Thymic APC Networks Orchestrate T‐Cell Selection: Mechanisms and Therapeutic Opportunities in Immune Disorders

ABSTRACT

The thymus is a primary lymphoid organ where antigen‐presenting cells (APCs) orchestrate the development of a self‐tolerant and functional T‐cell repertoire. Herein, we elucidate the pivotal role of thymic selection defects in autoimmune pathogenesis and evaluate targeted therapeutic strategies for these mechanisms. This review synthesises recent advances in understanding how cortical thymic epithelial cells (cTECs), medullary thymic epithelial cells (mTECs), dendritic cells (DCs), and B cells collaboratively mediate positive and negative selection. cTECs drive positive selection through thymus‐specific antigen processing machinery, including the β5t‐containing thymoproteasome and cathepsin L, which generate self‐peptide–MHC complexes with moderated affinity. mTECs broadly express tissue‐restricted antigens (TRAs) under the control of AIRE, establishing a foundational self‐antigen landscape for central tolerance. DCs execute efficient clonal deletion via cross‐presentation and antigen transfer, while B cells contribute to tolerance against soluble antigens through BCR‐mediated uptake. We further quantify the relative contributions of these APC subsets during thymic selection and discuss how defects in these processes underlie autoimmune diseases and immunodeficiencies. Finally, we highlight emerging therapeutic strategies that target thymic selection mechanisms, including AIRE modulation, tolerogenic DC vaccines, and thymic tissue engineering. These insights not only advance our understanding of T‐cell development but also offer novel avenues for immune reprogramming in disease.