Immune regulation of NADPH oxidase 2 in T cells

Abstract

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a professional reactive oxygen species (ROS) generating enzyme. NADPH oxidase 2 (Nox2) initially identified in phagocytes is responsible for the production of ROS that kills engulfed pathogens. Chronic granulomatous disease (CGD) is a rare hereditary disorder caused by mutations in a component of NADPH complex. Therefore, CGD patients are prone to be severely susceptible to life-threatening infections from bacteria and fungi. However, paradoxically, CGD patients also suffer from autoimmune diseases caused by excessive immune reactions. Despite the co-existence of these contradictory symptoms, the molecular mechanisms are still unclear and controversial. In this study, we uncovered Nox2 deficiency in T cells promotes in vitro T cell proliferation and type 1 help T cell (Th1) and Th17 cell-mediated immune responses in a T cell-intrinsic manner. Furthermore, using Th1 and Th17-mediated disease model, experimental autoimmune encephalomyelitis (EAE), we clarified Nox2 deficiency enhances Th1/Th17-mediated inflammation through augmented mitochondrial reactive oxygen species (ROS). These are due to increased mitochondrial respiration capacity and mitochondrial biogenesis induced by lack of Nox2. We revealed increased mitochondrial ROS diminishes tyrosine phosphatase SHP-1 activity and this attenuated SHP1 activity by mitochondrial ROS promotes Th1/Th17 immune responses through JAK/STAT signaling. Collectively, we show enhanced T cell proliferation and Th1/Th17 differentiation in Nox2 deficient CD4+ T cells via regulation of mitochondrial ROS and exaggerated EAE phenotypes through increased Th1/Th17-mediated inflammation. Therefore, our data indicate mitochondrial ROS-induced by a Nox2 deficiency in T cells is crucial for the Th1/Th17 inflammatory program.