Autophagy in thymic epithelium and T cell tolerance

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Thymic epithelial cells (TEC) are the only non-hematopoietic cells that constitutively express high levels of MHC class II (MHC II). The recognition of MHC II bound peptides on TEC by developing thymocytes ensures (i) the generation of a functional, i.e. self-MHC restricted, CD4 T cell repertoire, and (ii) the removal (negative selection) or functional deviation (regulatory T cell induction) of autoreactive CD4 T cells. MHC II / peptide ligands are primarily generated through processing of exogenous proteins. TEC, however, exhibit a remarkable inefficiency in capturing and processing extracellular antigens, suggesting alternative pathways of MHC II loading. Cell culture models have indicated that autophagy, a bulk protein degradation process up-regulated upon starvation to sustain metabolic fitness, may shuttle intracellular material into the MHC II pathway. We could recently show that interference with autophagy specifically in TEC led to altered selection of certain MHC II-restricted T cell specificities and resulted in severe colitis and multi-organ inflammation. Our findings suggest that autophagy contributes to T cell selection by focusing the MHC II / peptide repertoire of TEC on their intracellular milieu, which notably comprises a wide array of otherwise “peripheral” self-antigens. Here, we propose to test this hypothesis using two novel transgenic model systems and to address mechanistic aspects of the failure of tolerance that is caused by the absence of autophagy in TEC. Furthermore, we plan to explore the regulation of autophagy in TEC.