Tuomela, K.; Garcia, R. V.; Boardman, D. A.; Tavakoli, P.; Ancheta-Schmit, M.; Sham, H. P.; Chen, L.; Struthers, M.; Bressler, B.; Vallance, B. A.; Zhao, Q.; Levings, M. K.

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