Cellular and structural bases of MHC/peptide complex antigenicity in humans – pMHCantigenicity

The aim of our project is to determine the overall characteristics of naive T cell repertoires directed against various viral or tumoral antigens in humans as well as parameters influencing these repertoires both qualitatively and quantitatively. An in depth understanding of these mechanisms would provide important insights into the ability of a given individual to develop a subsequent efficient immune response against tumors, infectious pathogens or after vaccination. To this end we have set up a strategy allowing ex vivo quantification and phenotypic analysis of antigen-specific T lymphocytes present even at very low frequencies in biological samples (detection threshold : 10-7). Our results obtained with different peptide/MHC class I (pMHC-I) complexes have already shown that T cell repertoires specific for several viral and tumoral immunodominant antigens are differentially affected by both the expression of the HLA restricting-allele and the inherent reactivity of the TCRs found in those repertoires. During this analysis, we have also formally documented the presence of CD4+CD8- T cells reactive against pMHC-I complexes, while clearly selected against MHC class II molecules. Using the same approach, pMHC specific B cells have also been detected at significant frequencies (10-5 - 10-4). We thus have unique opportunity to dissect the parameters governing the overall pMHC antigenicity towards immune adaptive receptors. In particular we will address the role of thymic selection processes on both the quantity and quality of Ag specific T cell repertoires, determined the structural bases of TCR crossreactivity, peptide-dependency and biased usage of particular variable gene segment for recognition of particular pMHC, and investigate the role of pMHC class I specific B cells in immune responses and possible fallout for the production of highly specific antibodies against pMHC.
This project is based on a multidisciplinary approach, combining molecular and cellular immunology and structural biology, that relies on the competences of two teams acknowledged by numerous publications in the field of immunobiology of human lymphocytes in healthy, tumor or infectious situations and in the structural basis of TCR antigen recognition. The work program will provide key information about the mechanisms contributing to the shaping of the preimmune peripheral T cell repertoire in humans. This knowledge is a prerequisite for identifying predictive clues of an efficient immune response in a variety of physiopathological and vaccinal situations. The investigations on pMHC specific B cells may lead to a very promising alternative technique to identify antibodies with sufficient affinity and peptide specificity for a given pMHC and that will be extremely beneficial for diagnostic and therapeutic purposes.