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

TL;DR

A new compound converts memory T cells into regulatory T cells, offering a potential treatment for allergies and autoimmune diseases.

Contribution

A novel quinoxaline derivative (IFA005) is identified to induce regulatory T cells by inhibiting the Wnt/β-catenin pathway.

Findings

IFA005 converts human memory CD4+T cells into Foxp3-expressing regulatory T cells.

IFA005 suppresses Th2 cytokines and promotes iTreg phenotype via Wnt/β-catenin inhibition.

Upregulation of naked cuticle homolog 2 (NKD2) is a key mechanism in this conversion.

Abstract

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.

This study discovered the small molecule 9‐methoxy‐6‐methylindolo[3,2‐b] quinoxaline (IFA005) as a potent immunomodulator capable of converting human memory CD4⁺ T cells into functional Foxp3⁺ regulatory T cells. IFA005 suppresses Th2 cytokines (IL‐4, IL‐5, and IL‐13) and promotes the iTreg phenotype by inhibiting Wnt/β‐catenin signaling through NKD2 upregulation. These findings support small‐molecule‐mediated Wnt/β‐catenin blockade as a promising strategy to induce immune tolerance in allergic and chronic inflammatory diseases.

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