Cortical Thymic Epithelial Cells: Key Developers of the Code of T‐Cell Selection and TCR Repertoire Diversity

ABSTRACT The thymus is crucial for developing immunocompetent T cells expressing T cell receptors (TCRs) capable of responding to foreign antigens while remaining tolerant to self‐components. T cell development involves complex interactions with thymic stromal cells, including thymic epithelial cells (TECs). Particularly, T cell selection relies on the coordinated, yet spatially and temporally distinct functions of rare cortical (cTECs) and medullary (mTECs) subtypes. While cTECs are essential for T cell lineage commitment and positive selection, mTECs play a role in central tolerance by eliminating autoreactive cells and promoting regulatory T cell development. Thus, thymic selection refines the TCR repertoire, promoting immune competence to foreign antigens while ensuring tolerance to self. This review focuses on the instructive role of cTECs in positive selection and CD4/CD8 lineage commitment. It further explores recent discoveries on the molecular mechanisms underlying the generation of selective self‐peptide–MHC ligands, which are critical for TCR diversification. We also highlight recent findings on TEC heterogeneity and discuss their potential roles in T cell selection. Understanding TEC diversity and their specialized machinery in generating selective ligands reshapes our view of thymic biology and is key to comprehending their influence on peripheral CD4 + and CD8 + T cell functions.