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A Positive Feedback Loop of IL-21 Signaling Provoked by Homeostatic CD4⁺CD25^– T Cell Expansion Is Essential for the Development of Arthritis in Autoimmune K/BxN Mice ¹

Eunkyeong Jang^*, Sin-Hye Cho^*, Hyunjoo Park^*, Doo-Jin Paik, Jung Mogg Kim and Jeehee Youn^2,*,

^* Department of Biomedical Sciences and Institute of Biomedical Sciences, Department of Anatomy and Cell Biology, and Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea

Rheumatoid arthritis is a joint-specific autoimmune inflammatory disease of unknown etiology. The K/BxN mouse is a model of rheumatoid arthritis that is thought to be mainly due to autoantibody-mediated inflammatory responses. We showed previously that homeostatic proliferation of autoreactive CD4⁺ T cells is required for disease initiation in the K/BxN mice. In this study, we show that the homeostatically proliferating CD4⁺CD25^– T cells produce IL-21. We generated IL-21R-deficient (IL-21R^–/–) K/BxN mice and found that these mice were completely refractory to the development of spontaneous arthritis. They contained fewer CD4⁺ T cells with a reduced proportion of homeostatically proliferating cells, fewer follicular Th cells, and, surprisingly, more Th17 cells than their control counterparts. They also failed to develop IgG1⁺ memory B cells and autoantigen-specific IgG1 Ab-secreting cells. IL-21 induced expression of receptor activator of NF-B ligand (RANKL) a regulator of osteoclastogenesis, and few RANKL-expressing infiltrates were found in the synovia of IL-21R^–/– K/BxN mice. Thus, our results demonstrate that IL-21 forms a positive feedback autocrine loop involving homeostatically activated CD4⁺ cells and that it plays an essential role in the development of autoimmune arthritis by mechanisms dependent on follicular Th cell development, autoreactive B cell maturation, and RANKL induction but independent of Th17 cell function. Consistent with this, in vivo administration of soluble the IL-21R-Fc fusion protein delayed the onset and progression of arthritis. Our findings suggest that effective targeting of IL-21-mediated processes may be useful in treating autoimmune arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Korea Science and Engineering Foundation grant funded by the Korean government (Ministry of Education, Science and Technology) (R11-2002-098-05001-0) and a grant from the Korea Health 21 Research and Development Project, Ministry of Health and Welfare, Republic of Korea (A050445).

² Address correspondence and reprint requests to Dr. Jeehee Youn, Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul, 133-791, Korea. E-mail address: jhyoun{at}hanyang.ac.kr

³ Abbreviations used in this paper: RA, rheumatoid arthritis; LN, lymph node; dLN, joint draining LN; GPI, glucose-6-phosphate isomerase; RANKL, receptor activator of NF-B ligand; T_FH, follicular helper T; Treg, regulatory T; WT, wild type; β₂M, β₂-microglobulin; BM, bone marrow; ASC, Ab-secreting cell.

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