Dimethyl itaconate suppresses dendritic cell and CD8⁺ T cell responses to halt vitiligo

Although dendritic cell (DC)- and CD8⁺ T cell-mediated autoimmunity is critical for destroying melanocytes in vitiligo, treatment options remain limited by the absence of therapies that cotarget both cell types.

We first evaluated the association between the immunoregulatory metabolite itaconate and disease development, by determining human vitiligo serum itaconate levels and monitoring depigmentation progression in Acod1 knockout (KO) mice with endogenous itaconate deficiency. We further evaluated the therapeutic efficacy of the itaconate derivative, dimethyl itaconate (DI) in mice and assessed its effects on cutaneous infiltration and the functional properties of DCs and CD8⁺ T cells in vivo and ex vivo. The gene signatures and signaling pathways involved in DI-treated CD8⁺ T cells were also assessed.

We observed an elevation of circulating itaconate in vitiligo patients, whereas itaconate deficiency accelerated depigmentation in Acod1 KO mice after vitiligo induction. The administration of DI halted vitiligo development and promoted repigmentation, with elevated circulating itaconate levels, increased melanocyte counts, and decreased cutaneous CD8⁺ T cell densities. Mechanistically, DI dampened CD8⁺ T cell activation (CD69), effector function (Interferon-γ, IFN-γ), cytotoxicity (Gzmb), proliferation, and proinflammatory gene expression (Csf1, Ifitm1, CD49a, NKG2D, and NKG2A), partly by suppressing the Janus kinase (JAK)‒STAT pathway. Moreover, DI-treated mice exhibited reduced cutaneous DC infiltration, as well as fewer DCs with mature and migratory phenotypes.

Our findings identify DI as a metabolite-derived small molecule that protects against autoimmune injury by cotargeting DC and CD8⁺ T cell responses, thereby demonstrating a promising therapeutic strategy and providing a foundation for treating vitiligo and other cell-specific autoimmune diseases.