T‐cell selection in the thymus: New routes toward the identification of the self‐peptide ligandome presented by thymic epithelial cells

Abstract

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.

Transcriptomic profiling of thymic dysregulation and viral tropism after neonatal roseolovirus infection

“…This includes the DPbla (blast) stage that occurs after the ISP stage and is characterized by rapid proliferation, the DPre (rearranging) stage in which the TCRα locus is rearranged and the mature TCR can receive signal for positive selection, and the DPsel (selection) stage when cells undergo positive selection ( 53 ). Positive selection is mediated by antigen presenting cells called cortical thymic epithelial cells (cTECs) that express self-MHC molecules for DP thymocytes to sample TCR binding for sufficient affinity to promote survival ( 54 , 55 ). Upon completion of positive selection, DP thymocytes downregulate either CD4 or CD8 to become CD4SP or CD8 single positive (CD8SP) and migrate to the thymic medulla.…”

“…Upon completion of positive selection, DP thymocytes downregulate either CD4 or CD8 to become CD4SP or CD8 single positive (CD8SP) and migrate to the thymic medulla. Negative selection then occurs through a process of affinity-based selection in which MHC:self-antigen on mTECs and thymic dendritic cells is presented to CD4SP and CD8SP cells, although evidence exists suggesting that some negative selection can also occur at the DP stage in the cortex or corticomedullary junction ( 55 – 57 ). Expression of self-antigen (aka TRAs) is driven by key transcription regulators such as Aire and Fezf2 ( 58 ).…”

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“…This includes the DPbla (blast) stage that occurs after the ISP stage and is characterized by rapid proliferation, the DPre (rearranging) stage in which the TCRa locus is rearranged and the mature TCR can receive signal for positive selection, and the DPsel (selection) stage when cells undergo positive selection (53). Positive selection is mediated by antigen presenting cells called cortical thymic epithelial cells (cTECs) that express self-MHC molecules for DP thymocytes to sample TCR binding for sufficient affinity to promote survival (54,55). Upon completion of positive selection, DP thymocytes downregulate either CD4 or CD8 to become CD4SP or CD8 single positive (CD8SP) and migrate to the thymic medulla.…”

“…Upon completion of positive selection, DP thymocytes downregulate either CD4 or CD8 to become CD4SP or CD8 single positive (CD8SP) and migrate to the thymic medulla. Negative selection then occurs through a process of affinity-based selection in which MHC:self-antigen on mTECs and thymic dendritic cells is presented to CD4SP and CD8SP cells, although evidence exists suggesting that some negative selection can also occur at the DP stage in the cortex or corticomedullary junction (55)(56)(57). Expression of self-antigen (aka TRAs) is driven by key transcription regulators such as Aire and Fezf2 (58).…”