Targeting T cell activation and lupus autoimmune phenotypes with a novel glucose transporter inhibitor

Abstract

Abstract CD4+ T cells have numerous features of over-activated cellular metabolism in lupus patients and mouse models of the disease, including a higher glycolysis. We have previously shown that treatment of lupus-prone mice with 2-deoxy-D-glucose, which inhibits the first step of glycolysis, was sufficient to prevent autoimmune activation. Because 2DG has potential off-target effects, we sought to directly inhibit glycolysis by blocking glucose transporters. Here, we show that CG-5, a novel glucose transporter inhibitor, ameliorated lupus-like symptoms in a spontaneous lupus-prone mouse model, B6.NZM2410.Sle1.Sle2.Sle3 (Triple-congenic, TC), and in a chronic graft-versus-host-disease (cGVHD) model of induced lupus. Moreover, CG-5 treatment reduced lupus phenotypes including the expansion of germinal center B cells, as well as the production of autoantibodies in both TC mice and cGVHD models. In vitro, CG-5 blocked glycolysis in CD4+ T cells, and limited the expansion of CD4+ T cells induced by alloreactive stimulation. CG-5 also modulated CD4+ T cell polarization by inhibiting Th1 and Th17 differentiation and promoting regulatory T (Treg) induction. Finally, CG-5 blocked glycolysis in human T cells. Overall, our data suggest that blocking glucose uptake with a small molecule inhibitor ameliorates the symptoms of lupus, at least partially due to its inhibition of glycolysis in CD4+ T cells. Supported by grants from the NIH (RO1 AI128901) and the Lupus Research Alliance (LRA-TIL 416522) to LM, and by an Experimental Pathology Innovative Grant from the Department of Pathology, Immunology and Laboratory Medicine, University of Florida to WL.