Endocrine Abstracts

A key role of the thymic medulla is to negatively select CD4⁺ and CD8⁺ thymocytes expressing potentially autoreactive αβT-cell receptors (αβTCR), a process important for T-cell tolerance induction. It is known that tolerance induction in the thymus involves multiple processes, and the thymus medulla is also known to contribute through guiding the generation and selection of natural FoxP3⁺ regulatory T-cells (nT-Reg). Of the cells contained within the medulla, thymic medullary thymic epithelial cells (mTEC) have been implicated as a key regulator of the major aspects of tolerance induction. This is at least in part through their expression of the autoimmune regulator (AIRE) gene, the only known regulator of intrathymic peripheral tissue antigen (PTA) expression, and the gene mutated in autoimmune polyendocrinopathy (APECED). Importantly, the role of the Aire⁺ mTEC subset in T-cell tolerance mechanisms is poorly understood. Here we have investigated the cellular and molecular processes that lead to the formation of Aire⁺ mTEC, and investigated their role in T-cell tolerance induction. We provide evidence that the establishment of tolerogenic mTEC in the fetal and neonatal periods is under the control of cellular components of the innate immune system, including invariant gamma delta T-cells, and lymphoid tissue inducer cells. Thus, during a time window that is known to be essential for tolerance induction, the innate immune system acts to establish Aire-expressing tolerogenic thymic microenvironments that ultimately shape the nascent αβTCR repertoire. Moreover, by performing in vivo thymus transplantation experiments involving thymic tissue genetically deficient in mTEC, we provide evidence that the thymus medulla controls FoxP3⁺T-Reg development through the generation of their FoxP3⁻CD25⁺ precursors. Collectively, our data shows that medullary thymic microenvironments that are shaped by the innate immune system play an essential role in imposing tolerance on the emerging adaptive immune system through both central and peripheral tolerance mechanisms.

Declaration of funding

MRC Programme Grant.