Thymic APC networks critically shape T-cell selection, offering novel immune reprogramming strategies for autoimmune disorders

The development of a self-tolerant and functional T-cell repertoire is crucial for preventing autoimmune diseases. The thymus, a primary lymphoid organ, is where T cells undergo rigorous selection to eliminate self-reactive clones while preserving those capable of recognizing foreign pathogens. Current treatments for autoimmune disorders often manage symptoms rather than addressing the root cause of T-cell dysregulation. A deeper understanding of how thymic antigen-presenting cells (APCs) orchestrate this delicate balance is essential to identify precise therapeutic targets and develop strategies for immune reprogramming.

This comprehensive review synthesizes recent advances in understanding the intricate roles of thymic antigen-presenting cell (APC) networks in T-cell development. The authors critically evaluated existing literature to elucidate how cortical thymic epithelial cells (cTECs), medullary thymic epithelial cells (mTECs), dendritic cells (DCs), and B cells collaboratively mediate positive and negative T-cell selection. The review further quantified the relative contributions of these APC subsets and discussed how defects in these processes underpin autoimmune diseases and immunodeficiencies, ultimately proposing emerging therapeutic strategies.

The review elucidated distinct yet collaborative roles for various thymic APCs in T-cell selection. cTECs were found to drive positive selection through specialized thymus-specific antigen processing machinery, including the β5t-containing thymoproteasome and cathepsin L, which generate self-peptide-MHC complexes with moderated affinity. mTECs establish central tolerance by broadly expressing diverse tissue-restricted antigens (TRAs) under the transcriptional control of AIRE, creating a foundational self-antigen landscape. DCs execute efficient clonal deletion of highly self-reactive T cells via cross-presentation and antigen transfer mechanisms. B cells contribute to tolerance against soluble antigens through BCR-mediated uptake and presentation. The authors highlighted that defects in these finely tuned processes are foundational to autoimmune pathogenesis. For instance, dysregulation of AIRE expression in mTECs can lead to the escape of self-reactive T cells.

This collaborative network of cTECs, mTECs, DCs, and B cells is indispensable for orchestrating a self-tolerant T-cell repertoire, with specific defects directly linked to autoimmune disease development.