TNF-α is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist–deficient mice
Reiko Horai, … , Ryo Abe, Yoichiro Iwakura
Reiko Horai, … , Ryo Abe, Yoichiro Iwakura
Published December 1, 2004
Citation Information: J Clin Invest. 2004;114(11):1603-1611. https://doi.org/10.1172/JCI20742.
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Article Immunology

TNF-α is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist–deficient mice

Abstract

IL-1 receptor antagonist–deficient (IL-1Ra–/–) mice spontaneously develop autoimmune arthritis. We demonstrate here that T cells are required for the induction of arthritis; T cell–deficient IL-1Ra–/– mice did not develop arthritis, and transfer of IL-1Ra–/– T cells induced arthritis in nu/nu mice. Development of arthritis was also markedly suppressed by TNF-α deficiency. We found that TNF-α induced OX40 expression on T cells and blocking the interaction between either CD40 and its ligand or OX40 and its ligand suppressed development of arthritis. These findings suggest that IL-1 receptor antagonist deficiency in T cells disrupts homeostasis of the immune system and that TNF-α plays an important role in activating T cells through induction of OX40.

Authors

Reiko Horai, Akiko Nakajima, Katsuyoshi Habiro, Motoko Kotani, Susumu Nakae, Taizo Matsuki, Aya Nambu, Shinobu Saijo, Hayato Kotaki, Katsuko Sudo, Akihiko Okahara, Hidetoshi Tanioka, Toshimi Ikuse, Naoto Ishii, Pamela L. Schwartzberg, Ryo Abe, Yoichiro Iwakura

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Figure 1

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Splenocyte and T cell transfer into nu/nu mice. (A) Total splenocytes fr...
Splenocyte and T cell transfer into nu/nu mice. (A) Total splenocytes from IL-1Ra–/– mice (filled circles, n = 10) induced arthritis, while T cell_depleted splenocytes (open circles, n = 7) did not induce arthritis in nu/nu mice. (B) Arthritic severity score of splenocyte-transferred mice. (C) Purified T cells from spleen and LNs of either arthritic (filled squares, n = 10) or nonarthritic (open squares, n = 8) IL-1Ra–/– mice induced arthritis in nu/nu mice, while T cells from WT mice (triangles, n = 11) did not. (D) Arthritic severity score of T cell_transferred mice. (E_H) Histology of the ankle joints of WT (E) or IL-1Ra–/– (F_H) T cell_transferred nu/nu mice. (G) Infiltration of inflammatory cells (indicated by arrowheads). (H) Erosive bone destruction by replacement of bone matrix with fibroblastic cells (indicated by arrowheads). Magnification, ×40 (E and F); ×100 (G and H). (I) Serum IgG (left) and RF (right) levels in WT T cell_ or IL-1Ra–/– T cell_transferred nu/nu mice. The average in each group is shown as a horizontal bar. WT, WT donors (n = 10); KO+, arthritic-IL-1Ra–/– donors (n = 10); KO_, nonarthritic IL-1Ra–/– donors (n = 8). *P < 0.05.