partially mitigate oxidative stress. CONCLUSIONS CD161 may inhibit ENKTL tumor development by regulating cell cycle and T-cell phenotype.
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Affiliation(s)
- Chengxun Jin
- Department of Otolaryngology, The Second Hospital of Jilin University, No.4026, Yatai street, Nanguan District, Changchun, 130000, China
| | - Xin Li
- Department of Radiology, The Second Hospital of Jilin University, Changchun, 130000, China
| | - Chaohe Zhang
- Department of Tumor Hematology, The Second Hospital of Jilin University, No.4026, Yatai street, Nanguan District, Changchun, 130000, China.
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3
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Huang Y, Tian Z, Bi J. Intracellular checkpoints for NK cell cancer immunotherapy. Front Med 2024; 18:763-777. [PMID: 39340588 DOI: 10.1007/s11684-024-1090-6] [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: 02/08/2024] [Accepted: 05/17/2024] [Indexed: 09/30/2024]
Abstract
Natural killer (NK) cells are key innate immune lymphocytes, which play important roles against tumors. However, tumor-infiltrating NK cells are always hypofunctional/exhaustive. On the one hand, this state is contributed by context-dependent interactions between inhibitory NK cell checkpoint receptors and their ligands, which usually vary in different tumor types and stages during tumor development. On the other hand, the inhibitory functions of intracellular checkpoint molecules of NK cells are more similar across different tumor types, representing common mechanisms limiting the potential of NK cell therapy. In this review, representative NK cell intracellular checkpoint molecules in different aspects of NK cell biology were reviewed, and therapeutic potentials were discussed by targeting these molecules to promote antitumor NK cell therapy.
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Affiliation(s)
- Yingying Huang
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, 530021, China
- Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, 530021, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Key Laboratory of Colleges and Universities, Nanning, 530021, China
- Collaborative Innovation Center of Regenerative Medicine and Medical BioResource Development and Application, Guangxi Medical University, Nanning, 530021, China
| | - Zhigang Tian
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China
- Institute of Immunology, University of Science and Technology of China, Hefei, 230027, China
- Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Beijing, 100864, China
| | - Jiacheng Bi
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
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4
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Xu N, Meng X, Chu H, Yang Z, Jiao Y, Li Y. The prognostic significance of KLRB1 and its further association with immune cells in breast cancer. PeerJ 2023; 11:e15654. [PMID: 37520246 PMCID: PMC10373647 DOI: 10.7717/peerj.15654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 06/07/2023] [Indexed: 08/01/2023] Open
Abstract
Background Killer cell lectin-like receptor B1 (KLRB1) is an important member of the natural killer cell gene family. This study explored the potential value of KLRB1 as a breast cancer (BC) biomarker and its close association with the tumor immune microenvironment during the development of BC. Methods We examined the differential expression of KLRB1 in pan-cancer. Clinical and RNA-Seq data from BC samples were evaluated in The Cancer Genome Atlas (TCGA) and validated in Gene Expression Omnibus (GEO) datasets and by immunohistochemistry (IHC) staining. The relationship between KLRB1 and clinical parameters was explored through Chi-square tests. The diagnostic value of KLRB1 was evaluated using a receiver operating characteristic (ROC) curve. Survival analysis was tested by Kaplan-Meier curves to demonstrate the relationship between KLRB1 and survival. Univariable and multivariate cox regression analyses were carried out as well. The analysis of immune infiltration level and gene set enrichment analysis (GSEA) were conducted to examine KLRB1's mechanism during the progression of BC. We used the Tumor Immune Estimation Resource (TIMER), the Cancer Single-cell Expression Map (CancerSCEM) database, the Tumor Immune Single-cell Hub (TISCH) database, and the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) method to explore KLRB1's association with immune infiltration level and different quantitative distribution of immune cells. The relevant signaling pathways in BC associated with KLRB1 were identified using GSEA. Results The expression of KLRB1 was downregulated across the majority of cancers including BC. The lower KLRB1 expression group exhibited shorter relapse free survival (RFS) and overall survival (OS). IHC staining showed that KLRB1 staining was weaker in breast tumor tissues than in paratumors. Additionally, GSEA identified several pathway items distinctly enriched in BC. KLRB1 expression level was also positively related to the infiltrating number of immune cells in BC. Moreover, the CancerSCEM and TISCH databases as well as the CIBERSORT method demonstrated the close relationship between KLRB1 and immune cells, particularly macrophages. Conclusion Low KLRB1 expression was considered an independent prognostic biomarker and played an important role in the tumor immune microenvironment of BC patients.
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Affiliation(s)
- Ning Xu
- Department of Human Anatomy, Jilin University, Changchun, Jilin, China
| | - Xiangyu Meng
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Hongyu Chu
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Zhaoying Yang
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Youjun Li
- Department of Human Anatomy, Jilin University, Changchun, Jilin, China
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5
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Matsumoto A, Hiroi M, Mori K, Yamamoto N, Ohmori Y. Differential Anti-Tumor Effects of IFN-Inducible Chemokines CXCL9, CXCL10, and CXCL11 on a Mouse Squamous Cell Carcinoma Cell Line. Med Sci (Basel) 2023; 11:medsci11020031. [PMID: 37218983 DOI: 10.3390/medsci11020031] [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: 03/03/2023] [Revised: 04/11/2023] [Accepted: 04/23/2023] [Indexed: 05/24/2023] Open
Abstract
Chemokines are a group of cytokines involved in the mobilization of leukocytes, which play a role in host defense and a variety of pathological conditions, including cancer. Interferon (IFN)-inducible chemokines C-X-C motif ligand 9 (CXCL), CXCL10, and CXCL11 are anti-tumor chemokines; however, the differential anti-tumor effects of IFN-inducible chemokines are not completely understood. In this study, we investigated the anti-tumor effects of IFN-inducible chemokines by transferring chemokine expression vectors into a mouse squamous cell carcinoma cell line, SCCVII, to generate a cell line stably expressing chemokines and transplanted it into nude mice. The results showed that CXCL9- and CXCL11-expressing cells markedly inhibited tumor growth, whereas CXCL10-expressing cells did not inhibit growth. The NH2-terminal amino acid sequence of mouse CXCL10 contains a cleavage sequence by dipeptidyl peptidase 4 (DPP4), an enzyme that cleaves the peptide chain of chemokines. IHC staining indicated DPP4 expression in the stromal tissue, suggesting CXCL10 inactivation. These results suggest that the anti-tumor effects of IFN-inducible chemokines are affected by the expression of chemokine-cleaving enzymes in tumor tissues.
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Affiliation(s)
- Ari Matsumoto
- Division of Oral and Maxillofacial Surgery, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado 350-0283, Japan
| | - Miki Hiroi
- Division of Basic Biology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado 350-0283, Japan
| | - Kazumasa Mori
- Division of Oral and Maxillofacial Surgery, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado 350-0283, Japan
| | - Nobuharu Yamamoto
- Division of Oral and Maxillofacial Surgery, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado 350-0283, Japan
| | - Yoshihiro Ohmori
- Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado 350-0283, Japan
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6
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Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol 2023; 23:90-105. [PMID: 35637393 DOI: 10.1038/s41577-022-00732-1] [Citation(s) in RCA: 229] [Impact Index Per Article: 114.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2022] [Indexed: 02/04/2023]
Abstract
Great strides have been made in recent years towards understanding the roles of natural killer (NK) cells in immunity to tumours and viruses. NK cells are cytotoxic innate lymphoid cells that produce inflammatory cytokines and chemokines. By lysing transformed or infected cells, they limit tumour growth and viral infections. Whereas T cells recognize peptides presented by MHC molecules, NK cells display receptors that recognize stress-induced autologous proteins on cancer cells. At the same time, their functional activity is inhibited by MHC molecules displayed on such cells. The enormous potential of NK cells for immunotherapy for cancer is illustrated by their broad recognition of stressed cells regardless of neoantigen presentation, and enhanced activity against tumours that have lost expression of MHC class I owing to acquired resistance mechanisms. As a result, many efforts are under way to mobilize endogenous NK cells with therapeutics, or to provide populations of ex vivo-expanded NK cells as a cellular therapy, in some cases by equipping the NK cells with chimeric antigen receptors. Here we consider the key features that underlie why NK cells are emerging as important new additions to the cancer therapeutic arsenal.
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7
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Scur M, Parsons BD, Dey S, Makrigiannis AP. The diverse roles of C-type lectin-like receptors in immunity. Front Immunol 2023; 14:1126043. [PMID: 36923398 PMCID: PMC10008955 DOI: 10.3389/fimmu.2023.1126043] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 02/14/2023] [Indexed: 03/03/2023] Open
Abstract
Our understanding of the C-type lectin-like receptors (CTLRs) and their functions in immunity have continued to expand from their initial roles in pathogen recognition. There are now clear examples of CTLRs acting as scavenger receptors, sensors of cell death and cell transformation, and regulators of immune responses and homeostasis. This range of function reflects an extensive diversity in the expression and signaling activity between individual CTLR members of otherwise highly conserved families. Adding to this diversity is the constant discovery of new receptor binding capabilities and receptor-ligand interactions, distinct cellular expression profiles, and receptor structures and signaling mechanisms which have expanded the defining roles of CTLRs in immunity. The natural killer cell receptors exemplify this functional diversity with growing evidence of their activity in other immune populations and tissues. Here, we broadly review select families of CTLRs encoded in the natural killer cell gene complex (NKC) highlighting key receptors that demonstrate the complex multifunctional capabilities of these proteins. We focus on recent evidence from research on the NKRP1 family of CTLRs and their interaction with the related C-type lectin (CLEC) ligands which together exhibit essential immune functions beyond their defined activity in natural killer (NK) cells. The ever-expanding evidence for the requirement of CTLR in numerous biological processes emphasizes the need to better understand the functional potential of these receptor families in immune defense and pathological conditions.
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Affiliation(s)
- Michal Scur
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Brendon D Parsons
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Sayanti Dey
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Andrew P Makrigiannis
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
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8
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Taylor EB, George EM, Ryan MJ, Garrett MR, Sasser JM. Immunological comparison of pregnant Dahl salt-sensitive and Sprague-Dawley rats commonly used to model characteristics of preeclampsia. Am J Physiol Regul Integr Comp Physiol 2021; 321:R125-R138. [PMID: 34105357 PMCID: PMC8409910 DOI: 10.1152/ajpregu.00298.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 06/04/2021] [Accepted: 06/07/2021] [Indexed: 12/26/2022]
Abstract
The pregnant Dahl salt-sensitive (S) rat is an established preclinical model of superimposed spontaneous preeclampsia characterized by exacerbated hypertension, increased urinary protein excretion, and increased fetal demise. Because of the underlying immune system dysfunction present in preeclamptic pregnancies in humans, we hypothesized that the pregnant Dahl S rat would also have an altered immune status. Immune system activation was assessed during late pregnancy in the Dahl S model and compared with healthy pregnant Sprague-Dawley (SD) rats subjected to either a sham procedure or a procedure to reduce uterine perfusion pressure (RUPP). Circulating immunoglobulin and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA) and Milliplex bead assay, respectively, and percentages of circulating, splenic, and placental immune cells were determined using flow cytometry. The pregnant Dahl S rat exhibited an increase in CD4+ T cells, and specifically TNFα+CD4+ T cells, in the spleen compared with virgin Dahl S rats. The Dahl also had increased neutrophils and decreased B cells in the peripheral blood as compared with Dahl virgin rats. SD rats that received the RUPP procedure had increases in circulating monocytes and increased IFN-ɣ+CD4+ splenic T cells. Together these findings suggest that dysregulated T cell activity is an important factor in both the pregnant Dahl S rats and SD rats after the RUPP procedure.
