Synovial regulatory T cells expressing ST2 deteriorate joint inflammation through the suppression of immunoregulatory eosinophils

Koto Hattori; Shigeru Tanaka; Daisuke Hashiba; Jun Tamura; Keishi Etori; Takahiro Kageyama; Takashi Ito; Kazuyuki Meguro; Arifumi Iwata; Akira Suto; Kotaro Suzuki; Junichi Nakamura; Seiji Ohtori; Steven F Ziegler; Hiroshi Nakajima

doi:10.1016/j.jaut.2024.103333

Synovial regulatory T cells expressing ST2 deteriorate joint inflammation through the suppression of immunoregulatory eosinophils

J Autoimmun. 2024 Nov 6:149:103333. doi: 10.1016/j.jaut.2024.103333. Online ahead of print.

Authors

Koto Hattori¹, Shigeru Tanaka², Daisuke Hashiba³, Jun Tamura⁴, Keishi Etori⁵, Takahiro Kageyama⁶, Takashi Ito⁷, Kazuyuki Meguro⁸, Arifumi Iwata⁹, Akira Suto¹⁰, Kotaro Suzuki¹¹, Junichi Nakamura¹², Seiji Ohtori¹³, Steven F Ziegler¹⁴, Hiroshi Nakajima¹⁵

Affiliations

¹ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
² Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
³ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan; Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
⁴ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
⁵ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
⁶ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
⁷ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
⁸ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
⁹ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
¹⁰ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
¹¹ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
¹² Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
¹³ Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].
¹⁴ Center for Fundamental Immunology, Benaroya Research Institute, 1201 9th Ave, Seattle, WA, 98101-2795, USA. Electronic address: [email protected].
¹⁵ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba, 260-8670, Japan. Electronic address: [email protected].

PMID: 39509740
DOI: 10.1016/j.jaut.2024.103333

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic polyarthritis. It is well-established that helper T cells play crucial roles in the development and deterioration of RA. Recent studies also revealed the significant roles of regulatory T (Treg) cells in this context. Although Treg cells distributed in peripheral tissues exhibit various functions, the characteristics of synovial Treg cells remain unknown. In this study, we demonstrate that synovial Treg cells exacerbate synovial inflammation by reducing the number of immunoregulatory eosinophils through competitive consumption of IL-33. Synovial Treg cells expressed ST2 in a murine arthritis model, and surprisingly, Treg-specific ST2 knockout (ST2^ΔTreg) mice exhibited attenuated arthritis. In ST2^ΔTreg mice, an increase in immunoregulatory synovial eosinophils was observed. Additionally, immunoregulatory eosinophils were found to express ST2, and ST2-expressing Treg cells controlled the abundance of immunoregulatory eosinophils, possibly by consuming IL-33. Our results highlight that a subset of synovial Treg cells possesses the machinery to worsen arthritis by suppressing eosinophils. In the future landscape where Treg cell-based therapies are employed for autoimmune diseases, it is important to comprehend the characteristics of disease-related Treg cells. Understanding these aspects is crucial for ensuring safer treatment modalities that do not inadvertently worsen the diseases.

Keywords: Collagen-induced arthritis; Eosinophils; Regulatory T cells; Rheumatoid arthritis; ST2.