Molecular mechanism of T cell tolerance in the thymus

Autoimmune diseases arise due to a breakdown in immunological tolerance, a complex network of ‘central’ and ‘peripheral’ mechanisms. Immunological self-tolerance is a fundamental property of the immune system which not only averts autoimmune responses, but is also highly relevant to cancer immunity. Central tolerance is shaped in the thymus, where medullary thymic epithelial cells (mTECs) orchestrate the negative selection of a nascent repertoire of autoreactive T cells and positive selection of regulatory T cells (Treg). Although the cellular mechanisms involved in establishment and maintenance of immunological self-tolerance are significantly well-characterized, the molecular events preceding these mechanisms remain an area of intense investigative research.

We are investigating the molecular cascade promoting central tolerance in the thymus using the murine counterpart of a rare monogenic human autoimmune disorder, Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED), caused by mutations in the Autoimmune Regulator (AIRE) gene, as an experimental model. AIRE is a transcriptional regulator which drives the expression of scores of loci encoding tissue-specific self-antigens in mTECs, and ensures selective removal of thymocytes bearing T cell receptors that recognize these antigens. Combining a series of multidisciplinary experimental approaches, ranging from transcriptomics and epigenomics to genetic perturbation in mice, we aim to unravel the molecular circuitry of AIRE, and identify potential novel targets for patients with AIRE mutations.