the development of immunotherapies against viral infections and cancer require a better understanding of the key areas that control T cell-mediated immune responses, such as TCR-ligand binding avidity. The overall aim of this case was to improve our knowledge concerning the contribution of TCR binding advidity in mediating the long-term memory of antigen-specific CD8 T cells. We first performed a comprehensive study of TCR-pMHC binding avidity (i.e. off-rates) combined with various funeral assays on broad libraries of tumor- and virus-specific CD8 T cell cells from MELANOMA patients and healthy donors. We witnessed that TCR-pMHC off-rates accredited the functional potential of antigen-specific CD8 T cells. Our data also confirmed the superior binding avidities of virus-specific compared with tumor-specific T cell clonotypes. The TCR-pMHC off-rate is a more stable and robust Biomarker of CD8 T cell potency than frequently used functionally assays that depend on multiple parameters, including T cell activation state. Together, our data show that the TCR-pMHC binding avidity is a reliable biophysical parameter for patient monitoring during immunotherapy. In the second part of this thesis, we investigated whether TCR-ligand avidity is a determining factor for the clonal selection and evolution of antigen-specific T cells over time. We studied TCRαβ clonotype composition and persistence over a period of 15 years combined with TCR-pMHC binding advidity analyses on wide repertoires of cytomegalovirus (CMV) — and Epstein-Barr virus (EBV) — specific CD8 T cell cells from healthy donors. Within CMV-specific T cell repertoires, we observe the gradual contraction of clonotypes of higher TCR-pMHC avidity and lower CD8 binding dependence during chronic antigen exposure. Strikingly, we identified a unique transcriptional signature preferably expressed by high-avidity T cell clonotypes, including elevated expression of the inhibitory receptor LILRB1. Enhanced proliferative capacity was also observed on LILRB1 Blockade. This was not the case for the EBV-specific T cell composition and distribution that, once established, discarded an unspecified stability for at least 15 years, independent of TCR-pMHC avidity. Our findings regarding an overall long-term advidity line of CMV- but not EBV-specific T cell cell perpertoires, enhancing the role played by TCR-ligand over the race of these two latent herpesvirus infections. We propose that the mechanisms regulating the long-term outcome of CMV- and EBV-specific memory CD8 T cell responses in humans are distinct. — The development of immunotherapies targeting viral infections and cancers requires a better understanding of the key parameters that control T cell responses, such as the avidity of TCRS for their ligand. The overall objective of this thesis was to improve our knowledge of the contribution of CRT avidity to the mediation of cell functions and the maintenance of long-term memory of CD8 T cells. We initially conducted an analytical study on CRT avidity combined with various functional tests on CD8 T lymphocytes directed against viral and tumour antigens in healthy donors and melanoma patients. We have shown that the adidity of the TCR accurately predicts the cell functions of the CD8 T cells. Our results also confirm that the specific CD8 T cells for viral antigens are higher avidity than those specific for tumour antigens. Moreover, the adidity of the TCR is a biomarker of the functional capacity of T cells, which is more stable and robust than the functional tests usually used. Overall, our results show that the avidity of CRT is a reliable biophysical parameter for monitoring patients treated with immunotherapy. Subsequently, we assessed whether the adidity of the CRT was a determining factor for the clonal selection of CD8 T cells over time. Over a period of 15 years, we studied the composition and persistence of clonotypic repertoires against cytomegalovirus (CMV) and Epstein-Barr virus (EBV) and the avidity of CRT in healthy donors. In the case of the T lymphocyte response against the CVMP, we observed the gradual contraction of the clonotypes of higher avidity and not dependent on interaction with the CD8 beeceptor over time. We have identified a separate transcriptional signature in the highest-avidity clonotypes, including the high expression of the LILRB1 inhibitor receiver. An increase in the proliferative capacity of T cells was also observed when LILRB1 was blocked. This was not the case for the CD8 TC repertoires directed against EBV which, once established, are kept stable for at least 15 years, regardless of the adidity of the CRT. Our results show an overall long-term decline in the avidity of the clonal repertoires of CMV specific T lymphocytes, but not EBV, highlighting the different role played by TCRS avidity during latent infections induced by these two viruses. We suggest that separate mechanisms regulate the long-term evolution of CMV and EBV specific CD8 TC lymphocyte responses in humans.