Expression and Function of the Non‐phagocytic NADPH Oxidase, Duox1 in T Lymphocytes

Abstract

The family of NADPH oxidase enzymes serve to generate reactive oxygen species (ROS), and the prototypic phagocyte‐type NADPH oxidase produces large amounts of ROS that serve a host defense role. Fibroblasts, B lymphocytes and platelets also express NOX2/gp91phox protein which leads to ROS production. Recent discovery of multiple homologues of gp91phox (e.g., NOX1, NOX4, Duox1/2) has broadened the NADPH oxidase activity in “non‐phagocytic” cells. In non‐phagocytic cells and tissues, NOX family members produce lower levels of ROS and participate in regulatory and signaling roles. We have recently shown that T cells express the phagocyte‐type NADPH oxidase which regulates T cell responses. Our new data indicate that T cells also express mRNA and protein for the calcium‐dependent, non‐phagocytic oxidase Duox1 and Duox1 produces ROS early in TCR signaling. Downregulation of Duox1 expression in primary and cultured T cells with siRNA resulted in selective changes in T cell receptor induced signal transduction. While phosphorylation of early mediators of TCR signaling (ZAP‐70, PLC‐g) was largely unaffected, TCR‐induced activation of ERK was strongly inhibited and secretion of multiple cytokines including IL‐4, IFN‐g, and TNFa was also reduced. Thus, T cells express multiple NADPH oxidases and Duox1 serves to regulate early TCR signal transduction. Supported by NIH R01 AI070823.