# TGF-β signaling mediates crosstalk between CD8+ T cells and CD39+ induced Treg cells in autoimmune inflammation

## TL;DR

CD8+ T cells enhance the function of regulatory T cells through TGF-β signaling, offering a new approach for treating autoimmune diseases.

## Contribution

Discovers a novel CD8+ T cell–iTreg crosstalk mechanism via ROS/TGF-β–IRF4 signaling in autoimmune inflammation.

## Key findings

- CD8+ T cells promote CD39+ iTreg differentiation and enhance immunosuppressive capacity.
- CD8+ T cell–primed iTregs reduce autoimmune colitis and arthritis by suppressing Th1/Th17 responses.
- ROS/TGF-β–IRF4 signaling in CD8+ T cells regulates iTreg stability and function.

## Abstract

Autoimmune inflammation results from dysregulated immune responses, with dysfunction of regulatory T cells (Tregs) being a key contributor due to their critical role in maintaining immune tolerance. The stability and function of Tregs are strongly influenced by the inflammatory microenvironment, yet the regulatory interactions between CD8+ T cells and CD4+Foxp3+ Tregs remain poorly understood.

We investigated the role of CD8+ T cells in regulating induced Tregs (iTregs) using in vitro T cell co-culture assays and two in vivo models of autoimmune disease. A naïve CD4+ T cell transfer colitis model was used to evaluate the suppressive function of iTregs in the presence or absence of CD8+ T cells, while an autoimmune arthritis model was employed to assess therapeutic efficacy. Flow cytometry, functional suppression assays, and mechanistic analyses were performed to define signaling pathways.

CD8+ T cells promoted the differentiation of a CD39+ iTreg subset characterized by increased frequencies of CD103, CTLA-4, and Helios, leading to enhanced immunosuppressive capacity. In the colitis model, co-transfer of CD8+ naïve T cells alleviated disease by reinforcing iTreg-mediated suppression of Th1 and Th17 responses. Mechanistic studies revealed that CD8+ T cells regulated iTreg phenotype through a ROS/TGF-β signaling axis, with IRF4 in CD8+ T cells acting as a key mediator. Importantly, CD8+ T cell–primed iTregs showed superior therapeutic efficacy in the autoimmune arthritis model by suppressing pathogenic Th1/Th17 responses and supporting endogenous Treg homeostasis.

This study identifies a previously unrecognized role of CD8+ T cells in enhancing iTreg differentiation, stability, and suppressive function through the ROS/TGF-β–IRF4 pathway. These findings reveal a novel mechanism of immune regulation and suggest that harnessing CD8+ T cell–primed iTregs could represent a promising strategy to strengthen Treg-based therapies for autoimmune diseases.

The online version contains supplementary material available at 10.1186/s12929-026-01228-z.