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Affiliation(s)
- Erin B Taylor
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Eric M George
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - Michael J Ryan
- University of South Carolina School of Medicine, Columbia, South Carolina
- Columbia Veterans Affairs Medical Center, Columbia, South Carolina
| | - Michael R Garrett
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - Jennifer M Sasser
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
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9
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Formentini M, Navas A, Hassouneh F, Lopez-Sejas N, Alonso C, Tarazona R, Solana R, Pera A. Impact of CMV and age on T cell subsets defined by CD161, CD300a, and/or CD57 expression in healthy Andalusians. J Gerontol A Biol Sci Med Sci 2021; 76:1946-1953. [PMID: 33993242 DOI: 10.1093/gerona/glab140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Indexed: 11/14/2022] Open
Abstract
Immunosenescence affects innate and adaptive immunity impairing the response to pathogens and vaccines. Chronic infection with cytomegalovirus (CMV) has been shown to drive 'early immunosenescence' and can considerably impact both the function and phenotype of immune cells, especially T cells. We have previously shown that the expression of CD57, CD300a, and CD161 was differentially affected by age and chronic CMV infection, indicating that these markers are a hallmark of CMV infection and T cell ageing. The aim of this present study was to clarify whether these three markers define distinct T cell subpopulations with a specific functional and molecular signature. Specifically, we analyzed the effect of age and chronic CMV infection on the functionality of T cells according to CD161, CD300a, and CD57 expression. We found that these markers defined different T cell subsets, both at the phenotypic and functional levels. CD57 was the best biomarker for CD4+ T cell cytotoxicity and was a hallmark of CMV infection. CD300a+ T cells were heterogeneous and included different cell subsets. The population of CD161+ T cells dramatically decreased with age, independently of CMV infection, and represented a sign of age-associated immune system alterations. The latter could contribute to an increased risk of autoimmune disease and infection in older adults. Our results underline the importance of better understanding the factors involved in the immunosenescence process to be able to uncover new biomarkers and open new avenues for the investigation and development of novel age-related disease therapies.
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Affiliation(s)
- Martina Formentini
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain
| | - Ana Navas
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.,Immunology and Allergy service, Reina Sofia University Hospital, Córdoba, Spain
| | - Fakhri Hassouneh
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain
| | - Nelson Lopez-Sejas
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain
| | - Corona Alonso
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.,Immunology and Allergy service, Reina Sofia University Hospital, Córdoba, Spain
| | - Raquel Tarazona
- Immunology Unit, Department of Physiology, University of Extremadura, Cáceres, Spain
| | - Rafael Solana
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.,Immunology and Allergy service, Reina Sofia University Hospital, Córdoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
| | - Alejandra Pera
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
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10
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Ferez M, Knudson CJ, Lev A, Wong EB, Alves-Peixoto P, Tang L, Stotesbury C, Sigal LJ. Viral infection modulates Qa-1b in infected and bystander cells to properly direct NK cell killing. J Exp Med 2021; 218:e20201782. [PMID: 33765134 PMCID: PMC8006856 DOI: 10.1084/jem.20201782] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 01/13/2021] [Accepted: 02/19/2021] [Indexed: 11/12/2022] Open
Abstract
Natural killer (NK) cell activation depends on the signaling balance of activating and inhibitory receptors. CD94 forms inhibitory receptors with NKG2A and activating receptors with NKG2E or NKG2C. We previously demonstrated that CD94-NKG2 on NK cells and its ligand Qa-1b are important for the resistance of C57BL/6 mice to lethal ectromelia virus (ECTV) infection. We now show that NKG2C or NKG2E deficiency does not increase susceptibility to lethal ECTV infection, but overexpression of Qa-1b in infected cells does. We also demonstrate that Qa-1b is down-regulated in infected and up-regulated in bystander inflammatory monocytes and B cells. Moreover, NK cells activated by ECTV infection kill Qa-1b-deficient cells in vitro and in vivo. Thus, during viral infection, recognition of Qa-1b by activating CD94/NKG2 receptors is not critical. Instead, the levels of Qa-1b expression are down-regulated in infected cells but increased in some bystander immune cells to respectively promote or inhibit their killing by activated NK cells.
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Affiliation(s)
- Maria Ferez
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA
| | - Cory J. Knudson
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA
| | - Avital Lev
- Fox Chase Cancer Center, Philadelphia, PA
| | - Eric B. Wong
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA
| | - Pedro Alves-Peixoto
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Research Group in Biomaterials, Biodegradables and Biomimetics-Portugal Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Lingjuan Tang
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA
| | - Colby Stotesbury
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA
| | - Luis J. Sigal
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA
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11
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St-Pierre F, Bhatia S, Chandra S. Harnessing Natural Killer Cells in Cancer Immunotherapy: A Review of Mechanisms and Novel Therapies. Cancers (Basel) 2021; 13:1988. [PMID: 33924213 PMCID: PMC8074597 DOI: 10.3390/cancers13081988] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/01/2021] [Accepted: 04/16/2021] [Indexed: 12/15/2022] Open
Abstract
Natural killer (NK) cells are lymphocytes that are integral to the body's innate immunity, resulting in a rapid immune response to stressed or infected cells in an antigen-independent manner. The innate immune system plays an important role in the recognition of tumor-derived stress-related factors and is critical to subsequent adaptive immune responses against tumor antigens. The aim of this review is to discuss mechanisms by which tumor cells evade NK cells and to outline strategies that harness NK cells for cancer immunotherapy. We discuss strategies to relieve the exhausted state of NK cells, recent therapies focused on targeting NK-cell-specific activating and inhibitory receptors, the use of cytokines IL-2 and IL-15 to stimulate autologous or allogeneic NK cells, and ongoing trials exploring the use of genetically modified NK cells and chimeric antigen-receptor-modified NK (CAR-NK) cells.
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Affiliation(s)
- Frederique St-Pierre
- Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60208, USA;
| | - Shailender Bhatia
- Division of Medical Oncology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98195, USA;
| | - Sunandana Chandra
- Division of Hematology Oncology, Robert H. Lurie Comprehensive Cancer, Northwestern University, Chicago, IL 60208, USA
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12
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Araúzo-Bravo MJ, Delic D, Gerovska D, Wunderlich F. Protective Vaccination Reshapes Hepatic Response to Blood-Stage Malaria of Genes Preferentially Expressed by NK Cells. Vaccines (Basel) 2020; 8:vaccines8040677. [PMID: 33202767 PMCID: PMC7712122 DOI: 10.3390/vaccines8040677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/06/2020] [Accepted: 11/11/2020] [Indexed: 02/04/2023] Open
Abstract
The role of natural killer (NK) cells in the liver as first-line post infectionem (p.i.) effectors against blood-stage malaria and their responsiveness to protective vaccination is poorly understood. Here, we investigate the effect of vaccination on NK cell-associated genes induced in the liver by blood-stage malaria of Plasmodium chabaudi. Female Balb/c mice were vaccinated at weeks 3 and 1 before being infected with 106P. chabaudi-parasitized erythrocytes. Genes preferentially expressed by NK cells were investigated in livers of vaccination-protected and non-protected mice on days 0, 1, 4, 8, and 11 p.i. using microarrays, qRT-PCR, and chromosome landscape analysis. Blood-stage malaria induces expression of specific genes in the liver at different phases of infection, i.e., Itga1 in expanding liver-resident NK (lrNK) cells, Itga2 in immigrating conventional NK (cNK) cells; Eomes and Tbx21 encoding transcription factors; Ncr1, Tnfsf10, Prf1, Gzma, Gzmb, Gzmc, Gzmm, and Gzmk encoding cytolytic effectors; natural killer gene complex (NKC)-localized genes encoding the NK cell receptors KLRG1, KLRK1, KLRAs1, 2, 5, 7, KLRD1, KLRC1, KLRC3, as well as the three receptors KLRB1A, KLRB1C, KLRB1F and their potential ligands CLEC2D and CLEC2I. Vaccination enhances this malaria-induced expression of genes, but impairs Gzmm expression, accelerates decline of Tnfsf10 and Clec2d expression, whereas it accelerates increased expression of Clec2i, taking a very similar time course as that of genes encoding plasma membrane proteins of erythroblasts, whose malaria-induced extramedullary generation in the liver is known to be accelerated by vaccination. Collectively, vaccination reshapes the response of the liver NK cell compartment to blood-stage malaria. Particularly, the malaria-induced expansion of lrNK cells peaking on day 4 p.i. is highly significantly (p < 0.0001) reduced by enhanced immigration of peripheral cNK cells, and KLRB1F:CLEC2I interactions between NK cells and erythroid cells facilitate extramedullary erythroblastosis in the liver, thus critically contributing to vaccination-induced survival of otherwise lethal blood-stage malaria of P. chabaudi.
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Affiliation(s)
- Marcos J. Araúzo-Bravo
- Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastián, Spain;
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
- TransBioNet Thematic Network of Excellence for Transitional Bioinformatics, Barcelona Supercomputing Center, 08034 Barcelona, Spain
- Correspondence: (M.J.A.-B.); (D.D.); Tel.: +34-943006108 (M.J.A.-B.); +49-735154143839 (D.D.)
| | - Denis Delic
- Boeringer Ingelheim Pharma, 88400 Biberach, Germany
- Correspondence: (M.J.A.-B.); (D.D.); Tel.: +34-943006108 (M.J.A.-B.); +49-735154143839 (D.D.)
| | - Daniela Gerovska
- Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastián, Spain;
| | - Frank Wunderlich
- Department of Biology, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
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13
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Goldenson BH, Zhu H, Wang YM, Heragu N, Bernareggi D, Ruiz-Cisneros A, Bahena A, Ask EH, Hoel HJ, Malmberg KJ, Kaufman DS. Umbilical Cord Blood and iPSC-Derived Natural Killer Cells Demonstrate Key Differences in Cytotoxic Activity and KIR Profiles. Front Immunol 2020; 11:561553. [PMID: 33178188 PMCID: PMC7593774 DOI: 10.3389/fimmu.2020.561553] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 09/02/2020] [Indexed: 12/20/2022] Open
Abstract
Natural killer (NK) cells derived or isolated from different sources have been gaining in importance for cancer therapies. In this study, we evaluate and compare key characteristics between NK cells derived or isolated from umbilical cord blood, umbilical cord blood hematopoietic stem/progenitor cells, peripheral blood, and induced pluripotent stem cells (iPSCs). Specifically, we find CD56+ NK cells isolated and expanded directly from umbilical cord blood (UCB56) and NK cells derived from CD34+ hematopoietic stem/progenitors in umbilical cord blood (UCB34) differ in their expression of markers associated with differentiation including CD16, CD2, and killer Ig-like receptors (KIRs). UCB56-NK cells also displayed a more potent cytotoxicity compared to UCB34-NK cells. NK cells derived from iPSCs (iPSC-NK cells) were found to have variable KIR expression, with certain iPSC-NK cell populations expressing high levels of KIRs and others not expressing KIRs. Notably, KIR expression on UCB56 and iPSC-NK cells had limited effect on cytotoxic activity when stimulated by tumor target cells that express high levels of cognate HLA class I, suggesting that in vitro differentiation and expansion may override the KIR-HLA class I mediated inhibition when used across HLA barriers. Together our results give a better understanding of the cell surface receptor, transcriptional, and functional differences between NK cells present in umbilical cord blood and hematopoietic progenitor-derived NK cells which may prove important in selecting the most active NK cell populations for treatment of cancer or other therapies.
