Generation of Regulatory T Cells From Human Memory CD4⁺T Cells by Upregulation of Naked Cuticle Homolog 2

Regulatory T cells are indispensable for immune homeostasis and tolerance to self-antigens and allergens. The imbalance between immune responses and tolerance causes allergic and autoimmune diseases. A promising therapeutic strategy is to support immune tolerance by converting conventional T cells into suppressive regulatory T cells with small molecular weight compounds, an area that is underexplored. Here, we report the identification, characterization, and validation of a novel quinoxaline derivative (IFA005) that converts human memory CD4⁺T cells into suppressive Foxp3-expressing Tregs in vitro. Mechanistically, IFA005 regulated the expression of naked cuticle homolog 2 and impaired the phosphorylation of glycogen synthase kinase-3β, which led to the degradation of β-catenin and thus blocked the Wnt-β-catenin pathway. Our findings indicate that IFA005 could be a promising candidate for inducing immune tolerance by converting effector T cells into suppressive Treg cells through the inhibition of the Wnt-β-catenin pathway.