Immunogénétique et développement des lymphocytes T CD4-CD8- immunorégulateurs chez la souris

The immune system has the crucial role of defending us against pathogens, while remaining tolerant to self. When self-tolerance is broken, the immune system attacks self-antigens resulting in autoimmune diseases such as type 1 diabetes. To maintain self-tolerance and thereby prevent the development of autoimmunity, several regulatory T cell subsets are generated and patrol our different tissues. Of these, CD4-CD8-TCRβ+ T (DN T) cells found in the peripheral lymphoid organs are particularly interesting due to their unique antigen-specific immunoregulatory functions. Indeed, DN T cells play an important role in the induction of immune tolerance in various pathological settings. Finding new means to modulate the number of DN T cells could help prevent autoimmunity. As such, a better knowledge of the factors modulating DN T cell number is a first necessary step. This thesis is therefore aimed at understanding the mechanisms that regulate DN T cell homeostasis in vivo, as well as defining their developmental pathway.   Firstly, the NOD mouse strain, which spontaneously develops autoimmune diabetes, was shown to exhibit a low number of DN T cells relative to diabetes-resistant strains. It was thus a model of choice to perform immunogenetic studies for identifying genetic variants determining the proportion of DN T cells. By exploiting NOD mice, we determined that some loci contributing to the modulation of DN T cells overlap with diabetes susceptibility loci, including Idd2 and Idd13. We showed that genetic variants in each of these two loci influenced DN T cell proportion, and that their combination can has an additive effect in defining the number and proportion of DN T cells. Interestingly, the diabetes-resistant genetic variants at both the Idd2 and Idd13 loci were also associated with a decrease in diabetes incidence in NOD mice Idd2 and/or Idd13 congenic strains. This suggests that the regulation of DN T cell proportion is associated with autoimmune diabetes resistance.  Secondly, we aimed to determine the differentiation pathway of DN T cells. Using various reporter mouse models, we find that the majority of DN T cells originate directly from the thymus, specifically by transiting through the immature CD4+CD8+ (DP) thymocyte stage. We also show that DN T cells are selected by strong TCR signals in the thymus, a process refered to as agonist selection and associated with the development of other immunoregulatory T cells. Intringuingly, we also observed that, as opposed to other T cell subsets, DN T cells can develop in absence of MHC molecules. These unique properties may influence DN T cell regulatory function and specificity.  In summary, the results presented in this thesis show that DN T cells are regulated by diabetes-associated genetic loci and display unique differentiation properties relative to other T cell subsets. Together our findings provide a better understanding of the homeostasis and differentiation of immunoregulatory DN T cells, which is essential for the development of future immune therapy approaches.

Keyphrases: Idd2, Auto-anticorps, DN T cells, Autoimmune diabetes, Thymic selection, Auto-antibodies