Copper Shapes T Cell Metabolism and Epigenetics to Drive Pathogenic Th17 Cell Function in Autoimmunity 2259915

Abstract

Pathogenic T helper 17 (pTh17) cells are a subset of CD4+ T cells driving autoimmune diseases including multiple sclerosis (MS). To identify transporters controlling pTh17 cells, we conducted an in vivo shRNA-based forward genetic screen using the experimental autoimmune encephalomyelitis (EAE) model of MS. Copper Transporter 1 (CTR1), essential for copper uptake, emerged as a key regulator of pTh17 cell differentiation and function. Copper supports different cellular processes including mitochondrial metabolism and reactive oxygen species (ROS) balance. Deletion of CTR1 in CD4 T cells decreased intracellular copper levels, disrupting mitochondrial respiration and rewiring metabolism. These changes disrupted the epigenetic landscape of pTh17 cells by inducing DNA hypermethylation and altered chromatin accessibility, impairing transcription factor binding. As a result, CTR1-deficient T cells showed defective differentiation into pTh17 cells, with decreased production of IL-17A and expression of Th17 signature genes, while differentiation of other CD4 subsets remained unaffected. Moreover, T cell-specific deletion of CTR1 protected mice from EAE by suppressing clonal expansion of autoreactive CD4+ T cells and CNS inflammation. These findings establish copper as a critical regulator of pTh17 differentiation and function, revealing a previously unknown molecular link between copper homeostasis, metabolism and epigenetic regulation governing Th17-mediated autoimmunity. Colton Autoimmunity Center Immune Response Regulation: Molecular Mechanisms (IRM)