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Affiliation(s)
- Benjamin H Goldenson
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Huang Zhu
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - YunZu Michele Wang
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Naveen Heragu
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Davide Bernareggi
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Alessa Ruiz-Cisneros
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Andres Bahena
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Eivind Heggernes Ask
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Hanna Julie Hoel
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Karl-Johan Malmberg
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Dan S Kaufman
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CA, United States
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14
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Falco M, Pende D, Munari E, Vacca P, Mingari MC, Moretta L. Natural killer cells: From surface receptors to the cure of high-risk leukemia (Ceppellini Lecture). HLA 2020; 93:185-194. [PMID: 30828978 PMCID: PMC6767140 DOI: 10.1111/tan.13509] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 12/28/2022]
Abstract
Natural killer (NK) cells are innate immune effector cells involved in the first line of defense against viral infections and malignancies. In the last three decades, the identification of HLA class I‐specific inhibitory killer immunoglobulin‐like receptors (KIR) and of the main activating receptors has strongly improved our understanding of the mechanisms regulating NK cell functions. The increased knowledge on how NK cells discriminate healthy cells from damaged cells has made it possible to transfer basic research notions to clinical applications. Of particular relevance is the strong NK‐mediated anti‐leukemia effect in haploidentical hematopoietic stem cell transplantation to cure high‐risk leukemia.
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Affiliation(s)
- Michela Falco
- Laboratorio di Immunologia Clinica e Sperimentale, IRCCS Istituto G. Gaslini, Genoa, Italy
| | - Daniela Pende
- Laboratorio di Immunologia, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Enrico Munari
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy
| | - Paola Vacca
- Department of Immunology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Maria C Mingari
- Laboratorio di Immunologia, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.,Department of Experimental Medicine (DIMES) and CEBR, Università di Genova, Genoa, Italy
| | - Lorenzo Moretta
- Department of Immunology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
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15
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Abstract
The continuous interactions between host and pathogens during their coevolution have shaped both the immune system and the countermeasures used by pathogens. Natural killer (NK) cells are innate lymphocytes that are considered central players in the antiviral response. Not only do they express a variety of inhibitory and activating receptors to discriminate and eliminate target cells but they can also produce immunoregulatory cytokines to alert the immune system. Reciprocally, several unrelated viruses including cytomegalovirus, human immunodeficiency virus, influenza virus, and dengue virus have evolved a multitude of mechanisms to evade NK cell function, such as the targeting of pathways for NK cell receptors and their ligands, apoptosis, and cytokine-mediated signaling. The studies discussed in this article provide further insights into the antiviral function of NK cells and the pathways involved, their constituent proteins, and ways in which they could be manipulated for host benefit.
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Affiliation(s)
- Mathieu Mancini
- Department of Human Genetics, McGill University, Montreal, Quebec H3A 0C7, Canada;,
- McGill University Research Centre on Complex Traits, McGill University, Montreal, Quebec H3G 0B1, Canada
| | - Silvia M. Vidal
- Department of Human Genetics, McGill University, Montreal, Quebec H3A 0C7, Canada;,
- McGill University Research Centre on Complex Traits, McGill University, Montreal, Quebec H3G 0B1, Canada
- Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada
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16
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Wang H, Zhu N, Ye X, Wang L, Wang B, Shan W, Lai X, Tan Y, Fu S, Xiao H, Huang H. PTPN21-CDS long isoform inhibits the response of acute lymphoblastic leukemia cells to NK-mediated lysis via the KIR/HLA-I axis. J Cell Biochem 2020; 121:3298-3312. [PMID: 31898344 DOI: 10.1002/jcb.29601] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/11/2019] [Indexed: 12/11/2022]
Abstract
Protein tyrosine phosphatase non-receptor type 21 (PTPN21) is a member of the non-receptor tyrosine phosphatase family. We have found that PTPN21 is mutated in relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation. PTPN21 consists of three types of isoforms according to the length of the protein encoded. However, the roles of different isoforms in leukemic cells have not been elucidated. In the study, PTPN21 isoform constitution in five ALL cell lines were identified by transcriptome polymerase chain reaction combined with Sanger sequencing, and the relationship between PTPN21 isoforms and sensitivity to natural killer (NK) cells mediated killing in ALL cell lines were further assessed by knock-out of different isoforms of PTPN21 using CRISPR-Cas9 technique. Subsequently, we explored the functional mechanisms through RNA sequencing and confirmatory testing. The results showed that there was no significant change when all PTPN21 isoforms were knocked out in ALL cells, but the sensitivity of NALM6 cells with PTPN21-CDSlong knock-out (NALM6-PTPN21lk ) to NK-mediated killing was significantly increased. Whole transcriptome sequencing and further validation testing showed that human leukocyte antigen class I (HLA-I) molecules were significantly decreased, accompanied by a significantly downregulated expression of antigen presenting-related chaperones in NALM6-PTPN21lk cells. Our results uncovered a previously unknown mechanism that PTPN21-CDSlong and CDSshort isoforms may play opposite roles in NK-mediated killing in ALL cells, and showed that the endogenous PTPN21-CDSlong isoform inhibited ALL cells to NK cell-mediated lysis by regulating the KIR-HLA-I axis.
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Affiliation(s)
- Huafang Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China
| | - Ni Zhu
- Department of Hematology, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xiaohang Ye
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Limengmeng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China
| | - Binsheng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China
| | - Wei Shan
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China
| | - Xiaoyu Lai
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yamin Tan
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shan Fu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Haowen Xiao
- Department of Hematology, The Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Engineering Laboratory for Stem cell and Immunotherapy, Hangzhou, Zhejiang, China
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17
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Minetto P, Guolo F, Pesce S, Greppi M, Obino V, Ferretti E, Sivori S, Genova C, Lemoli RM, Marcenaro E. Harnessing NK Cells for Cancer Treatment. Front Immunol 2019; 10:2836. [PMID: 31867006 PMCID: PMC6908847 DOI: 10.3389/fimmu.2019.02836] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 11/18/2019] [Indexed: 12/12/2022] Open
Abstract
In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. NK cells are innate lymphocytes with an array of functional competences, including anti-cancer, anti-viral, and anti-graft-vs.-host disease potential. The intriguing idea of harnessing such potent innate immune system effectors for cancer treatment led to the development of clinical trials based on the adoptive therapy of NK cells or on the use of monoclonal antibodies targeting the main NK cell immune checkpoints. Indeed, checkpoint immunotherapy that targets inhibitory receptors of T cells, reversing their functional blocking, marked a breakthrough in anticancer therapy, opening new approaches for cancer immunotherapy and resulted in extensive research on immune checkpoints. However, the clinical efficacy of T cell-based immunotherapy presents a series of limitations, including the inability of T cells to recognize and kill HLA-Ineg tumor cells. For these reasons, new strategies for cancer immunotherapy are now focusing on NK cells. Blockade with NK cell checkpoint inhibitors that reverse their functional block may overcome the limitations of T cell-based immunotherapy, mainly against HLA-Ineg tumor targets. Here, we discuss recent anti-tumor approaches based on mAb-mediated blocking of immune checkpoints (either restricted to NK cells or shared with T cells), used either as a single agent or in combination with other compounds, that have demonstrated promising clinical responses in both solid tumors and hematological malignancies.
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Affiliation(s)
- Paola Minetto
- Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy.,Ospedale Policlinico San Martino IRCCS, Genova, Italy
| | - Fabio Guolo
- Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy.,Ospedale Policlinico San Martino IRCCS, Genova, Italy
| | - Silvia Pesce
- Department of Experimental Medicine, University of Genoa, Genova, Italy
| | - Marco Greppi
- Department of Experimental Medicine, University of Genoa, Genova, Italy.,Centre of Excellence for Biomedical Research, University of Genoa, Genova, Italy
| | - Valentina Obino
- Department of Experimental Medicine, University of Genoa, Genova, Italy.,Centre of Excellence for Biomedical Research, University of Genoa, Genova, Italy
| | - Elisa Ferretti
- Department of Experimental Medicine, University of Genoa, Genova, Italy.,Centre of Excellence for Biomedical Research, University of Genoa, Genova, Italy
| | - Simona Sivori
- Department of Experimental Medicine, University of Genoa, Genova, Italy.,Centre of Excellence for Biomedical Research, University of Genoa, Genova, Italy
| | - Carlo Genova
- Lung Cancer Unit, Ospedale Policlinico San Martino IRCCS, Genova, Italy
| | - Roberto Massimo Lemoli
- Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy.,Ospedale Policlinico San Martino IRCCS, Genova, Italy
| | - Emanuela Marcenaro
- Department of Experimental Medicine, University of Genoa, Genova, Italy.,Centre of Excellence for Biomedical Research, University of Genoa, Genova, Italy
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18
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Pende D, Falco M, Vitale M, Cantoni C, Vitale C, Munari E, Bertaina A, Moretta F, Del Zotto G, Pietra G, Mingari MC, Locatelli F, Moretta L. Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation. Front Immunol 2019; 10:1179. [PMID: 31231370 PMCID: PMC6558367 DOI: 10.3389/fimmu.2019.01179] [Citation(s) in RCA: 261] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 05/09/2019] [Indexed: 12/19/2022] Open
Abstract
Natural killer (NK) cells contribute to the first line of defense against viruses and to the control of tumor growth and metastasis spread. The discovery of HLA class I specific inhibitory receptors, primarily of killer Ig-like receptors (KIRs), and of activating receptors has been fundamental to unravel NK cell function and the molecular mechanisms of tumor cell killing. Stemmed from the seminal discoveries in early '90s, in which Alessandro Moretta was the major actor, an extraordinary amount of research on KIR specificity, genetics, polymorphism, and repertoire has followed. These basic notions on NK cells and their receptors have been successfully translated to clinical applications, primarily to the haploidentical hematopoietic stem cell transplantation to cure otherwise fatal leukemia in patients with no HLA compatible donors. The finding that NK cells may express the PD-1 inhibitory checkpoint, particularly in cancer patients, may allow understanding how anti-PD-1 therapy could function also in case of HLA class Ineg tumors, usually susceptible to NK-mediated killing. This, together with the synergy of therapeutic anti-checkpoint monoclonal antibodies, including those directed against NKG2A or KIRs, emerging in recent or ongoing studies, opened new solid perspectives in cancer therapy.
