TYK2 inhibition enhances Treg differentiation and function while preventing Th1 and Th17 differentiation.

Janus kinase (JAK) inhibitors are widely used to inhibit inflammatory cytokine signaling in autoimmune and inflammatory diseases, but their effect on regulatory T cells (Tregs) is poorly characterized. We investigated the effect of a JAK inhibitor, upadacitinib, on human Treg differentiation and phenotype in comparison to BMS-986202, a selective Tyrosine kinase 2 (TYK2) inhibitor. Both upadacitinib and BMS-986202 blocked naive CD4⁺ T cell differentiation into Th1/17 cells, but only BMS-986202 and a related TYK2 inhibitor, deucravacitinib, spared interleukin-2 (IL-2) signaling and Treg induction. BMS-986202 also increased Treg suppressive function and stability under Th1/17-polarizing conditions, whereas upadacitinib significantly impaired the phenotype and viability of ex vivo Tregs. In lamina propria mononuclear cells from patients with inflammatory bowel disease cultured under Th17-polarizing conditions, BMS-986202 redirected CD4⁺ T cells toward a Treg phenotype. The Treg-sparing and enhancing properties of TYK2 inhibition suggest that TYK2 inhibitors are a promising pharmacological approach for tolerance induction.