Overall avidity declines in TCR repertoires during latent CMV but not EBV infection
IntroductionThe avidity of the T-cell receptor (TCR) for antigenic peptides presented by the MHC (pMHC) on cells is an essential parameter for efficient T cell-mediated immunity. Yet, whether the TCR-ligand avidity can drive the clonal evolution of virus antigen-specific CD8 T cells, and how this pr...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1293090/full |
| _version_ | 1797563987213156352 |
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| author | Barbara Couturaud Bastien Doix Laura Carretero-Iglesia Mathilde Allard Sylvain Pradervand Sylvain Pradervand Michael Hebeisen Nathalie Rufer |
| author_facet | Barbara Couturaud Bastien Doix Laura Carretero-Iglesia Mathilde Allard Sylvain Pradervand Sylvain Pradervand Michael Hebeisen Nathalie Rufer |
| author_sort | Barbara Couturaud |
| collection | DOAJ |
| description | IntroductionThe avidity of the T-cell receptor (TCR) for antigenic peptides presented by the MHC (pMHC) on cells is an essential parameter for efficient T cell-mediated immunity. Yet, whether the TCR-ligand avidity can drive the clonal evolution of virus antigen-specific CD8 T cells, and how this process is determined in latent Cytomegalovirus (CMV)- against Epstein-Barr virus (EBV)-mediated infection remains largely unknown.MethodsTo address these issues, we quantified monomeric TCR-pMHC dissociation rates on CMV- and EBV-specific individual TCRαβ clonotypes and polyclonal CD8 T cell populations in healthy donors over a follow-up time of 15-18 years. The parameters involved during the long-term persistence of virus-specific T cell clonotypes were further evaluated by gene expression profiling, phenotype and functional analyses.ResultsWithin CMV/pp65-specific T cell repertoires, a progressive contraction of clonotypes with high TCR-pMHC avidity and low CD8 binding dependency was observed, leading to an overall avidity decline during long-term antigen exposure. We identified a unique transcriptional signature preferentially expressed by high-avidity CMV/pp65-specific T cell clonotypes, including the inhibitory receptor LILRB1. Interestingly, T cell clonotypes of high-avidity showed higher LILRB1 expression than the low-avidity ones and LILRB1 blockade moderately increased T cell proliferation. Similar findings were made for CD8 T cell repertoires specific for the CMV/IE-1 epitope. There was a gradual in vivo loss of high-avidity T cells with time for both CMV specificities, corresponding to virus-specific CD8 T cells expressing enhanced LILRB1 levels. In sharp contrast, the EBV/BMFL1-specific T cell clonal composition and distribution, once established, displayed an exceptional stability, unrelated to TCR-pMHC binding avidity or LILRB1 expression.ConclusionsThese findings reveal an overall long-term avidity decline of CMV- but not EBV-specific T cell clonal repertoires, highlighting the differing role played by TCR-ligand avidity over the course of these two latent herpesvirus infections. Our data further suggest that the inhibitor receptor LILRB1 potentially restricts the clonal expansion of high-avidity CMV-specific T cell clonotypes during latent infection. We propose that the mechanisms regulating the long-term outcome of CMV- and EBV-specific memory CD8 T cell clonotypes in humans are distinct. |
| first_indexed | 2024-03-10T18:52:00Z |
| format | Article |
| id | doaj.art-0bda0ac473c242f7b564903799614b19 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-10T18:52:00Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-0bda0ac473c242f7b564903799614b192023-11-20T05:04:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12930901293090Overall avidity declines in TCR repertoires during latent CMV but not EBV infectionBarbara Couturaud0Bastien Doix1Laura Carretero-Iglesia2Mathilde Allard3Sylvain Pradervand4Sylvain Pradervand5Michael Hebeisen6Nathalie Rufer7Department of Oncology, Lausanne University Hospital and University of Lausanne, Epalinges, SwitzerlandDepartment of Oncology, Lausanne University Hospital and University of Lausanne, Epalinges, SwitzerlandDepartment of Oncology, Lausanne University Hospital and University of Lausanne, Epalinges, SwitzerlandDepartment of Oncology, Lausanne