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Affiliation(s)
- Daniela Pende
- Laboratory of Immunology, Department of Integrated Oncological Therapies, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Michela Falco
- Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto G. Gaslini, Genoa, Italy
| | - Massimo Vitale
- Laboratory of Immunology, Department of Integrated Oncological Therapies, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Claudia Cantoni
- Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto G. Gaslini, Genoa, Italy
- Department of Experimental Medicine (DIMES), Center of Excellence for Biomedical Research, Università di Genova, Genoa, Italy
| | - Chiara Vitale
- Laboratory of Immunology, Department of Integrated Oncological Therapies, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Experimental Medicine (DIMES), Università di Genova, Genoa, Italy
| | - Enrico Munari
- Department of Pathology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy
| | - Alice Bertaina
- Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics Stanford School of Medicine, Stanford, CA, United States
| | - Francesca Moretta
- Department of Laboratory Medicine, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy
| | - Genny Del Zotto
- Core Facilities, Integrated Department of Services and Laboratories, IRCCS Istituto G. Gaslini, Genoa, Italy
| | - Gabriella Pietra
- Laboratory of Immunology, Department of Integrated Oncological Therapies, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Experimental Medicine (DIMES), Università di Genova, Genoa, Italy
| | - Maria Cristina Mingari
- Laboratory of Immunology, Department of Integrated Oncological Therapies, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Department of Experimental Medicine (DIMES), Center of Excellence for Biomedical Research, Università di Genova, Genoa, Italy
| | - Franco Locatelli
- Department of Oncohematology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Lorenzo Moretta
- Laboratory of Tumor Immunology, Department of Immunology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
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19
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Parham P, Guethlein LA. Genetics of Natural Killer Cells in Human Health, Disease, and Survival. Annu Rev Immunol 2018; 36:519-548. [PMID: 29394121 DOI: 10.1146/annurev-immunol-042617-053149] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Natural killer (NK) cells have vital functions in human immunity and reproduction. In the innate and adaptive immune responses to infection, particularly by viruses, NK cells respond by secreting inflammatory cytokines and killing infected cells. In reproduction, NK cells are critical for genesis of the placenta, the organ that controls the supply of oxygen and nutrients to the growing fetus. Controlling NK cell functions are interactions of HLA class I with inhibitory NK cell receptors. First evolved was the conserved interaction of HLA-E with CD94:NKG2A; later established were diverse interactions of HLA-A, -B, and -C with killer cell immunoglobulin-like receptors. Characterizing the latter interactions is rapid evolution, which distinguishes human populations and all species of higher primate. Driving this evolution are the different and competing selections imposed by pathogens on NK cell-mediated immunity and by the constraints of human reproduction on NK cell-mediated placentation. Promoting rapid evolution is independent segregation of polymorphic receptors and ligands throughout human populations.
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Affiliation(s)
- Peter Parham
- Department of Structural Biology and Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, California 94305, USA; ,
| | - Lisbeth A Guethlein
- Department of Structural Biology and Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, California 94305, USA; ,
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20
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Friede ME, Leibelt S, Dudziak D, Steinle A. Select Clr-g Expression on Activated Dendritic Cells Facilitates Cognate Interaction with a Minor Subset of Splenic NK Cells Expressing the Inhibitory Nkrp1g Receptor. THE JOURNAL OF IMMUNOLOGY 2017; 200:983-996. [DOI: 10.4049/jimmunol.1701180] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 11/13/2017] [Indexed: 11/19/2022]
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21
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Hassouneh F, Lopez-Sejas N, Campos C, Sanchez-Correa B, Tarazona R, Solana R, Pera A. Differential Effect of Cytomegalovirus Infection with Age on the Expression of CD57, CD300a, and CD161 on T-Cell Subpopulations. Front Immunol 2017. [PMID: 28626460 PMCID: PMC5454039 DOI: 10.3389/fimmu.2017.00649] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Immunosenescence is a progressive deterioration of the immune system with aging. It affects both innate and adaptive immunity limiting the response to pathogens and to vaccines. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, and its persistent infection results in functional and phenotypic changes to the T-cell repertoire, the aim of this study was to analyze the effect of CMV-seropositivity and aging on the expression of CD300a and CD161 inhibitory receptors, along with the expression of CD57 marker on CD4+, CD8+, CD8+CD56+ (NKT-Like) and CD4−CD8− (DN) T-cell subsets. Our results showed that, regardless of the T-cell subset, CD57−CD161−CD300a+ T-cells expand with age in CMV-seropositive individuals, whereas CD57−CD161+CD300a+ T-cells decrease. Similarly, CD57+CD161−CD300a+ T-cells expand with age in CMV-seropositive individuals in all subsets except in DN cells and CD57−CD161+CD300a− T-cells decrease in all T-cell subsets except in CD4+ T-cells. Besides, in young individuals, CMV latent infection associates with the expansion of CD57+CD161−CD300a+CD4+, CD57−CD161−CD300a+CD4+, CD57+CD161−CD300a+CD8+, CD57−CD161−CD300a+CD8+, CD57+CD161−CD300a+NKT-like, and CD57+CD161−CD300a+DN T-cells. Moreover, in young individuals, CD161 expression on T-cells is not affected by CMV infection. Changes of CD161 expression were only associated with age in the context of CMV latent infection. Besides, CD300a+CD57+CD161+ and CD300a−CD57+CD161+ phenotypes were not found in any of the T-cell subsets studied except in the DN subpopulation, indicating that in the majority of T-cells, CD161 and CD57 do not co-express. Thus, our results show that CMV latent infection impact on the immune system depends on the age of the individual, highlighting the importance of including CMV serology in any study regarding immunosenescence.
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Affiliation(s)
- Fakhri Hassouneh
- Maimonides Biomedicine Institute of Cordoba (IMIBIC), Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
| | - Nelson Lopez-Sejas
- Maimonides Biomedicine Institute of Cordoba (IMIBIC), Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
| | - Carmen Campos
- Maimonides Biomedicine Institute of Cordoba (IMIBIC), Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
| | | | - Raquel Tarazona
- Immunology Unit, Department of Physiology, University of Extremadura, Cáceres, Spain
| | - Rafael Solana
- Maimonides Biomedicine Institute of Cordoba (IMIBIC), Reina Sofia Hospital, University of Cordoba, Cordoba, Spain.,Immunology Unit, Department of Physiology, University of Extremadura, Cáceres, Spain
| | - Alejandra Pera
- Maimonides Biomedicine Institute of Cordoba (IMIBIC), Reina Sofia Hospital, University of Cordoba, Cordoba, Spain.,Division of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom
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Rutkowski E, Leibelt S, Born C, Friede ME, Bauer S, Weil S, Koch J, Steinle A. Clr-a: A Novel Immune-Related C-Type Lectin-like Molecule Exclusively Expressed by Mouse Gut Epithelium. THE JOURNAL OF IMMUNOLOGY 2016; 198:916-926. [PMID: 27956531 DOI: 10.4049/jimmunol.1600666] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 11/14/2016] [Indexed: 11/19/2022]
Abstract
The mouse gut epithelium represents a constitutively challenged environment keeping intestinal commensal microbiota at bay and defending against invading enteric pathogens. The complex immunoregulatory network of the epithelial barrier surveillance also involves NK gene complex (NKC)-encoded C-type lectin-like molecules such as NKG2D and Nkrp1 receptors. To our knowledge, in this study, we report the first characterization of the orphan C-type lectin-like molecule Clr-a encoded by the Clec2e gene in the mouse NKC. Screening of a panel of mouse tissues revealed that Clec2e transcripts are restricted to the gastrointestinal tract. Using Clr-a-specific mAb, we characterize Clr-a as a disulfide-linked homodimeric cell surface glycoprotein. Of note, a substantial fraction of Clr-a molecules are retained intracellularly, and analyses of Clr-a/Clr-f hybrids attribute intracellular retention to both the stalk region and parts of the cytoplasmic domain. Combining quantitative PCR analyses with immunofluorescence studies revealed exclusive expression of Clr-a by intestinal epithelial cells and crypt cells throughout the gut. Challenge with polyinosinic-polycytidylic acid results in a rapid and strong downregulation of intestinal Clr-a expression in contrast to the upregulation of Clr-f, a close relative of Clr-a, that also is specifically expressed by the intestinal epithelium and acts as a ligand of the inhibitory Nkrp1g receptor. Collectively, we characterize expression of the mouse NKC-encoded glycoprotein Clr-a as strictly associated with mouse intestinal epithelium. Downregulation upon polyinosinic-polycytidylic acid challenge and expression by crypt cells clearly distinguish Clr-a from the likewise intestinal epithelium-restricted Clr-f, pointing to a nonredundant function of these highly related C-type lectin-like molecules in the context of intestinal immunosurveillance.
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Affiliation(s)
- Emilia Rutkowski
- Institute for Molecular Medicine, Johann Wolfgang Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany
| | - Stefan Leibelt
- Institute for Molecular Medicine, Johann Wolfgang Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany
| | - Christina Born
- Institute for Molecular Medicine, Johann Wolfgang Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany
| | - Miriam E Friede
- Institute for Molecular Medicine, Johann Wolfgang Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany
| | - Stefan Bauer
- Institute for Immunology, Philipps University Marburg, 35043 Marburg, Germany
| | - Sandra Weil
- Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany; and.,Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany
| | - Joachim Koch
- Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany; and.,Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany
| | - Alexander Steinle
- Institute for Molecular Medicine, Johann Wolfgang Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany;
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23
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Li XP, Hu YH. CD94 of tongue sole Cynoglossus semilaevis binds a wide arrange of bacteria and possesses antibacterial activity. FISH & SHELLFISH IMMUNOLOGY 2016; 58:641-649. [PMID: 27720695 DOI: 10.1016/j.fsi.2016.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 10/01/2016] [Accepted: 10/03/2016] [Indexed: 06/06/2023]
Abstract
In this study, we examined the expression patterns and the functions of the tongue sole Cynoglossus semilaevis CD94, CsCD94. CsCD94 is composed of 209 amino acid residues and shares 43.0-50.2% overall identities with known teleost CD94 sequence. CsCD94 has a C-type lectin-like domain. Expression of CsCD94 occurred in multiple tissues and was upregulated during bacterial infection. Recombinant CsCD94 (rCsCD94) exhibited apparent binding and agglutinating activities against both Gram-positive and Gram-negative bacteria in a Ca2+-dependent manner. Treatment of bacteria with rCsCD94 enhanced phagocytosis of the bacteria by peripheral blood leukocytes. Furthermore, incubation of rCsCD94 with bacteria reduced the survival of the bacteria in vitro. Taken together, these results indicate that rCsCD94 is a key factor in the bactericidal and phagocytic effects of tongue sole, and reveal for the first time an essential role of fish CD94 in antibacterial immunity, thereby adding insight into the function of CD94.
