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The impact of major histocompatibility complex (MHC) phenotype on the shaping of the peripheral naive T cell repertoire in humans remains unknown. Here we exploited a pMHC multimer-based sorting approach to analyze the impact of expression of a given human leukocyte Ag (HLA) class I allele on the frequency and quality of peripheral blood and thymic T cells directed against immunodominant self, viral and tumor antigens 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 antigen specificity to another but were restrained for a given specificity. While 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.

We recently evidenced a dramatic enrichment for T cells reactive against Epstein-Barr virus (EBV) within inflamed joints of two rheumatoid arthritis patients. To assess the generality of this phenomenon and its relevance to autoimmunity, we studied the responses of CD8 T cells from patients with either acute or chronic inflammatory diseases (rheumatoid arthritis: n = 18, ankylosing spondylitis: n = 5, psoriatic arthritis: n = 4, Reiter's syndrome: n = 3, arthrosis: n = 2, uveitis: n = 2, multiple sclerosis: n = 2, encephalitis: n = 1) against viral proteins derived from EBV and another common herpes virus, human cytomegalovirus (CMV). T cell responses against EBV and/or CMV epitopes were frequently observed within CD8 T cells derived from chronic inflammatory lesions, irrespective of their location (knee, eye, brain) and autoimmune features. In most cases, CD8 T cells derived from affected organs yielded stronger anti-viral T cell responses than CD8 T cells derived from patients' PBL, even in chronic inflammatory diseases devoid of autoimmune features or induced by defined bacterial agents. Taken together, these results suggest that the presence of virus-specific T cells within inflamed lesions of patients suffering from autoimmune diseases is a general phenomenon associated with chronic inflammation rather than the initiating cause of the autoimmune process. Since this phenomenon was sometimes associated with long-term T repertoire biases within inflamed lesions, the physiopathological significance of T cell clonal expansions found in a recurrent fashion within chronically inflamed autoimmune lesions should be interpreted with caution.