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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\u2010specific antigen processing machinery, including the \u03b25t\u2010containing thymoproteasome and cathepsin L, which generate self\u2010peptide\u2013MHC complexes with moderated affinity. mTECs broadly express tissue\u2010restricted antigens (TRAs) under the control of AIRE, establishing a foundational self\u2010antigen landscape for central tolerance. DCs execute efficient clonal deletion via cross\u2010presentation and antigen transfer, while B cells contribute to tolerance against soluble antigens through BCR\u2010mediated 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\u2010cell development but also offer novel avenues for immune reprogramming in disease.<\/jats:p>","DOI":"10.1111\/imm.70160","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T08:31:33Z","timestamp":1782289893000},"page":"210-223","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Thymic\n                    <scp>APC<\/scp>\n                    Networks Orchestrate T\u2010Cell Selection: Mechanisms and Therapeutic Opportunities in Immune Disorders"],"prefix":"10.1111","volume":"179","author":[{"given":"Yuqi","family":"Luo","sequence":"first","affiliation":[{"name":"College of Medicine and Health Sciences, China Three Gorges University  Yichang Hubei China"},{"name":"Laboratory of Brain Disorders, Collaborative Innovation Center for Brain Disorders Beijing Institute of Brain Disorders, Ministry of Science and Technology, Capital 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