Nuno L. Alves

Within the thymus, thymic epithelial cells (TECs) provide a dedicated niche for the selection of functional T cells expressing a highly variable and self‐tolerant T‐cell receptor (TCR) repertoire. In this minireview, we start by summarizing recent studies that have improved our understanding on the composition of cortical TEC and medullary TEC microenvironments. Next, we focus on the molecular processes that control the function of TECs in T‐cell selection. In particular, we discuss the role of cortical TECs in positive selection and the pathways employed by these cells to generate and present selecting self‐peptides:MHC II complexes. Several studies have underscored the role of the β5t‐containing thymoproteasome in the production of unique MHC I‐bound peptides critical for CD8 T‐cell selection. Contrarily, the identity of the molecular determinants that regulate the generation of MHC II‐bound self‐peptides capable of positive selecting CD4 T cells is far more uncertain. We highlight recent advances that interconnect the autophagy‐lysosomal pathway, the presentation of specific sets of self‐peptide:MHC II complexes, and the diversification of CD4 TCR repertoire. Lastly, we discuss how these findings may open up new avenues for deciphering the identity of the MHC I and MHC II ligandome in the thymus.