TYK2 inhibition enhances Treg differentiation and function while preventing Th1 and Th17 differentiation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40834860.
- Also identified by DOI 10.1016/j.xcrm.2025.102303 and PMC identifier 12490244.
- Licence recorded as CC BY-NC-ND.
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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<sup>+</sup> 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<sup>+</sup> 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.
Medical subject headings
- TYK2 Kinase
- Th17 Cells
- T-Lymphocytes, Regulatory
- Cell Differentiation
- Th1 Cells
- Protein Kinase Inhibitors