How thymic antigen presenting cells sample the body's self-antigens

Our perception of the scope self-antigen availability for tolerance induction in the thymus has profoundly changed over the recent years following new insights into the cellular and molecular complexity of intrathymic antigen presentation. The diversity of self-peptide display is on the one hand afforded by the remarkable heterogeneity of thymic antigen presenting cells (APCs) and on the other hand by the endowment of these cells with unconventional molecular pathways. Recent studies show that each APC subset appears to carry its specific antigen cargo as a result of cell-type specific features: firstly, transcriptional control (i.e. promiscuous gene expression in medullary thymic epithelial cells); secondly, antigen processing (i.e. proteasome composition and protease sets); thirdly, intracellular antigen sampling (i.e. autophagy in thymic epithelial cells) and fourthly, extracellular antigen sampling (i.e. immigrating dendritic cells sampling extrathymic milieus). The combinatorial expression patterns of these attributes in distinct APC subsets result in a self-peptide display partly unique to the cortex mediating positive selection and to the medulla mediating tolerance induction.