The immune system is a powerful mechanism of defence against pathogens and is constituted by the innate and the adaptive system, whereof CD8+ T lymphocytes are a key cell type. Whereas, the innate immune system provides quick and unspecific protection, the adaptive response is slower, but highly spécifié and long lasting. Major histocompatibility complex (MHC) class I molecules are fundamental for adaptive immune system functions. Firstly, in the context of an infection, specialized cells called dendritic cells (DCs) present microbial peptides in complex with MHC class I to specific CD8+ T cells, activating them. Activated CD8+ T lymphocytes fulfil their effector function by killing infected cells upon récognition of microbial peptide-MHC class I complex.
Recently, NLRC5 (NLR caspase recruitment domain containing protein 5) has been identified as transcriptional regulator of MHC class I genes. This NLR exerts its function particularly in lymphocytes, however in DCs its contribution to MHC class I expression is less well characterized. Considering the important function of DCs in activating CD8+ T cells, we asked whether NLRC5 impacts on antigen présentation capacity by DCs. Our work showed that NLRC5 significantly induces MHC class I transcription/neo-synthesis under inflammatory condition in DCs. However, surface expression was only mildly affected by Mrc5-deficiency, revealing a mechanism rescuing MHC class I display. Importantly, the ability of Nlrc5- deficient DCs to prime CD8+ T cells was unaltered, underlining the robustness of the T cell priming process by activated DC.
However, upon prolonged antigen présentation during persistent infections or cancer, T cells acquire an "exhausted" phenotype. In fact, to protect the host from an excessive cytotoxic response, CD8+ T cells express inhibitory receptors that dampen their effector functions. The phosphatase SHP-2 (Src homology 2 (SH2) domain-containing tyrosine phosphatase 2) has been shown to interact with inhibitory receptors, although its contribution to their signalling in exhausted T cells has not been investigated. By generating a mouse model with SHP-2- deficient CD8+ T cells, we showed that these lymphocytes are more abundant and persist longer upon chronic infection. This indicates that SHP-2 contributes to exhaustion of antigen- specific T cells representing a potential drug target to revert T cell exhaustion. Altogether this thesis work describes the rôle of NLRC5 and SHP-2 in différent aspects of the immune response, from priming to exhaustion of T cells.