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TCR avidity governs CD8 T cell competitive fitness in an antigen dose-dependent manner but does not reliably predict fate

ABSTRACT: T cell receptor (TCR) avidity for cognate peptide–MHC (pMHC) has been proposed to influence both the magnitude and differentiation of CD8 T cell responses, but its effects have been difficult to isolate from confounding factors such as epitope specificity and antigen presentation kinetics. To address this, we generated TCR-transgenic mice (CoVT1lo and CoVT1hi) expressing low- or high-avidity receptors for the same conserved H2-Kb–restricted epitope (VVLSFELL) derived from SARS-CoV-1/2 Spike. We show that TCR avidity governs expansion and differentiation through distinct mechanisms. Higher avidity consistently confers a competitive advantage only when antigen is abundant, with inter-clonal competition increasing in a dose-dependent manner. In contrast, the impact of avidity on differentiation varied with inflammatory context: across peptide vaccines, mRNA vaccination, and viral infection, higher avidity was associated with divergent effector versus memory precursor outcomes. These findings support a model in which TCR avidity determines competitive fitness in an antigen-dependent manner, whereas fate decisions integrate avidity with context-specific innate signals.

ORGANISM(S): Mus musculus

PROVIDER: GSE317702 | GEO | 2026/01/26

REPOSITORIES: GEO

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Project description: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. Here, we quantified monomeric TCR-pMHC dissociation rates on CMV- and EBV-specific individual TCR-alpha-beta clonotypes and polyclonal CD8 T cell populations in healthy donors over a follow-up time of 15-18 years. 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. Together, 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 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.

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	GSE317702_BD_Rhaposody_sample_tags.csv.gz	Csv
	GSE317702_RAW.tar	Raw
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TCR avidity governs CD8 T cell competitive fitness in an antigen dose-dependent manner but does not reliably predict fate

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