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RANK-RANKL Signaling Pathway Is Critically Involved in the Function of CD4⁺CD25⁺ Regulatory T Cells in Chronic Colitis¹

Teruji Totsuka^2,*, Takanori Kanai^2,3,*, Yasuhiro Nemoto^*, Takayuki Tomita^*, Ryuichi Okamoto^*, Kiichiro Tsuchiya^*, Tetsuya Nakamura^*, Naoya Sakamoto^*, Hisaya Akiba, Ko Okumura, Hideo Yagita and Mamoru Watanabe^*

^* Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo; and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

It is now clear that functional CD4⁺CD25⁺ regulatory T (T_R) cells exist as part of the normal immune population and prevent the development of intestinal inflammation. We have recently shown that CD4⁺CD25⁺ T_R cells reside in the intestine and control intestinal homeostasis in humans and mice. In this study, we demonstrate that the TNF family molecule RANKL and its receptor RANK are critically involved in controlling the function of CD4⁺CD25⁺ T_R cells in the intestine. We first found that RANKL was preferentially expressed on both CD4⁺CD25⁺ T_R cells and colitogenic CD4⁺ T cells, whereas RANK was expressed on dendritic cells. Although neutralizing anti-RANKL mAb did not affect T_R activity of CD4⁺CD25⁺ T_R cells to suppress the proliferation of CD4⁺ responder cells in vitro, in vivo administration of anti-RANKL mAb abrogated CD4⁺CD25⁺ T_R cell-mediated suppression of colitis induced by adoptive transfer of CD4⁺CD45RB^high T cells into SCID mice. Interestingly, an adoptive transfer experiment using Ly5.1⁺CD4⁺CD45RB^high cells and Ly5.2⁺CD4⁺CD25⁺ T_R cells revealed that the ratio of CD4⁺CD25⁺ T_R cells in total CD4⁺ T cells in inflamed mucosa was significantly decreased by anti-RANKL mAb treatment. Consistent with this, the expression of RANK on lamina propria CD11c⁺ cells from colitic mice was significantly increased as compared with that from normal mice, and in vitro treatment with anti-RANKL mAb suppressed the expansion of CD4⁺Foxp3⁺ T_R cells in culture with colitic lamina propria CD11c⁺ cells. Together, these results suggest that the RANK-RANKL signaling pathway is critically involved in regulating the function of CD4⁺CD25⁺ T_R cells in colitis.

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 study was supported in part by Grants-in-Aid for Scientific Research, Scientific Research on Priority Areas, Exploratory Research and Creative Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology; the Japanese Ministry of Health, Labor and Welfare, the Japan Medical Association, and the Foundation for Advancement of International Science.

² T.T. and T.K. contributed equally to this work.

³ Address correspondence to Dr. Takanori Kanai at the current address: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan. E-mail address: takagast{at}sc.itc.keio.ac.jp

⁴ Abbreviations used in this paper: IBD, inflammatory bowel disease; LP, lamina propria; MLN, mesenteric lymph node; RANK, receptor activator of NF-B; SP, spleen; RANKL, receptor activator of NF-B ligand; T_R, regulatory T; IEL, intraepithelial lymphocyte; HPF, high-power field; Fwd, forward; Rev, reverse; MMC, mitomycin C; DC, dendritic cell; RA, retinoic acid.

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