Gene Regulatory Events in Establishing Mature T Cell Tolerance

National Institute Of Allergy And Infectious Diseases

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Abstract

Inborn errors of immunity (IEI) can affect global cellular regulatory systems. In this project we are researching two different IEI that affect different organ systems with devastating disease. In the first project, we examine G protein-coupled receptor 15 (GPR15), a chemokine receptor, primarily expressed in T cells based on human single-cell RNA sequencing data. Its natural ligand, GPR15L, is found in the gastrointestinal basal epithelial region and presumably guide GPR15+ T cells to that location. Previous studies showed that Gpr15 knockout mice were more susceptible to C. rodentium-induced colitis but the function of GPR15 and whether its deficiency plays a role in inflammatory bowel disease (IBD) in humans are unclear. We recruited four pediatric patients who developed severe early-onset IBD and found novel GPR15 mutations using whole-exome sequencing. A reduction in T cells was observed in patient colon biopsies. We showed that the GPR15 mutations led to impaired GPR15 surface expression and signaling causing altered immune cells in the colon wall including reduced CD8+ T cells, enriched NK cells, and unchanged CD4+ Tregs, which was not observed in ulcerative colitis, Crohns disease, or healthy controls. Loss of GPR15 in mice caused reduced CD8+ intraepithelial lymphocytes (IELs) in the colon, dysbiosis, and susceptibility to intestinal inflammation. Using sc-RNA sequencing, we found a comparable GPR15+ CD8+ T cell population in human colon that expressed inhibitory killer cell immunoglobulin-like receptors and immunoregulatory genes. Further adoptive transfer experiments show that this unique CD8+ T cell population controls immune homeostasis and inflammation in the intestine. Thus, this new genetic disease offers new insights into IBD pathogenesis and novel therapeutics. In the last few months we have started a second project, focusing on atherosclerosis, a complex inflammatory disease characterized by the accumulation of lipids within arterial walls. Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide. Identifying key regulators involved in this pathogenic process is critical for developing targeted therapeutic strategies. Recent investigations have focused on GIMAP6, a GTPase of the immune-associated protein (GIMAP) family, as a potential candidate influencing atherosclerotic development and lipid homeostasis. We found GIMAP6 knockout mice to have significantly increased heart size and accumulation of lipids within macrophages compared to wild type. These intriguing findings raise the question of whether GIMAP6 could serve as a novel modulator of lipid metabolism and atherosclerotic development.