Overall avidity declines in TCR repertoires during latent CMV but not EBV infection.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_CC9F31B195B6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Overall avidity declines in TCR repertoires during latent CMV but not EBV infection.
Journal
Frontiers in immunology
Author(s)
Couturaud B., Doix B., Carretero-Iglesia L., Allard M., Pradervand S., Hebeisen M., Rufer N.
ISSN
1664-3224 (Electronic)
ISSN-L
1664-3224
Publication state
Published
Issued date
2023
Peer-reviewed
Oui
Volume
14
Pages
1293090
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
The 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.
To 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.
Within 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.
These 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.
Keywords
Humans, Epstein-Barr Virus Infections, Cytomegalovirus, Leukocyte Immunoglobulin-like Receptor B1, Herpesvirus 4, Human, Ligands, Receptors, Antigen, T-Cell, Cytomegalovirus Infections, CD8 T cells, LILRB1, TCR clonotype, TCR off-rates, healthy donors, latent herpesvirus infection, longitudinal study, persistence
Pubmed
Web of science
Open Access
Yes
Create date
07/12/2023 16:57
Last modification date
08/08/2024 7:40
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