University Hospital and University of Lausanne, Epalinges, SwitzerlandDepartment of Oncology, Lausanne University Hospital and University of Lausanne, Epalinges, SwitzerlandLausanne Genomic Technologies Facility (LGTF), University of Lausanne, Lausanne, SwitzerlandDepartment of Oncology, Lausanne University Hospital and University of Lausanne, Epalinges, SwitzerlandDepartment of Oncology, Lausanne University Hospital and University of Lausanne, Epalinges, SwitzerlandIntroductionThe avidity of the T-cell receptor (TCR) for antigenic peptides presented by the MHC (pMHC) on cells is an essential parameter for efficient T cell-mediated immunity. Yet, whether the TCR-ligand avidity can drive the clonal evolution of virus antigen-specific CD8 T cells, and how this process is determined in latent Cytomegalovirus (CMV)- against Epstein-Barr virus (EBV)-mediated infection remains largely unknown.MethodsTo address these issues, we quantified monomeric TCR-pMHC dissociation rates on CMV- and EBV-specific individual TCRαβ clonotypes and polyclonal CD8 T cell populations in healthy donors over a follow-up time of 15-18 years. The parameters involved during the long-term persistence of virus-specific T cell clonotypes were further evaluated by gene expression profiling, phenotype and functional analyses.ResultsWithin CMV/pp65-specific T cell repertoires, a progressive contraction of clonotypes with high TCR-pMHC avidity and low CD8 binding dependency was observed, leading to an overall avidity decline during long-term antigen exposure. We identified a unique transcriptional signature preferentially expressed by high-avidity CMV/pp65-specific T cell clonotypes, including the inhibitory receptor LILRB1. Interestingly, T cell clonotypes of high-avidity showed higher LILRB1 expression than the low-avidity ones and LILRB1 blockade moderately increased T cell proliferation. Similar findings were made for CD8 T cell repertoires specific for the CMV/IE-1 epitope. There was a gradual in vivo loss of high-avidity T cells with time for both CMV specificities, corresponding to virus-specific CD8 T cells expressing enhanced LILRB1 levels. In sharp contrast, the EBV/BMFL1-specific T cell clonal composition and distribution, once established, displayed an exceptional stability, unrelated to TCR-pMHC binding avidity or LILRB1 expression.ConclusionsThese findings reveal an overall long-term avidity decline of CMV- but not EBV-specific T cell clonal repertoires, highlighting the differing role played by TCR-ligand avidity over the course of these two latent herpesvirus infections. Our data further suggest that the inhibitor receptor LILRB1 potentially restricts the clonal expansion of high-avidity CMV-specific T cell clonotypes during latent infection. We propose that the mechanisms regulating the long-term outcome of CMV- and EBV-specific memory CD8 T cell clonotypes in humans are distinct.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1293090/fullhealthy donorslongitudinal studylatent herpesvirus infectionCD8 T cellsTCR clonotypepersistence |
| spellingShingle | Barbara Couturaud Bastien Doix Laura Carretero-Iglesia Mathilde Allard Sylvain Pradervand Sylvain Pradervand Michael Hebeisen Nathalie Rufer Overall avidity declines in TCR repertoires during latent CMV but not EBV infection Frontiers in Immunology healthy donors longitudinal study latent herpesvirus infection CD8 T cells TCR clonotype persistence |
| title | Overall avidity declines in TCR repertoires during latent CMV but not EBV infection |
| title_full | Overall avidity declines in TCR repertoires during latent CMV but not EBV infection |
| title_fullStr | Overall avidity declines in TCR repertoires during latent CMV but not EBV infection |
| title_full_unstemmed | Overall avidity declines in TCR repertoires during latent CMV but not EBV infection |
| title_short | Overall avidity declines in TCR repertoires during latent CMV but not EBV infection |
| title_sort | overall avidity declines in tcr repertoires during latent cmv but not ebv infection |
| topic | healthy donors longitudinal study latent herpesvirus infection CD8 T cells TCR clonotype persistence |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1293090/full |
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