Copper Transporter 1 (CTR1) regulates T cell metabolism and pathogenic Th17 cell polarization 4345

Abstract Description Pathogenic T helper 17 (pTh17) cells are a subset of CD4+ T cells that is critical for the pathogenesis of several autoimmune diseases including multiple sclerosis (MS). To identify transporters controlling pTh17 cells in autoimmune disease, we conducted an in vivo forward genetic screen in pTh17 cells using the experimental autoimmune encephalomyelitis (EAE) model of MS. We identified several new transporters including the copper transporter 1 (CTR1). Inside cells, copper binds to cuproenzymes that control cellular processes including oxidative phosphorylation (OXPHOS) via cytochrome C oxidase and reactive oxygen species (ROS) homeostasis via superoxide dismutase 1 (SOD1). Here we show that deletion of CTR1 in murine CD4+ T cells decreases intracellular copper levels affecting mitochondrial ROS production and respiration. Deletion of CTR1 suppresses CD4+ T cell differentiation into pTh17 cells, production of IL-17A and expression of Th17 signature genes in vitro. These effects appear to be specific to pTh17 cells because Th1 differentiation and function were not affected. Additionally, T cell-specific deletion of CTR1 protects mice from EAE in vivo which is associated with strongly reduced clonal expansion of autoreactive CD4+ T cells and CNS inflammation. Taken together, our data demonstrate that maintaining intracellular copper homeostasis is essential for the differentiation and function of pTh17 cells and their ability to cause autoimmune inflammation. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)