Phosphorylated TYK2 orchestrates the pathogenic program of CD4 + T cells in the development of CNS autoimmunity

The imbalance between pathogenic Th1/Th17 cells and regulatory T cells (Tregs) is a central mechanism in central nervous system (CNS) autoimmune diseases, including autoimmune uveitis (AU) and multiple sclerosis. Tyrosine kinase 2 (TYK2) mediates signaling downstream of multiple cytokines implicated in CD4 + T cell differentiation, yet its subset-specific activation and therapeutic potential in CNS autoimmunity remain unclear. Here, we investigated the subset-specific activation of TYK2 and evaluated the therapeutic potential of selective TYK2 inhibition in CNS autoimmune diseases.

TYK2 phosphorylation was examined in CD4 + T cell subsets from AU patients and from experimental autoimmune uveitis (EAU) and encephalomyelitis (EAE) models. The therapeutic effects and mechanisms of a selective TYK2 inhibitor were assessed using flow cytometry, single-cell RNA sequencing, adoptive transfer, in vitro cellular assays, and ex vivo stimulation of patient peripheral blood mononuclear cells.

TYK2 phosphorylation was preferentially activated in Th1 and Th17 cells compared with Tregs in both patients and disease models. TYK2 inhibition significantly reduced clinical and histopathological scores in EAU and EAE, suppressing Th1/Th17 differentiation and production of IFN-γ and IL-17A, while Treg proportion and function remained intact. Mechanistically, IFN-α/β, IL-12, and IL-23-but not IL-2-induced TYK2 phosphorylation in CD4 + T cells. Accordingly, TYK2 blockade selectively inhibited STAT1/2/3/4 activation downstream of these cytokines without affecting IL-2-induced STAT5 phosphorylation in Tregs. These lineage-selective effects were confirmed in peripheral blood mononuclear cells from AU patients.

TYK2 acts as a lineage-selective therapeutic target in CNS autoimmunity. Its inhibition suppresses pathogenic Th1/Th17 responses while preserving Treg proportion and function by targeting cytokine-specific signaling pathways, thereby rebalancing the effector-regulatory immune axis.