How Thymocyte Deletion in the Cortex May Curtail Antigen-Specific T-Regulatory Cell Development in the Medulla

CD4⁺ T cell responses to self-antigens are pivotal for immunological self-tolerance. Activation of Foxp3^- T-conventional (T-conv) cells can precipitate autoimmune disease, whereas activation of Foxp3⁺ T-regulatory (T-reg) cells is essential to prevent autoimmune disease. This distinction indicates the importance of the thymus in controlling the differentiation of self-reactive CD4⁺ T cells. Thymocytes and thymic antigen-presenting cells (APC) depend on each other for normal maturation and differentiation. In this Hypothesis and Theory article, we propose this mutual dependence dictates which self-antigens induce T-reg cell development in the thymic medulla. We postulate self-reactive CD4⁺ CD8^- thymocytes deliver signals that stabilize and amplify the presentation of their cognate self-antigen by APC in the thymic medulla, thereby seeding a niche for the development of T-reg cells specific for the same self-antigen. By limiting the number of antigen-specific CD4⁺ thymocytes in the medulla, thymocyte deletion in the cortex may impede the formation of medullary T-reg niches containing certain self-antigens. Susceptibility to autoimmune disease may arise from cortical deletion creating a "hole" in the self-antigen repertoire recognized by T-reg cells.