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

Area of Science:

• Immunology
• Pharmacology
• Autoimmune Diseases

Background:

• Janus kinase (JAK) inhibitors are used for inflammatory diseases but their impact on regulatory T cells (Tregs) is unclear.
• Understanding Treg modulation is crucial for developing effective immunotherapies.

Purpose of the Study:

• To compare the effects of a JAK inhibitor (upadacitinib) and a Tyrosine kinase 2 (TYK2) inhibitor (BMS-986202) on human Treg differentiation and function.
• To evaluate the potential of TYK2 inhibition for inducing immune tolerance.

Main Methods:

• Investigated human Treg differentiation and phenotype using upadacitinib and BMS-986202.
• Assessed Treg induction, suppressive function, and stability under inflammatory conditions.
• Analyzed CD4+ T cell differentiation in cells from inflammatory bowel disease patients.

Main Results:

• Both upadacitinib and BMS-986202 inhibited naive CD4+ T cell differentiation into Th1/17 cells.
• Only BMS-986202 and deucravacitinib spared interleukin-2 (IL-2) signaling and Treg induction.
• BMS-986202 enhanced Treg suppressive function and stability, and redirected CD4+ T cells toward a Treg phenotype in IBD cells.

Conclusions:

• TYK2 inhibition spares and enhances regulatory T cell function, unlike JAK inhibition.
• TYK2 inhibitors represent a promising strategy for inducing immune tolerance in autoimmune and inflammatory diseases.