OX40 signaling is involved in the autoactivation of CD4+CD28-T cells and contributes to the pathogenesis of autoimmune arthritis.
CD4+CD28-T cells exhibit autoreactive potential in autoimmune disorders, including rheumatoid arthritis (RA). It is not well known which costimulator functions as an alternative second signal in the activation of this subset after CD28 expression is downregulated. Tumor necrosis factor receptor superfamily member OX40 is a key costimulator in the activation of T cells. The aim of this study was to investigate the costimulatory effects of OX40 on CD4+CD28-T cells in autoimmune arthritis.



Clinical samples were collected from patients with RA and control subjects. Collagen-induced arthritis (CIA) was induced with collagen type II (CII) in DBA/1 mice. The CD4+CD28-OX40+T-cell subset and its cytokine production were detected by flow cytometry. After T-cell purification, adoptive transfer was performed in CIA mice. The regulatory role of OX40 was determined by blocking experiments in vitro and in vivo.



OX40 and OX40L were abnormally expressed in patients with RA and CIA mice. Further analysis showed that CD4+CD28-OX40+T cells accumulated in patients with RA and in animal models. These cells produced higher levels of proinflammatory cytokines and were closely correlated with the clinicopathological features of the affected individuals. Adoptive transfer of CII-specific CD4+CD28-OX40+T cells remarkably aggravated arthritic development and joint pathology in CIA mice. Moreover, OX40 blockade significantly reduced the proinflammatory responses and ameliorated arthritis development.



OX40 acts as an alternative costimulator of CD4+CD28-T cells and plays a pathogenic role in autoimmune arthritic development, suggesting that it is a potential target for immunomodulatory therapy of RA.
Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No. 708 Renmin Road, Suzhou, 215006, Jiangsu, China.
Juean
J
Jiang
Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No. 708 Renmin Road, Suzhou, 215006, Jiangsu, China.
Cuiping
C
Liu
Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No. 708 Renmin Road, Suzhou, 215006, Jiangsu, China.
Mi
M
Liu
Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No. 708 Renmin Road, Suzhou, 215006, Jiangsu, China.
Yu
Y
Shen
Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No. 708 Renmin Road, Suzhou, 215006, Jiangsu, China.
Xiaohan
X
Hu
Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No. 708 Renmin Road, Suzhou, 215006, Jiangsu, China.
Qin
Q
Wang
Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No. 708 Renmin Road, Suzhou, 215006, Jiangsu, China.
Jian
J
Wu
Departments of Rheumatology, Third Affiliated Hospital of Soochow University, No. 185 Juqian Road, Changzhou, 213003, Jiangsu, China.
Min
M
Wu
Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No. 708 Renmin Road, Suzhou, 215006, Jiangsu, China. fangqi_008@126.com.
Qi
Q
Fang
Jiangsu Institute of Clinical Immunology & Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, No. 708 Renmin Road, Suzhou, 215006, Jiangsu, China. xueguangzh@126.com.
Xueguang
X
Zhang
D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D053278:OX40 Ligand / Q000276:immunology; D053262:Receptors, OX40 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology
D053278:OX40 Ligand; D053262:Receptors, OX40
CD4+CD28− T cells; OX40; Rheumatoid arthritis