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Affiliation(s)
- Xue-Peng Li
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yong-Hua Hu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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24
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Multi-functional lectin-like transcript-1: A new player in human immune regulation. Immunol Lett 2016; 177:62-9. [DOI: 10.1016/j.imlet.2016.07.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 07/05/2016] [Accepted: 07/07/2016] [Indexed: 12/31/2022]
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25
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Konduri V, Li D, Halpert MM, Liang D, Liang Z, Chen Y, Fisher WE, Paust S, Levitt JM, Yao QC, Decker WK. Chemo-immunotherapy mediates durable cure of orthotopic K rasG12D/p53 -/- pancreatic ductal adenocarcinoma. Oncoimmunology 2016; 5:e1213933. [PMID: 27757308 DOI: 10.1080/2162402x.2016.1213933] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 07/05/2016] [Accepted: 07/06/2016] [Indexed: 12/30/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, exhibiting a five-year overall survival (OS) of only 7% despite aggressive standard of care. Recent advances in immunotherapy suggest potential application of immune-based treatment approaches to PDAC. To explore this concept further, we treated orthotopically established K-rasG12D/p53-/- PDAC tumors with gemcitabine and a cell-based vaccine previously shown to generate durable cell-mediated (TH1) immunity. Tumor progression was monitored by IVIS. The results indicated that the combination of chemotherapy and dendritic cell (DC) vaccination was effective in eliminating tumor, preventing metastasis and recurrence, and significantly enhancing OS. No animal that received the combination therapy relapsed, while mice that received gemcitabine-only or vaccine-only regimens relapsed and progressed. Analysis of circulating PBMC demonstrated that mice receiving the combination therapy exhibited significantly elevated levels of CD8+IFNγ+CCR7+NK1.1+ T-cells with significantly reduced levels of exhausted GITR+CD8+ T-cells after the cessation of treatment. Retro-orbital tumor re-challenge of surviving animals at six-months post-treatment demonstrated durable antitumor immunity only among mice that had received the combination therapy. CD8+ splenocytes derived from surviving mice that had received the combination therapy were sorted into NK1.1pos and NK1.1neg populations and adoptively transferred into naive recipients. Transfer of only 1,500 CD8+NK1.1pos T-cells was sufficient to mediate tumor rejection whereas transfer of 1,500 CD8+NK1.1neg T-cells imparted only minimal effects. The data suggest that addition of a TH1 DC vaccine regimen as an adjuvant to existing therapies can mediate eradication of tumors and offer durable protection against PDAC.
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Affiliation(s)
- Vanaja Konduri
- Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX, USA
| | - Dali Li
- Michael E. Debakey Department of Surgery, Baylor College of Medicine , Houston, TX, USA
| | - Matthew M Halpert
- Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX, USA
| | - Dan Liang
- Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX, USA
| | - Zhengdong Liang
- Michael E. Debakey Department of Surgery, Baylor College of Medicine , Houston, TX, USA
| | - Yunyu Chen
- Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX, USA
| | - William E Fisher
- Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Elkins Pancreas Center, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Silke Paust
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Center for Human Immunobiology, Baylor College of Medicine, Houston, TX, USA
| | - Jonathan M Levitt
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA
| | - Qizhi Cathy Yao
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Elkins Pancreas Center, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX, USA
| | - William K Decker
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA
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26
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Fišerová A, Richter J, Čapková K, Bieblová J, Mikyšková R, Reiniš M, Indrová M. Resistance of novel mouse strains different in MHC class I and the NKC domain to the development of experimental tumors. Int J Oncol 2016; 49:763-72. [PMID: 27279019 DOI: 10.3892/ijo.2016.3561] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 04/18/2016] [Indexed: 11/05/2022] Open
Abstract
To elucidate the immunological mechanisms critical for tumor progression, we bred novel mouse strains, different in the NKC and H-2D domains. We used inbreeding to generate hybrids of Balb/c and C57BL/6 of stable H-2Db+d-NK1.1neg and H-2Db-d+NK1.1high phenotypes. We analyzed the growth of three established MHC class I-deficient tumor cell lines: TC-1/A9 tumor (HPV-associated) and B16F10 melanoma, both syngeneic to C57BL/6, and the MCB8 (3-methycholanthrene-induced tumor) syngeneic to Balb/c. Furthermore, we induced colorectal carcinoma by azoxymethane-DSS treatment to test the susceptibility to chemically-induced primary cancer. We found that the novel strains spontaneously regressed the tumor transplants syngeneic to both Balb/c (MCB8) and C57BL/6 (B16F10 and TC-1/A9) mice. The H2-Db+d-NK1.1neg, but not the H2-Db-d+NK1.1high strain was also highly resistant to chemically-induced colorectal cancer in comparison to the parental mice. The immune changes during TC-1/A9 cancer development involved an increase of the NK cell distribution in the peripheral blood and spleen along with higher expression of NKG2D activation antigen; this was in correlation with the time-dependent rise of cytotoxic activity in comparison to C57BL/6 mice. The TC-1/A9 cancer regression was accompanied by higher proportion of B cells in the spleen and B220+/CD86+ activated antigen-presenting B cells distributed in the lymphoid organs, as well as in the periphery. The changes in the T-cell population were represented mainly by the prevalence of T helper cells reflected by grown CD4/CD8 ratio, most prominent in the b+d-NK1.1neg strain. The results of the present study imply usefulness of the two novel mouse strains as an experimental model for further studies of tumor resistance mechanisms.
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Affiliation(s)
- Anna Fišerová
- Department of Health Care Disciplines and Population Protection, Czech Technical University in Prague, Faculty of Biomedical Engineering, Sportovců 2311, 27201 Kladno, Czech Republic
| | - Jan Richter
- Department of Health Care Disciplines and Population Protection, Czech Technical University in Prague, Faculty of Biomedical Engineering, Sportovců 2311, 27201 Kladno, Czech Republic
| | - Katarína Čapková
- Department of Health Care Disciplines and Population Protection, Czech Technical University in Prague, Faculty of Biomedical Engineering, Sportovců 2311, 27201 Kladno, Czech Republic
| | - Jana Bieblová
- Department of Transgenic Models of Diseases, Institute of Molecular Genetics of the AS CR, v.v.i., Prague, Czech Centre for Phenogenomics, Division BIOCEV, Průmyslová 595, 252 42 Vestec, Czech Republic
| | - Romana Mikyšková
- Department of Transgenic Models of Diseases, Institute of Molecular Genetics of the AS CR, v.v.i., Prague, Czech Centre for Phenogenomics, Division BIOCEV, Průmyslová 595, 252 42 Vestec, Czech Republic
| | - Milan Reiniš
- Department of Transgenic Models of Diseases, Institute of Molecular Genetics of the AS CR, v.v.i., Prague, Czech Centre for Phenogenomics, Division BIOCEV, Průmyslová 595, 252 42 Vestec, Czech Republic
| | - Marie Indrová
- Department of Transgenic Models of Diseases, Institute of Molecular Genetics of the AS CR, v.v.i., Prague, Czech Centre for Phenogenomics, Division BIOCEV, Průmyslová 595, 252 42 Vestec, Czech Republic
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27
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Guethlein LA, Norman PJ, Hilton HG, Parham P. Co-evolution of MHC class I and variable NK cell receptors in placental mammals. Immunol Rev 2016; 267:259-82. [PMID: 26284483 DOI: 10.1111/imr.12326] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Shaping natural killer (NK) cell functions in human immunity and reproduction are diverse killer cell immunoglobulin-like receptors (KIRs) that recognize polymorphic MHC class I determinants. A survey of placental mammals suggests that KIRs serve as variable NK cell receptors only in certain primates and artiodactyls. Divergence of the functional and variable KIRs in primates and artiodactyls predates placental reproduction. Among artiodactyls, cattle but not pigs have diverse KIRs. Catarrhine (humans, apes, and Old World monkeys) and platyrrhine (New World monkeys) primates, but not prosimians, have diverse KIRs. Platyrrhine and catarrhine systems of KIR and MHC class I are highly diverged, but within the catarrhines, a stepwise co-evolution of MHC class I and KIR is discerned. In Old World monkeys, diversification focuses on MHC-A and MHC-B and their cognate lineage II KIR. With evolution of C1-bearing MHC-C from MHC-B, as informed by orangutan, the focus changes to MHC-C and its cognate lineage III KIR. Evolution of C2 from C1 and fixation of MHC-C drove further elaboration of MHC-C-specific KIR, as exemplified by chimpanzee. In humans, the evolutionary trajectory changes again. Emerging from reorganization of the KIR locus and selective attenuation of KIR avidity for MHC class I are the functionally distinctive KIR A and KIR B haplotypes.
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Affiliation(s)
- Lisbeth A Guethlein
- Department of Structural Biology and Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, USA
| | - Paul J Norman
- Department of Structural Biology and Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, USA
| | - Hugo G Hilton
- Department of Structural Biology and Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, USA
| | - Peter Parham
- Department of Structural Biology and Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, USA
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28
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Turowski V, Sperling B, Hanczaruk MA, Göbel TW, Viertlboeck BC. Chicken TREM-B1, an Inhibitory Ig-Like Receptor Expressed on Chicken Thrombocytes. PLoS One 2016; 11:e0151513. [PMID: 26967520 PMCID: PMC4788293 DOI: 10.1371/journal.pone.0151513] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 02/29/2016] [Indexed: 12/22/2022] Open
Abstract
Triggering receptors expressed on myeloid cells (TREM) form a multigene family of immunoregulatory Ig-like receptors and play important roles in the regulation of innate and adaptive immunity. In chickens, three members of the TREM family have been identified on chromosome 26. One of them is TREM-B1 which possesses two V-set Ig-domains, an uncharged transmembrane region and a long cytoplasmic tail with one ITSM and two ITIMs indicating an inhibitory function. We generated specific monoclonal antibodies by immunizing a Balb/c mouse with a TREM-B1-FLAG transfected BWZ.36 cell line and tested the hybridoma supernatants on TREM-B1-FLAG transfected 2D8 cells. We obtained two different antibodies specific for TREM-B1, mab 7E8 (mouse IgG1) and mab 1E9 (mouse IgG2a) which were used for cell surface staining. Single and double staining of different tissues, including whole blood preparations, revealed expression on thrombocytes. Next we investigated the biochemical properties of TREM-B1 by using the specific mab 1E9 for immunoprecipitation of either lysates of surface biotinylated peripheral blood cells or stably transfected 2D8 cells. Staining with streptavidin coupled horse radish peroxidase revealed a glycosylated monomeric protein of about 50 kDa. Furthermore we used the stably transfected 2D8 cell line for analyzing the cytoplasmic tyrosine based signaling motifs. After pervanadate treatment, we detected phosphorylation of the tyrosine residues and subsequent recruitment of the tyrosine specific protein phosphatase SHP-2, indicating an inhibitory potential for TREM-B1. We also showed the inhibitory effect of TREM-B1 in chicken thrombocytes using a CD107 degranulation assay. Crosslinking of TREM-B1 on activated primary thrombocytes resulted in decreased CD107 surface expression of about 50-70%.
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Affiliation(s)
- Vanessa Turowski
- Institute for Animal Physiology, Department for Veterinary Sciences, University of Munich, Munich, Germany
| | - Beatrice Sperling
- Institute for Animal Physiology, Department for Veterinary Sciences, University of Munich, Munich, Germany
| | - Matthias A. Hanczaruk
- Institute for Animal Physiology, Department for Veterinary Sciences, University of Munich, Munich, Germany
| | - Thomas W. Göbel
- Institute for Animal Physiology, Department for Veterinary Sciences, University of Munich, Munich, Germany
| | - Birgit C. Viertlboeck
- Institute for Animal Physiology, Department for Veterinary Sciences, University of Munich, Munich, Germany
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29
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Natural killer cells in the innate immunity network of atherosclerosis. Immunol Lett 2015; 168:51-7. [DOI: 10.1016/j.imlet.2015.09.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 08/20/2015] [Accepted: 09/07/2015] [Indexed: 12/11/2022]
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30
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Crouse J, Xu HC, Lang PA, Oxenius A. NK cells regulating T cell responses: mechanisms and outcome. Trends Immunol 2015; 36:49-58. [PMID: 25432489 DOI: 10.1016/j.it.2014.11.001] [Citation(s) in RCA: 161] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Revised: 10/28/2014] [Accepted: 11/06/2014] [Indexed: 12/11/2022]
Abstract
Natural killer (NK) cells are important innate effectors in immunity. NK cells also have a role in the regulation of the adaptive immune response, and have been shown, in different contexts, to stimulate or inhibit T cell responses. Recent findings have expanded our understanding of the mechanisms underlying this regulation, revealing that regulation by NK cells can result from both direct interactions between NK cells and T cells, as well as indirectly, involving interactions with antigen presenting cells and the impact of NK cells on infected cells and pathogen load. We review these recent findings here, and outline emerging principles of how this regulation influences the overall outcome of adaptive immunity in infection and disease.
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31
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HERNYCHOVÁ L, MRÁZEK H, IVANOVA L, KUKAČKA Z, CHMELÍK J, NOVÁK P. Recombinant Expression, In Vitro Refolding and Characterizing Disulfide Bonds of a Mouse Inhibitory C-Type Lectin-Like Receptor Nkrp1b. Physiol Res 2015; 64:S85-93. [DOI: 10.33549/physiolres.933136] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
As a part of the innate immunity, NK (Natural Killer) cells provide an early immune response to different stimuli, e.g. viral infections and tumor growths. However, their functions are more complex; they play an important role in reproduction, alloimmunity, autoimmunity and allergic diseases. NK cell activities require an intricate system of regulation that is ensured by many different receptors on a cell surface which integrate signals from interacting cells and soluble factors. One way to understand NK cell biology is through the structure of NK receptors, which can reveal ligand binding conditions. We present a modified protocol for recombinant expression in Escherichia coli and in vitro refolding of the ligand-binding domain of the inhibitory Nkrp1b (SJL/J) protein. Nkrp1b identity and folding was confirmed using mass spectrometry (accurate mass of the intact protein and evaluation of disulfide bonds) and one-dimensional nuclear magnetic resonance spectroscopy. The intention is to provide the basis for conducting structural studies of the inhibitory Nkrp1b protein, since only the activating Nkrp1a receptor structure is known.
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Affiliation(s)
- L. HERNYCHOVÁ
- Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | | | | | | | | | - P. NOVÁK
- Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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32
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Biron CA, Tarrio ML. Immunoregulatory cytokine networks: 60 years of learning from murine cytomegalovirus. Med Microbiol Immunol 2015; 204:345-54. [PMID: 25850988 DOI: 10.1007/s00430-015-0412-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 03/23/2015] [Indexed: 10/23/2022]
Abstract
Innate immunity defends against infection but also mediates immunoregulatory effects shaping innate and adaptive responses. Studies of murine cytomegalovirus (MCMV) infections have helped elucidate the mechanisms inducing, as well as the elicited soluble and cellular networks contributing to, innate immunity. Specialized receptors are engaged by infection-induced structures to stimulate production of key innate cytokines. These then stimulate cytokine and cellular responses such as activation of natural killer (NK) cells to mediate elevated killing by type 1 interferon (IFN) and/or to produce the pro-inflammatory and antiviral cytokine IFN-γ by interleukin 12 (IL-12). An inter-systemic loop, with IL-6 inducing glucocorticoid release, negatively regulates these early cytokine responses. As infections advance into periods of overlapping innate and adaptive responses, however, the cells are intrinsically conditioned to modify the biological effects of exposure to individual cytokines. Some pathways are turned off to inhibit an existing, whereas others are broadened for acquisition of a new, response function. Remarkably, extended NK cell proliferation during MCMV infection is associated with epigenetic modifications shifting the state of the inhibitory cytokine IL-10 gene from closed to open and results in their becoming equipped to produce this cytokine. When induced, NK cell IL-10 negatively regulates the magnitude of adaptive responses to protect against immune pathology. Thus, innate immunoregulatory cytokine networks are integral to pro-inflammatory and defense functions, but responding cells have the flexibility to undergo cell intrinsic conditioning with changing network characteristics to result in a new negative immunoregulatory function, and consequently, both promote beneficial and limit detrimental immune responses.
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Affiliation(s)
- Christine A Biron
- Department of Molecular Microbiology and Immunology, The Division of Biology and Medicine and The Warren Alpert Medical School, Brown University, 171 Meeting Street, Providence, RI, 02912, USA,
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33
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The mouse NKR-P1B:Clr-b recognition system is a negative regulator of innate immune responses. Blood 2015; 125:2217-27. [PMID: 25612621 DOI: 10.1182/blood-2014-02-556142] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 01/06/2015] [Indexed: 12/11/2022] Open
Abstract
NKR-P1B is a homodimeric type II transmembrane C-type lectinlike receptor that inhibits natural killer (NK) cell function upon interaction with its cognate C-type lectin-related ligand, Clr-b. The NKR-P1B:Clr-b interaction represents a major histocompatibility complex class I (MHC-I)-independent missing-self recognition system that monitors cellular Clr-b levels. We have generated NKR-P1B(B6)-deficient (Nkrp1b(-/-)) mice to study the role of NKR-P1B in NK cell development and function in vivo. NK cell inhibition by Clr-b is abolished in Nkrp1b(-/-) mice, confirming the inhibitory nature of NKR-P1B(B6). Inhibitory receptors also promote NK cell tolerance and responsiveness to stimulation; hence, NK cells expressing NKR-P1B(B6) and Ly49C/I display augmented responsiveness to activating signals vs NK cells expressing either or none of the receptors. In addition, Nkrp1b(-/-) mice are defective in rejecting cells lacking Clr-b, supporting a role for NKR-P1B(B6) in MHC-I-independent missing-self recognition of Clr-b in vivo. In contrast, MHC-I-dependent missing-self recognition is preserved in Nkrp1b(-/-) mice. Interestingly, spontaneous myc-induced B lymphoma cells may selectively use NKR-P1B:Clr-b interactions to escape immune surveillance by wild-type, but not Nkrp1b(-/-), NK cells. These data provide direct genetic evidence of a role for NKR-P1B in NK cell tolerance and MHC-I-independent missing-self recognition.
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34
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Mitchell RA, Yaddanapudi K. Stromal-dependent tumor promotion by MIF family members. Cell Signal 2014; 26:2969-78. [PMID: 25277536 PMCID: PMC4293307 DOI: 10.1016/j.cellsig.2014.09.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 09/23/2014] [Indexed: 12/25/2022]
Abstract
Solid tumors are composed of a heterogeneous population of cells that interact with each other and with soluble and insoluble factors that, when combined, strongly influence the relative proliferation, differentiation, motility, matrix remodeling, metabolism and microvessel density of malignant lesions. One family of soluble factors that is becoming increasingly associated with pro-tumoral phenotypes within tumor microenvironments is that of the migration inhibitory factor family which includes its namesake, MIF, and its only known family member, D-dopachrome tautomerase (D-DT). This review seeks to highlight our current understanding of the relative contributions of a variety of immune and non-immune tumor stromal cell populations and, within those contexts, will summarize the literature associated with MIF and/or D-DT.
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Affiliation(s)
- Robert A Mitchell
- JG Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY 40202, United States.
| | - Kavitha Yaddanapudi
- JG Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY 40202, United States
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35
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Fergusson JR, Smith KE, Fleming VM, Rajoriya N, Newell EW, Simmons R, Marchi E, Björkander S, Kang YH, Swadling L, Kurioka A, Sahgal N, Lockstone H, Baban D, Freeman GJ, Sverremark-Ekström E, Davis MM, Davenport MP, Venturi V, Ussher JE, Willberg CB, Klenerman P. CD161 defines a transcriptional and functional phenotype across distinct human T cell lineages. Cell Rep 2014; 9:1075-88. [PMID: 25437561 PMCID: PMC4250839 DOI: 10.1016/j.celrep.2014.09.045] [Citation(s) in RCA: 231] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 08/28/2014] [Accepted: 09/24/2014] [Indexed: 11/20/2022] Open
Abstract
The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCRγδ+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage.
CD161 expression defines specific T cell subsets, including CD8+, CD4+, and TCRγδ+ CD161-expressing lymphocytes possess a conserved transcriptional signature CD161-expressing lymphocytes display a shared innate response to IL-12+18 CD161 can act as a costimulatory receptor
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Affiliation(s)
- Joannah R Fergusson
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Kira E Smith
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Vicki M Fleming
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK; Department of Microbiology and Infectious Disease, Oxford University Hospitals NHS Trust, Oxford OX3 9DU, UK
| | - Neil Rajoriya
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Evan W Newell
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA; Agency for Science, Technology and Research (A(∗)STAR), Singapore Immunology Network (SIgN), Singapore 138632, Singapore
| | - Ruth Simmons
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Emanuele Marchi
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Sophia Björkander
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden
| | - Yu-Hoi Kang
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Leo Swadling
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Ayako Kurioka
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Natasha Sahgal
- Bioinformatics and Statistical Genetics Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Helen Lockstone
- Bioinformatics and Statistical Genetics Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Dilair Baban
- Bioinformatics and Statistical Genetics Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Gordon J Freeman
- Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Eva Sverremark-Ekström
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden
| | - Mark M Davis
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| | - Miles P Davenport
- Department of Haematology, Prince of Wales Hospital, Kensington, NSW NS2 2052, Australia
| | - Vanessa Venturi
- Department of Haematology, Prince of Wales Hospital, Kensington, NSW NS2 2052, Australia
| | - James E Ussher
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK; Department of Microbiology and Immunology, University of Otago, Dunedin 9054, New Zealand
| | - Christian B Willberg
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK; NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9TU, UK.
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Watzl C, Urlaub D, Fasbender F, Claus M. Natural killer cell regulation - beyond the receptors. F1000PRIME REPORTS 2014; 6:87. [PMID: 25374665 PMCID: PMC4191275 DOI: 10.12703/p6-87] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Natural killer (NK) cells are lymphocytes that are important for early and effective immune responses against infections and cancer. In the last 40 years, many receptors, their corresponding ligands and signaling pathways that regulate NK cell functions have been identified. However, we now know that additional processes, such as NK cell education, differentiation and also the formation of NK cell memory, have a great impact on the reactivity of these cells. Here, we summarize the current knowledge about these modulatory processes.
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Affiliation(s)
- Carsten Watzl
- IfADo - Leibniz Research Centre for Working Environment and Human Factors Ardeystrasse 67, 44139 Dortmund Germany
| | - Doris Urlaub
- IfADo - Leibniz Research Centre for Working Environment and Human Factors Ardeystrasse 67, 44139 Dortmund Germany
| | - Frank Fasbender
- IfADo - Leibniz Research Centre for Working Environment and Human Factors Ardeystrasse 67, 44139 Dortmund Germany
| | - Maren Claus
- IfADo - Leibniz Research Centre for Working Environment and Human Factors Ardeystrasse 67, 44139 Dortmund Germany
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37
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Moretta L, Montaldo E, Vacca P, Del Zotto G, Moretta F, Merli P, Locatelli F, Mingari MC. Human natural killer cells: origin, receptors, function, and clinical applications. Int Arch Allergy Immunol 2014; 164:253-64. [PMID: 25323661 DOI: 10.1159/000365632] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Natural killer (NK) cells are important effectors playing a relevant role in innate immunity, primarily in tumor surveillance and in defenses against viruses. Human NK cells recognize HLA class I molecules through surface receptors (KIR and NKG2A) that inhibit NK cell function and kill target cells that have lost (or underexpress) HLA class I molecules as it occurs in tumors or virus-infected cells. NK cell activation is mediated by an array of activating receptors and co-receptors that recognize ligands expressed primarily on tumors or virus-infected cells. In vivo anti-tumor NK cell activity may be suppressed by tumor or tumor-associated cells. Alloreactive NK cells (i.e. those that are not inhibited by the HLA class I alleles of the patient) derived from HSC of haploidentical donors play a major role in the cure of high-risk leukemia, by killing leukemia blasts and patient's DC, thus preventing tumor relapses and graft-versus-host disease. The expression of the HLA-C2-specific activating KIR2DS1 may also contribute to NK alloreactivity in patients expressing C2 alleles. A clear correlation has been proven between the size of the alloreactive NK cell population and the clinical outcome. Recently, haplo-HSCT has been further improved with the direct infusion, together with HSC, of donor-derived, mature alloreactive NK cells and TCRγδ(+) T cells - both contributing to a prompt anti-leukemia effect together with an efficient defense against pathogens during the 6- to 8-week interval required for the generation of alloreactive NK cells from HSC.
