Abstract
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.