SLC39A10 is a key zinc transporter in T cells and its loss mitigates autoimmune disease.

Abstract

Zinc homeostasis plays an essential role in maintaining immune function and is tightly regulated by zinc transporters. We previously reported that the zinc transporter SLC39A10, located in the cell membrane, critically regulates the susceptibility of macrophages to inflammatory stimuli; however, the functional role of SLC39A10 in T cells is currently unknown. Here, we identified two SNPs in SLC39A10 that are associated with inflammatory bowel disease (IBD). We then generated transgenic mice with T cell-specific deletion of Slc39a10 (cKO) and found that its loss not only protects against disease progression in IBD and experimental autoimmune encephalomyelitis (EAE), but also induces massive apoptosis via a p53/p21- and Bcl2-independent process. Mechanistically, we show that Slc39a10 serves as a key zinc importer upon activation of T cell receptor to safeguard DNA replication. Together, these findings provide new mechanistic insights and potential targets for the development of new therapeutic strategies for the treatment and/or prevention of T cell-mediated autoimmune diseases.