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Affiliation(s)
- Lorenzo Moretta
- Istituto Giannina Gaslini, Università di Genova, Genoa, Italy
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38
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Rolstad B. The early days of NK cells: an example of how a phenomenon led to detection of a novel immune receptor system - lessons from a rat model. Front Immunol 2014; 5:283. [PMID: 24982659 PMCID: PMC4058755 DOI: 10.3389/fimmu.2014.00283] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 06/01/2014] [Indexed: 02/05/2023] Open
Abstract
In this review, I summarize some of the early research on NK cell biology and function that led to the discovery of a totally new receptor system for polymorphic MHC class I molecules. That NK cells both could recognize and kill tumor cells but also normal hematopoietic cells through expression of MHC class I molecules found a unifying explanation in the “missing self” hypothesis. This initiated a whole new area of leukocyte receptor research. The common underlying mechanism was that NK cells expressed receptors that were inhibited by recognition of unmodified “self” MHC-I molecules. This could explain both the killing of tumor cells with poor expression of MHC-I molecules and hybrid resistance, i.e., that F1 hybrid mice sometimes could reject parental bone marrow cells. However, a contrasting phenomenon termed allogeneic lymphocyte cytotoxicity in rats gave strong evidence that some of these receptors were activated rather than inhibited by recognition of polymorphic MHC-I. This was soon followed by molecular identification of both inhibitory and stimulatory Ly49 receptors in mice and rats and killer cell immunoglobulin-like receptors in humans that could be either inhibited or activated when recognizing their cognate MHC-I ligand. Since most of these receptors now have been molecularly characterized, their ligands and the intracellular pathways leading to activation or inhibition identified, we still lack a more complete understanding of how the repertoire of activating and inhibitory receptors is formed and how interactions between these receptors for MHC-I molecules on a single NK cell are integrated to generate a productive immune response. Although several NK receptor systems have been characterized that recognize MHC-I or MHC-like molecules, I here concentrate on the repertoires of NK receptors encoded by the natural killer cell gene complex and designed to recognize polymorphic MHC-I molecules in rodents, i.e., Ly49 (KLRA) receptors.
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Affiliation(s)
- Bent Rolstad
- Immunobiological Laboratory, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo , Oslo , Norway
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39
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Kirkham CL, Carlyle JR. Complexity and Diversity of the NKR-P1:Clr (Klrb1:Clec2) Recognition Systems. Front Immunol 2014; 5:214. [PMID: 24917862 PMCID: PMC4041007 DOI: 10.3389/fimmu.2014.00214] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 04/28/2014] [Indexed: 11/26/2022] Open
Abstract
The NKR-P1 receptors were identified as prototypical natural killer (NK) cell surface antigens and later shown to be conserved from rodents to humans on NK cells and subsets of T cells. C-type lectin-like in nature, they were originally shown to be capable of activating NK cell function and to recognize ligands on tumor cells. However, certain family members have subsequently been shown to be capable of inhibiting NK cell activity, and to recognize proteins encoded by a family of genetically linked C-type lectin-related ligands. Some of these ligands are expressed by normal, healthy cells, and modulated during transformation, infection, and cellular stress, while other ligands are upregulated during the immune response and during pathological circumstances. Here, we discuss historical and recent developments in NKR-P1 biology that demonstrate this NK receptor–ligand system to be far more complex and diverse than originally anticipated.
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Affiliation(s)
- Christina L Kirkham
- Department of Immunology, University of Toronto, Sunnybrook Research Institute , Toronto, ON , Canada
| | - James R Carlyle
- Department of Immunology, University of Toronto, Sunnybrook Research Institute , Toronto, ON , Canada
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40
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Shifrin N, Raulet DH, Ardolino M. NK cell self tolerance, responsiveness and missing self recognition. Semin Immunol 2014; 26:138-44. [PMID: 24629893 PMCID: PMC3984600 DOI: 10.1016/j.smim.2014.02.007] [Citation(s) in RCA: 143] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 02/12/2014] [Indexed: 01/01/2023]
Abstract
Natural killer (NK) cells represent a first line of defense against pathogens and tumor cells. The activation of NK cells is regulated by the integration of signals deriving from activating and inhibitory receptors expressed on their surface. However, different NK cells respond differently to the same stimulus, be it target cells or agents that crosslink activating receptors. The processes that determine the level of NK cell responsiveness have been referred to collectively as NK cell education. NK cell education plays an important role in steady state conditions, where potentially auto-reactive NK cells are rendered tolerant to the surrounding environment. According to the "tuning" concept, the responsiveness of each NK cell is quantitatively adjusted to ensure self tolerance while at the same time ensuring useful reactivity against potential threats. MHC-specific inhibitory receptors displayed by NK cells play a major role in tuning NK cell responsiveness, but recent studies indicate that signaling from activating receptors is also important, suggesting that the critical determinant is an integrated signal from both types of receptors. An important and still unresolved question is whether NK cell education involves interactions with a specific cell population in the environment. Whether hematopoietic and/or non-hematopoietic cells play a role is still under debate. Recent results demonstrated that NK cell tuning exhibits plasticity in steady state conditions, meaning that it can be re-set if the MHC environment changes. Other evidence suggests, however, that inflammatory conditions accompanying infections may favor high responsiveness, indicating that inflammatory agents can over-ride the natural tendency of NK cells to adjust to the steady state environment. These findings raise many questions such as whether viruses and tumor cells manipulate NK cell responsiveness to evade immune-recognition. As knowledge of the underlying processes grows, the possibility of modulating NK cell responsiveness for therapeutic purposes is becoming increasingly attractive, and is now under serious investigation in clinical studies.
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Affiliation(s)
- Nataliya Shifrin
- Department of Molecular and Cell Biology and Cancer Research Laboratory, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA
| | - David H Raulet
- Department of Molecular and Cell Biology and Cancer Research Laboratory, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA.
| | - Michele Ardolino
- Department of Molecular and Cell Biology and Cancer Research Laboratory, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA
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41
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42
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Moretta L, Pietra G, Montaldo E, Vacca P, Pende D, Falco M, Del Zotto G, Locatelli F, Moretta A, Mingari MC. Human NK cells: from surface receptors to the therapy of leukemias and solid tumors. Front Immunol 2014; 5:87. [PMID: 24639677 PMCID: PMC3945935 DOI: 10.3389/fimmu.2014.00087] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 02/19/2014] [Indexed: 01/22/2023] Open
Abstract
Natural Killer (NK) cells are major effector cells of the innate immunity. The discovery, over two decades ago, of major histocompatibility complex-class I-specific inhibitory NK receptors and subsequently of activating receptors, recognizing ligands expressed by tumor or virus-infected cells, paved the way to our understanding of the mechanisms of selective recognition and killing of tumor cells. Although NK cells can efficiently kill tumor cells of different histotypes in vitro, their activity may be limited in vivo by their inefficient trafficking to tumor lesions and by the inhibition of their function induced by tumor cells themselves and by the tumor microenvironment. On the other hand, the important role of NK cells has been clearly demonstrated in the therapy of high risk leukemias in the haploidentical hematopoietic stem cell (HSC) transplantation setting. NK cells derived from donor HSC kill leukemic cells residual after the conditioning regimen, thus preventing leukemia relapses. In addition, they also kill residual dendritic cells and T lymphocytes, thus preventing both GvH disease and graft rejection.
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Affiliation(s)
| | - Gabriella Pietra
- Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genova , Genova , Italy ; IRCCS AOU San Martino-IST , Genova , Italy
| | - Elisa Montaldo
- Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genova , Genova , Italy
| | - Paola Vacca
- Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genova , Genova , Italy
| | | | | | | | - Franco Locatelli
- Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù , Rome , Italy ; Università di Pavia , Pavia , Italy
| | - Alessandro Moretta
- Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genova , Genova , Italy
| | - Maria Cristina Mingari
- Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genova , Genova , Italy ; IRCCS AOU San Martino-IST , Genova , Italy
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43
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Abstract
The functions of Natural Killer (NK) cells are regulated by a highly redundant set of germline-encoded surface receptors that can inhibit or activate NK cell activities. NK cells can be activated by cytokines or through the interaction with transformed or infected cells. This typically results in the production of cytokines, chemokines, and the induction of cellular cytotoxicity. However, the reactivity of NK cells is modulated on various levels and shaped by processes such as development, education, priming, exposure to antigens and cytokines, and the formation of memory-like phenotypes. Here, I will summarize our current understanding of these processes and describe how they influence NK cell reactivity on a molecular level.
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Affiliation(s)
- Carsten Watzl
- Leibniz Research Center for Working Environment and Human Factors, IfADo, Dortmund, Germany.
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44
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Straub C, Neulen ML, Sperling B, Windau K, Zechmann M, Jansen CA, Viertlboeck BC, Göbel TW. Chicken NK cell receptors. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2013; 41:324-333. [PMID: 23542703 DOI: 10.1016/j.dci.2013.03.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 03/19/2013] [Accepted: 03/19/2013] [Indexed: 06/02/2023]
Abstract
Natural killer cells are innate immune cells that destroy virally infected or transformed cells. They recognize these altered cells by a plethora of diverse receptors and thereby differ from other lymphocytes that use clonally distributed antigen receptors. To date, several receptor families that play a role in either activating or inhibiting NK cells have been identified in mammals. In the chicken, NK cells have been functionally and morphologically defined, however, a conclusive analysis of receptors involved in NK cell mediated functions has not been available. This is partly due to the low frequencies of NK cells in blood or spleen that has hampered their intensive characterization. Here we will review recent progress regarding the diverse NK cell receptor families, with special emphasis on novel families identified in the chicken genome with potential as chicken NK cell receptors.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/immunology
- Chickens/genetics
- Chickens/immunology
- Gene Expression Regulation
- Genome/immunology
- Immunity, Innate
- Killer Cells, Natural/cytology
- Killer Cells, Natural/immunology
- Lectins, C-Type/classification
- Lectins, C-Type/genetics
- Lectins, C-Type/immunology
- Ligands
- Mammals/immunology
- Phylogeny
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/immunology
- Receptors, Natural Killer Cell/classification
- Receptors, Natural Killer Cell/genetics
- Receptors, Natural Killer Cell/immunology
- Signal Transduction
- Signaling Lymphocytic Activation Molecule Family Member 1
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Affiliation(s)
- Christian Straub
- Institute for Animal Physiology, Department of Veterinary Sciences, University of Munich, Germany
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45
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Ullrich E, Koch J, Cerwenka A, Steinle A. New prospects on the NKG2D/NKG2DL system for oncology. Oncoimmunology 2013; 2:e26097. [PMID: 24353908 PMCID: PMC3862635 DOI: 10.4161/onci.26097] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2013] [Revised: 08/06/2013] [Accepted: 08/09/2013] [Indexed: 11/19/2022] Open
Abstract
The activating immunoreceptor NKG2D endows cytotoxic lymphocytes with the capacity to recognize and eliminate infected or malignant cells. The recognition of such harmful cells is enabled by binding of NKG2D to various MHC class I-related glycoproteins, which are upregulated in the course of viral infection or malignant transformation. The past years have witnessed substantial progress in our understanding of the mechanisms underlying the regulation of NKG2D ligands (NKG2DLs) by malignant cells, of tumor-associated countermeasures promoting escape from NKG2D-dependent immunosurveillance, and of therapeutic measures that may bolster the NKG2D/NKG2DL system against malignancies. Here, we summarize the current knowledge on the NKG2D/NKG2DL system and outline opportunities to exploit the tumoricidal function of NKG2D for anticancer immunotherapy.
