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

Abstract

In the thymus, a T-cell repertoire able to confer protection against infectious and noninfectious agents in a peptide-dependent, self-MHC-restricted manner is selected. Direct detection of Ag-specific thymocytes, and analysis of the impact of the expression of the MHCrestricting allele on their frequency or function has never been studied in humans because of the extremely low precursor frequency. Here, we used a tetramer-based enrichment protocol to analyze the ex vivo frequency and activation-phenotype of human thymocytes specific for self, viral and tumor-antigens presented by HLA-A*0201 (A2) in individuals expressing or not this allele. Ag-specific thymocytes were quantified within both CD4CD8 double or single-positive compartments in every donor. Our data indicate that the maturation efficiency of Ag-specific thymocytes is poorly affected by HLA-A2 expression, in terms of frequencies. Nevertheless, A2-restricted T-cell lines from A2 + donors reacted to A2 + cell lines in a highly peptide-specific fashion, whereas their alloreactive counterparts showed off-target activity. This first ex vivo analysis of human antigen-specific thymocytes at different stages of human T-cell development should open new perspectives in the understanding of the human thymic selection process. Keywords: Antigen r Human T cells r MHC r Tetramers r Thymocytes See accompanying Commentary by Ciucci and BosselutAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe thymus generates a highly diverse T-cell repertoire able to recognize virtually any antigen that could be encountered by a given individual along his/her life. This diversity is achieved through two main mechanisms. First by the acquisition by CD4 + CD8 + double-positive (DP) thymocytes of a clonally distributed T cell receptor (TCR) that is generated after somatic recombination of TCR V(D)J gene segments and nontemplated nucleotide Correspondence: Dr. Xavier Saulquin e-mail: xavier.saulquin@univ-nantes.fradditions. This quasi-random mechanism allows for the generation of up to 10 15 different receptors [1]. Second, by the shaping of this initial T-cell repertoire by positive and negative thymic selection processes that will favor emergence of a self major histocompatibility molecules (MHC)-restricted, yet self-tolerant, TCR repertoire carried by mature naïve single-positive (SP) T cells. As a consequence of this maturation process, the diversity of SP αβ T cells in a given individual falls in the range of 10 6 to 10 8 [2]. * LH and FL equally contributed to this work. The respective contributions of positive and negative thymic selection processes to the generation of a mature T-cell repertoire possibly biased towards recognition of peptides restricted by host MHC alleles are still debated. Indeed, this phenomenon referred to as "host or Self-MHC-restriction" is a consequence of a balance between (i) the need for a thymocyte to get survival signals from TCR upon interactions of weak/intermediate avidi...

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Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35–55 epitope implicated in multiple sclerosis

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