CTR1-mediated copper uptake orchestrates metabolic-epigenetic regulation of pathogenic T H 17 cells in autoimmune disease
Year: 2026
Type: preprint
Abstract: ABSTRACT Pathogenic T helper 17 (pT H 17) cells are a subset of CD4 + T cells driving autoimmune diseases including multiple sclerosis (MS). Compared to homeostatic T H 17 cells and other T H subsets, pT H 17 have enhanced mitochondrial function and oxidative phosphorylation (OXPHOS) that supports their differentiation and pathogenic function. Here we identify Copper Transporter 1 (CTR1), encoded by Slc31a1, as essential for copper uptake in CD4 + T cells, OXPHOS and pT H 17 cell differentiation and function. While copper levels are known to be higher in the cerebrospinal fluid of patients with MS compared to healthy individuals, and excess copper contributes to oligodendrocyte loss in murine models of MS, the effect of copper on T cell function and pathogenicity in MS are unclear. We demonstrate that deletion of Slc31a1 in CD4 + T cells decreased intracellular copper levels, disrupting mitochondrial respiration and rewiring metabolism. These changes altered the epigenetic landscape of pT H 17 cells by impairing DNA demethylation capacity, leading to hypermethylated DNA and altered chromatin accessibility at key binding sites for AP-1 transcription factors essential for pT H 17 differentiation. As a result, CTR1-deficient T cells showed defective differentiation into pT H 17 cells, with decreased production of IL-17A and expression of T H 17 signature genes, while the differentiation of other CD4 + T cell subsets remained largely unaffected. Moreover, T cell-specific deletion of Slc31a1 protected mice from central nervous system (CNS) inflammation in the experimental autoimmune encephalomyelitis (EAE) model of MS by suppressing clonal expansion of autoreactive CD4 + T cells. These findings establish copper as a critical regulator of pT H 17 differentiation and function, revealing a previously unknown molecular link between copper homeostasis, metabolism and epigenetic regulation governing pT H 17-mediated autoimmunity.
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214574100