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Affiliation(s)
- Evelyn Ullrich
- Children's Hospital; Department of Pediatric Hematology and Oncology; Goethe-University Frankfurt am Main; Frankfurt am Main, Germany ; Center for Cell and Gene Therapy; Goethe University Frankfurt am Main; Frankfurt am Main, Germany
| | - Joachim Koch
- Center for Cell and Gene Therapy; Goethe University Frankfurt am Main; Frankfurt am Main, Germany ; Institute for Biomedical Research: Georg-Speyer-Haus; NK Cell Biology; Frankfurt am Main, Germany
| | - Adelheid Cerwenka
- German Cancer Research Center (DKFZ); Innate Immunity Group; Heidelberg, Germany
| | - Alexander Steinle
- Institute for Molecular Medicine; Goethe-University Frankfurt am Main; Frankfurt am Main, Germany
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46
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Lysenko O, Schulte D, Mittelbronn M, Steinle A. BACL is a novel brain-associated, non-NKC-encoded mammalian C-type lectin-like receptor of the CLEC2 family. PLoS One 2013; 8:e65345. [PMID: 23776472 PMCID: PMC3679072 DOI: 10.1371/journal.pone.0065345] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 04/20/2013] [Indexed: 11/24/2022] Open
Abstract
Natural Killer Gene Complex (NKC)–encoded C-type lectin-like receptors (CTLRs) are expressed on various immune cells including T cells, NK cells and myeloid cells and thereby contribute to the orchestration of cellular immune responses. Some NKC-encoded CTLRs are grouped into the C-type lectin family 2 (CLEC2 family) and interact with genetically linked CTLRs of the NKRP1 family. While many CLEC2 family members are expressed by hematopoietic cells (e.g. CD69 (CLEC2C)), others such as the keratinocyte-associated KACL (CLEC2A) are specifically expressed by other tissues. Here we provide the first characterization of the orphan gene CLEC2L. In contrast to other CLEC2 family members, CLEC2L is conserved among mammals and located outside of the NKC. We show that CLEC2L-encoded CTLRs are expressed as non-glycosylated, disulfide-linked homodimers at the cell surface. CLEC2L expression is fairly tissue-restricted with a predominant expression in the brain. Thus CLEC2L-encoded CTLRs were designated BACL (brain-associated C-type lectin). Combining in situ hybridization and immunohistochemistry, we show that BACL is expressed by neurons in the CNS, with a pronounced expression by Purkinje cells. Notably, the CLEC2L locus is adjacent to another orphan CTLR gene (KLRG2), but reporter cell assays did neither indicate interaction of BACL with the KLRG2 ectodomain nor with human NK cell lines or lymphocytes. Along these lines, growth of BACL-expressing tumor cell lines in immunocompetent mice did not provide evidence for an immune-related function of BACL. Altogether, the CLEC2L gene encodes a homodimeric cell surface CTLR that stands out among CLEC2 family members by its conservation in mammals, its biochemical properties and the predominant expression in the brain. Future studies will have to reveal insights into the functional relevance of BACL in the context of its neuronal expression.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Differentiation, T-Lymphocyte/genetics
- Antigens, Differentiation, T-Lymphocyte/metabolism
- Brain/metabolism
- Cell Line
- Flow Cytometry
- Humans
- Immunoblotting
- Immunohistochemistry
- Immunoprecipitation
- In Situ Hybridization
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Mice
- Mice, Inbred C57BL
- Receptors, NK Cell Lectin-Like/genetics
- Receptors, NK Cell Lectin-Like/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- Olga Lysenko
- Institute for Molecular Medicine, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Dorothea Schulte
- Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Michel Mittelbronn
- Institute of Neurology (Edinger Institute), Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Alexander Steinle
- Institute for Molecular Medicine, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
- * E-mail:
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47
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Schenkel AR, Kingry LC, Slayden RA. The ly49 gene family. A brief guide to the nomenclature, genetics, and role in intracellular infection. Front Immunol 2013; 4:90. [PMID: 23596445 PMCID: PMC3627126 DOI: 10.3389/fimmu.2013.00090] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 04/04/2013] [Indexed: 12/19/2022] Open
Abstract
Understanding the Ly49 gene family can be challenging in terms of nomenclature and genetic organization. The Ly49 gene family has two major gene nomenclature systems, Ly49 and Killer Cell Lectin-like Receptor subfamily A (klra). Mice from different strains have varying numbers of these genes with strain specific allelic variants, duplications, deletions, and pseudogene sequences. Some members activate NK lymphocytes, invariant NKT (iNKT) lymphocytes and γδ T lymphocytes while others inhibit killing activity. One family member, Ly49Q, is expressed only on myeloid cells and is not found on NK, iNKT, or γδ T cells. There is growing evidence that these receptors may regulate not just the immune response to viruses, but other intracellular pathogens as well. Thus, this review’s primary goal is to provide a guide for researchers first encountering the Ly49 gene family and a foundation for future studies on the role that these gene products play in the immune response, particularly the response to intracellular viral and bacterial pathogens.
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Affiliation(s)
- Alan Rowe Schenkel
- Department of Microbiology, Immunology and Pathology, Colorado State University Fort Collins, CO, USA
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48
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Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 2013; 31:227-58. [PMID: 23516982 PMCID: PMC3868343 DOI: 10.1146/annurev-immunol-020711-075005] [Citation(s) in RCA: 916] [Impact Index Per Article: 76.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Understanding how signals are integrated to control natural killer (NK) cell responsiveness in the absence of antigen-specific receptors has been a challenge, but recent work has revealed some underlying principles that govern NK cell responses. NK cells use an array of innate receptors to sense their environment and respond to alterations caused by infections, cellular stress, and transformation. No single activation receptor dominates; instead, synergistic signals from combinations of receptors are integrated to activate natural cytotoxicity and cytokine production. Inhibitory receptors for major histocompatibility complex class I (MHC-I) have a critical role in controlling NK cell responses and, paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing. MHC-I-specific inhibitory receptors both block activation signals and trigger signals to phosphorylate and inactivate the small adaptor Crk. These different facets of inhibitory signaling are incorporated into a revocable license model for the reversible tuning of NK cell responsiveness.
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Affiliation(s)
- Eric O. Long
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852
| | - Hun Sik Kim
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852
- Department of Medicine, Graduate School, University of Ulsan, Seoul 138-736, Korea;
| | - Dongfang Liu
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852
- Center for Human Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030;
| | - Mary E. Peterson
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852
| | - Sumati Rajagopalan
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852
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Neulen ML, Göbel TW. Chicken CD56 defines NK cell subsets in embryonic spleen and lung. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2012; 38:410-415. [PMID: 22922589 DOI: 10.1016/j.dci.2012.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Revised: 08/06/2012] [Accepted: 08/07/2012] [Indexed: 06/01/2023]
Abstract
NK cells have been widely investigated in various mammalian species, but their characterization in non-mammalian vertebrates has been hampered by the lack of appropriate markers. Here, we tested the suitability of a novel anti-chicken CD56 mab as a marker on NK cells. The entire CD56 extracellular domain was cloned into a vector providing a FLAG epitope as well as the CD8 transmembrane and CD3ζ cytoplasmic domain. This construct was used to stably transfect the chicken 2D8 B cell line as monitored by anti-FLAG staining. BALB/c mice were repeatedly immunized with this cell line before generation of hybridomas and screening of supernatants on the transfected cell line versus untransfected cells. The 4B5 hybridoma was further selected due to its reactivity with transfected cells only. Staining of various cell preparations isolated from blood, spleen, embryonic spleen, lung and intestine revealed a CD56 positive subpopulation in lung and embryonic spleen, whereas no reactivity could be observed with other cells. In two colour immunofluorescence, some of the CD56(+) lung cells coexpressed CD8, while they were largely negative for the markers 28-4 and 20E5. CD8 expression was also observed for a subset of CD56(+) embryonic splenocytes and 28-4 was found to be coexpressed on about half of the CD56(+) embryonic splenocytes. CD56 is therefore expressed on a subset of chicken NK cells predominantly found in embryonic spleen and lung.
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Affiliation(s)
- Marie-Luise Neulen
- Institute for Animal Physiology, Department of Veterinary Sciences, University of Munich, Veterinärstr. 13, 80539 Munich, Germany
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Morandi B, Mortara L, Chiossone L, Accolla RS, Mingari MC, Moretta L, Moretta A, Ferlazzo G. Dendritic cell editing by activated natural killer cells results in a more protective cancer-specific immune response. PLoS One 2012; 7:e39170. [PMID: 22723958 PMCID: PMC3378645 DOI: 10.1371/journal.pone.0039170] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Accepted: 05/16/2012] [Indexed: 02/06/2023] Open
Abstract
Over the last decade, several studies have extensively reported that activated natural killer (NK) cells can kill autologous immature dendritic cells (DCs) in vitro, whereas they spare fully activated DCs. This led to the proposal that activated NK cells might select a more immunogenic subset of DCs during a protective immune response. However, there is no demonstration that autologous DC killing by NK cells is an event occurring in vivo and, consequently, the functional relevance of this killing remains elusive. Here we report that a significant decrease of CD11c(+) DCs was observed in draining lymph nodes of mice inoculated with MHC-devoid cells as NK cell targets able to induce NK cell activation. This in vivo DC editing by NK cells was perforin-dependent and it was functionally relevant, since residual lymph node DCs displayed an improved capability to induce T cell proliferation. In addition, in a model of anti-cancer vaccination, the administration of MHC-devoid cells together with tumor cells increased the number of tumor-specific CTLs and resulted in a significant increase in survival of mice upon challenge with a lethal dose of tumor cells. Depletion of NK cells or the use of perforin knockout mice strongly decreased the tumor-specific CTL expansion and its protective role against tumor cell challenge. As a whole, our data support the hypothesis that NK cell-mediated DC killing takes place in vivo and is able to promote expansion of cancer-specific CTLs. Our results also indicate that cancer vaccines could be improved by strategies aimed at activating NK cells.
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Affiliation(s)
- Barbara Morandi
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Lorenzo Mortara
- Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy
| | | | - Roberto S. Accolla
- Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy
| | - Maria Cristina Mingari
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
- Istituto Di Ricovero e Cura a Carattere Scientifico A.O.U. San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | | | | | - Guido Ferlazzo
- Department of Human Pathology, University of Messina, Messina, Italy
- * E-mail:
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