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

Ye Chen; Jun Long Dang; Qi Long; Nianke Zang; Ling Liu; Yang Lu; Wei Zhao; Rong Zhen Liang; Yi Yang; Jun Zhao; Jing Rong Chen; Yi Ding Xiong; Julie Wang; Yun Feng Pan; Nancy Olsen; Song Guo Zheng

doi:10.1186/s12929-026-01228-z

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

J Biomed Sci. 2026 Feb 24;33(1):21. doi: 10.1186/s12929-026-01228-z.

Authors

Ye Chen^#^{1

2

3

4}, Jun Long Dang^#¹, Qi Long^#¹, Nianke Zang^#⁵, Ling Liu¹, Yang Lu¹, Wei Zhao¹, Rong Zhen Liang¹, Yi Yang⁶, Jun Zhao¹, Jing Rong Chen¹, Yi Ding Xiong¹, Julie Wang¹, Yun Feng Pan⁴, Nancy Olsen⁷, Song Guo Zheng^{8

9

10}

Affiliations

¹ Division of Rheumatology and Immunology, Department of Internal Medicine, Shanghai Songjiang Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
² Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
³ State Key Lab of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 201600, China.
⁴ Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, China.
⁵ The First Dongguan Affiliated Hospital, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, State Key Laboratory of Pathogenesis, Guangdong Medical University, Dongguan, 523710, China.
⁶ Department of Endocrinology and Metabolic Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
⁷ Division of Rheumatology, Penn State College of Medicine and Milton S. Hershey Medical Center, Hershey, PA, 17033, USA.
⁸ Division of Rheumatology and Immunology, Department of Internal Medicine, Shanghai Songjiang Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China. Song.Zheng@shsmu.edu.cn.
⁹ Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang Hospital Affiliated to the Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China. Song.Zheng@shsmu.edu.cn.
¹⁰ State Key Lab of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 201600, China. Song.Zheng@shsmu.edu.cn.

^# Contributed equally.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Autoimmune inflammation; CD8+ T cells; IRF4; Induced Treg cells; ROS; TGF-β.

MeSH terms

Animals
Antigens, CD* / immunology
Antigens, CD* / metabolism
Apyrase* / genetics
Apyrase* / immunology
Apyrase* / metabolism
Autoimmune Diseases* / immunology
CD8-Positive T-Lymphocytes* / immunology
Colitis / immunology
Inflammation* / immunology
Mice
Mice, Inbred C57BL
Signal Transduction* / immunology
T-Lymphocytes, Regulatory* / immunology
Transforming Growth Factor beta* / genetics
Transforming Growth Factor beta* / immunology
Transforming Growth Factor beta* / metabolism

Substances

Transforming Growth Factor beta
Apyrase
CD39 antigen
Antigens, CD

Abstract

MeSH terms

Substances

Grants and funding