Identification des cellules présentatrices d'antigène qui sélectionnent/induisent les cellules MAIT et T régulatrices dans le thymus

Since 1961, when Jacques Miller almost accidentally discovered the function of the thymus, the development of mainstream T cells has been widely studied. A number of smaller populations of T cells, such as mucosal associated invariant T (MAIT) cells and CD4+ CD25+ Foxp3+ regulatory T (Treg) cells are currently gaining attention in the field. While little is known of MAIT cell development, Treg cell development is somewhat controversial. The purpose of this thesis has been to determine which types of cell are responsible for the intrathymic selection/induction of these two relatively recently discovered αβT cells that are of interest to our laboratory, i. E. MAIT and Treg cells. To do this we used several in vitro thymic organ culture systems, some of them allowing the manipulation of the cell types present in the thymus during development. We showed that MAIT cell development is intrathymic and independent of peripheral antigens or B cells (although they are both needed for a further phase of peripheral expansion). Further, in order to identify the cell that selects MAIT cells in the thymus, we set up the reaggregate thymic organ culture (RTOC) technique. By the time of writing this thesis, the technical aspects of MAIT RTOCs were established. This means that the first key aspects of MAIT cell intrathymic selection should be revealed in the near future. In a parallel study, we set out to determine the relative contribution of medullary thymic epithelial (mTEC) cells and the three types of thymic dendritic cell (TDC) subpopulations to Treg induction and to unify the conflicting results published on the subject by others. We showed that the four populations were all capable of inducing SP4 into Tregs when loaded with the cognate antigen. However, they did it with very different “intensities”, suggesting that the relative contribution to Treg induction in a normal thymus is different for each of these APC populations. We found that Sirpα- conventional DCs that develop intrathymically (here called cDCthy) were the strongest Treg inducer, followed by Sirpα+ recirculatory cDCs (here called cDCrec). PDC and mTECs were weak Treg inducers in our system. Further, we showed that this difference was not explained by the level of MHC expression on each APC, suggesting that some other still unknown quantitative or qualitative difference between cDCthy and the other thymic APCs must be responsible. Understanding what makes cDCthy more suited for Treg induction will also help identifying what needs to be triggered on a thymocyte for Treg-lineage commitment in the thymus.