Gene Regulatory Events in Establishing Mature T Cell Tolerance

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

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 are studying G protein-coupled receptor 15 (GPR15), a chemokine receptor that is 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 is unclear. We have now identified several patients carrying loss of function GPR15 mutations who have early-onset IBD. Our studies provided evidence that GPR15 normally mediates CD8+ T cell homing in both humans and mice. Although traditional regulatory T lymphocytes are critical to maintain colon epithelium homeostasis, in GPR15 deficiency, loss of a different T cell subset in the colon leads to colitis. Mechanistically, we identified that this new T cell subset prevents colitis by targeting activated macrophages through a signaling pathway that controls apoptosis. Thus, GPR15, as a chemokine receptor, plays an important role in the T cells’ homing to maintain intestinal barrier homeostasis, which provides a promising target on T cells for IBD therapy. Our second project, focusing on atherosclerosis, is 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 the homeostasis of lipids. We previously reported that GIMAP6 knockout mice have enlarged hearts and lipid and immune abnormalities. These intriguing findings raise the question of whether GIMAP6 could function as a modulator of metabolism and atherosclerotic development. For this project, we have set up and are characterizing genetically defined mouse and cell culture models of disease, focusing on immune and endothelial cells, which highly express GIMAP6 and are likely to play a role in disease pathogenesis.