CD4CD126 Foxp3 Cell Population Represents a Superior Subset of Regulatory T Cells in Treating Autoimmune Diseases.

Ye Chen, Zhenjian Xu, Rongzhen Liang, Julie Wang, Anping Xu, Ning Na, Bin Li, Ruoning Wang, Miller Joseph, Nancy Olsen, Willa Hsueh, Song Guo Zheng

Journal: Molecular therapy : the journal of the American Society of Gene Therapy 2021;28(11):2406-2416

PMID: 32738192

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Abstract

CD4Foxp3 regulatory T (Treg) cells are crucial for maintaining homeostasis and preventing autoimmune diseases. Nonetheless, we and others have previously reported that natural Treg cells are unstable and dysfunctional in the inflamed environment with a high-salt diet, limiting the Treg function in disease control. In this study, we made an innovative observation showing a high degree of heterogeneity within the Treg pool. We identified that CD126, interleukin (IL)-6 receptor alpha chain, contributed to Treg cell instability. Using a series of in vitro and in vivo experimental approaches, we demonstrated that CD126 Treg cells presented greater function and were more stable than CD126 nTreg cells, even in the presence of IL-6 and inflammation. Blockade of programmed death-1 (PD-1) interrupted CD126 nTreg cell stability. Additionally, CD126 Treg cells can treat colitis and established collagen-induced arthritis, while the CD126 cell population failed to do this. Moreover, we noted that CD126 expression of Treg cells had a positive correlation to rheumatoid arthritis (RA) severity and the stability of Treg cells. Our results strongly suggest that the manipulation of CD126 nTreg cells could be a novel strategy for the treatment of autoimmune diseases and for other conditions associated with a deficit of Treg cells.

Address: Department of Clinical Immunology, Third Hospital at Sun Yat-sen University, 510630 Guangzhou, China; Division of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH 43201, USA; Division of Rheumatology, Penn State College of Medicine and Milton S. Hershey Medical Center, Hershey, PA 17033, USA.; Division of Rheumatology, Penn State College of Medicine and Milton S. Hershey Medical Center, Hershey, PA 17033, USA; Department of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China.; Department of Clinical Immunology, Third Hospital at Sun Yat-sen University, 510630 Guangzhou, China.; Division of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH 43201, USA.; Department of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China.; Department of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200021, China.; Center for Childhood Cancer and Blood Disease, Abigail Wexner Research Institute, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH 43205, USA.; Division of Rheumatology, Penn State College of Medicine and Milton S. Hershey Medical Center, Hershey, PA 17033, USA.; Division of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH 43201, USA. Electronic address: [email protected].

DOI: 10.1016/j.ymthe.2020.07.020

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https://medlineplus.gov/autoimmunediseases.html

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-CD4-1

MeSH Terms: Autoimmune Diseases, Autoimmunity, Biomarkers, Forkhead Transcription Factors, Gene Expression, Humans, Immunophenotyping, Immunotherapy, Interleukin-6, Receptors, Interleukin-6, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory