Identification and characterization of B cell dependent regulatory T cells 3244

Abstract Description A sizable fraction of peripheral B cells express immunoglobulin receptors that exhibit reactivity to self-antigens, necessitating multiple layers of regulation to constrain these cells and prevent autoimmunity. We are investigating the hypothesis that a thymically-selected population of regulatory T cells (Tregs), termed “B cell-dependent” (BCD) Treg cells, are specialized to constrain these self-reactive B cells via direct interactions in the periphery. Consistent with this notion, we demonstrate that the number of the polyclonal Tregs in the spleen is reduced in mice lacking MHC-II expression on B cells. In addition, using single cell RNA-sequencing, we identified two distinct clusters of clonally related Treg cells that are significantly underrepresented in this setting. Treg cells in these putative BCD Treg clusters co-express numerous genes enabling their molecular identification and functional study. Further, these clusters are marked by shared, expanded αβTCRs that are uniquely expressed by Tregs in these clusters, enabling downstream clonal analysis of BCD Tregs. In parallel, using a TCRα profiling screen in fixed TCRβ transgenic mice, we identified recurrent Treg clones lost in settings of restricted B cell diversity, and demonstrated the steady state activation of these clones requires MHC-II expression by B cells. Ongoing studies aim to define the differentiation, specificity, and function of these Treg cells and define their role in regulating B cell responses. Funding Sources Immunology Training Grant: T32-AI007090 U01-AI154560 Robert E. Priest Fellowship, Department of Pathology, University of Chicago Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)