Glucose metabolism in CD4+ T cell subsets modulates inflammatory disease and autoimmunity (P4126)

Abstract

Upon stimulation, CD4+ T cells differentiate into effector (Teff) or regulatory (Treg) T cells, the balance of which is crucial to prevent inflammation or autoimmunity. One approach to treat autoimmune disease is to modulate T cell differentiation to favor Treg over Teff cells. We examined the metabolite and metabolic gene expression profiles of the subsets and found that they have distinct metabolic requirements and programs. Teff have a high expression of the glucose transporter GLUT1 as well as glucose metabolism genes and a high rate of glycolysis. In contrast, Treg instead have high expression of mitochondrial metabolism genes and low GLUT1 levels. The effect of metabolic differences to modulate the Teff:Treg balance can be tested directly via genetic modulation of GLUT1. In vitro, T cells from GLUT1 transgenic mice are more inflammatory than wildtype littermates. Alternatively, T cells from GLUT1 knockout mice are unable to increase glucose metabolism upon activation and have fewer Th1, Th2 and Th17 cells. Despite less total CD4+ T cells, these mice have normal natural and inducible Treg numbers. In a mouse model of inflammatory bowel disease (IBD), deletion of GLUT1 in T cells inhibits IBD disease progression. The mice have less CD4+ T cells in the mesenteric lymph nodes and decreased inflammatory cytokine production than wildtype control T cells. Thus, the modulation of glucose metabolism may provide an alternative treatment for inflammatory and autoimmune disease.