Wednesday, December 4, 2024
12/4/2024
Autoimmune diseases are a growing health problem: there are many of them (>100); they are quite frequent in toto (~10% of Americans); and their incidence has been increasing for decades. Autoimmunity results from a breakdown in one or more central or peripheral mechanisms of lymphocyte tolerance induction or maintenance. In the case of T cells, central tolerance is imposed within the thymus, key orchestrators being medullary thymic epithelial cells (mTECs), which play critical roles in both negative selection of T effector cells and positive selection of T regulatory cells (Tregs). A unique feature of mTECs is expression of hundreds of loci encoding antigens typically associated with fully differentiated peripheral parenchymal cells (peripheral-tissue antigens or PTAs). Most of this “misplaced” gene expression is driven by the transcriptional regulator Aire. Loss of Aire in both mice and humans results in a multi-organ autoimmune disease; in addition, recent studies have uncovered an association of Aire with several common human autoimmune diseases. During the last funding-cycle, we serendipitously discovered a second, previously unappreciated arm of thymocyte tolerization: thymic mimetic cells. These cells are a heterogeneous set of (mostly) Aire-dependent, post-Aire mTECs that have co-opted the lineage-defining transcription factors (LDTFs), chromatin-accessibility landscapes, and gene-expression profiles of particular extra-thymic cell-types, while maintaining their mTEC identity. To date, 15 different mimetic-cell subtypes have been identified, including tuft, muscle, ciliated, microfold and sebocyte mTECs. Accrual of thymic mimetic cells depends critically on the LDTF(s) they express and differentially on Aire. Directing expression of a neoantigen to mimetic cells tolerizes cognate thymocytes. Building on this discovery, and abiding by the molecular focus of this grant, THE OVERALL GOAL OF THIS PROPOSED PROJECT IS TO ELUCIDATE THE MOLECULAR MECHANISMS UNDERLYING MIMETIC mTEC GENERATION, IN PARTICULAR MOLECULAR RELATIONSHIPS BETWEEN THE AIRE-BASED AND MIMETIC-CELL BASED PATHWAYS OF T-CELL TOLERANCE INDUCTION. This goal will be addressed by three independent and cross-informing Aims: A. To determine how Aire and LDTFs influence each other’s genomic activities. B. To determine how modulating the binding of Aire to chromatin in Aire-stage mTECs influences the accrual of mimetic-cell subtypes at the post-Aire stage. C. To unravel the lineage relationships of thymic mimetic cells. This study will yield novel (potentially the first) information on how thymic mimetic cells are generated – in particular how the Aire-based and mimetic-cell-based arms of thymocyte tolerance induction are integrated. This information should prove highly valuable in both dissecting mechanisms of diverse autoimmune diseases and, potentially, manipulating thymic cells or molecules to treat or avoid them.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
