Impact of TCR Reactivity and HLA Phenotype on Naive CD8 T Cell Frequency in Humans

Abstract

The impact of MHC phenotype on the shaping of the peripheral naive T cell repertoire in humans remains unknown. To address this, we compared the frequency and antigenic avidity of naive T cells specific for immunodominant self-, viral, and tumor Ags presented by a human MHC class I allele (HLA-A*02, referred to as A2) in individuals expressing or not this allele. Naive T cell frequencies varied from one Ag specificity to another but were restrained for a given specificity. Although A2-restricted T cells showed similar repertoire features and antigenic avidities in A2+ and A2− donors, A2 expression had either a positive, neutral, or negative impact on the frequency of A2-restricted naive CD8 T cells, depending on their fine specificity. We also identified in all donors CD4 T cells specific for A2/peptide complexes, whose frequencies were not affected by MHC class I expression, but nevertheless correlated with those of their naive CD8 T cell counterparts. Therefore, both selection by self-MHC and inherent TCR reactivity regulate the frequency of human naive T cell precursors. Moreover this study also suggests that T cell repertoire shaping by a given self-MHC allele is dispensable for generation of immunodominant T cell responses restricted by this particular allele.

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

“…3B). In line with our previous analysis of peripheral CD8 T cells [11], the higher the frequency of p-A2-specific SP8 thymocytes, the higher the frequency difference between A2 + and A2 − individuals. …”

“…2). In particular, MelA-A2, PGT-A2 and MP-A2 tetramer + thymocytes within the three thymic compartments (DP, SP8 or SP4) were characterized by a marked bias towards the usage of particular TCR V regions (TRAV12.2 for MelA-and PGT-tetramer + cells; TRBV17.1 for MP-specific T cells), previously reported as a hallmark of the corresponding peripheral Ag-specific T cells [11,[14][15][16] (Fig. 2B).…”

“…Each dot corresponds to the mean frequencies of Ag specific cells found in each comparment (n = 8 for SP8; n = 10 for CD8). Data for the CD8 peripheral T-cell compartment were already published by our group (Legoux et al, 2010). the quantitative impact of A2 expression on Ag-specific cell frequencies seems to be mainly due to thymic selection mechanisms, and barely affected by peripheral homeostatic expansion processes.…”

“…In particular, p-MHC tetramer-based cell enrichment methods have allowed estimation of the preimmune peripheral frequency of CD8 + and CD4 + T-cell populations specific for several defined p-MHC class I and class II complexes (reviewed in [13]). In this regard, we and others recently analyzed the frequencies of peripheral naïve T cells in healthy humans donors and showed that these frequencies were differentially affected by the expression of the MHC-restricting allele [9,11].Here, we applied this p-MHC tetramer-based enrichment approach to analyze the specificity and the activation status of human thymocytes against several immunodominant self, viral and tumor antigens presented by HLA-A*0201 (A2) in individuals expressing or not this allele. Our study indicates that the frequency of p-MHC-specific naive T cells in peripheral blood is determined by thymic maturation rather than peripheral repertoire remolding.…”

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

“…The frequency of circulating antigen‐reactive CD8 + T‐cell precursors in humans is typically very low, often in the order of one cell per million within the lineage as a whole (Alanio et al ., 2010; Legoux et al ., 2010; Iglesias et al ., 2013). To circumvent this biological obstacle to the reliable study of antigen‐specific priming in vitro , we exploited the observation that individuals expressing the HLA‐A2 allotype harbor exceptionally high frequencies of precursors (i.e., 10–100 naïve cells per million CD8 + T‐cells) specific for the heteroclitic Melan‐A/MART‐1 epitope ELAGIGILTV (ELA from hereon) (Dutoit et al ., 2002; Zippelius et al ., 2002).…”