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Am J Physiol Gastrointest Liver Physiol 294: G199-G207, 2008. First published October 25, 2007; doi:10.1152/ajpgi.00286.2007
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INFLAMMATION/IMMUNITY/MEDIATORS

Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis

Y. Ito,1 T. Kanai,1 T. Totsuka,1 R. Okamoto,1 K. Tsuchiya,1 Y. Nemoto,1 A. Yoshioka,1 T. Tomita,1 T. Nagaishi,1 N. Sakamoto,1 T. Sakanishi,2 K. Okumura,3 H. Yagita,3 and M. Watanabe1

1Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo; and 2Division of Cell Biology and 3Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Submitted 23 June 2007 ; accepted in final form 17 October 2007

It has been recently demonstrated that NKG2D is an activating costimulatory receptor on natural killer (NK) cells, natural killer T (NKT) cells, activated CD8+ T cells, and {gamma}{delta} T cells, which respond to cellular stress, such as inflammation, transformation, and infection. Here we show that intestinal inflammation in colitic SCID mice induced by adoptive transfer of CD4+CD45RBhigh T cells is characterized by significant increase of CD4+NKG2D+ T cells and constitutive expression of NKG2D ligands, such as H60, Mult-1, and Rae-1, by lamina propria CD11c+ dendritic cells. Furthermore, treatment with nondepleting and neutralizing anti-NKG2D MAb after transfer of CD4+CD45RBhigh T cells into SCID mice significantly suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of IFN-{gamma} by lamina propria CD4+ T cells. These findings demonstrate that NKG2D signaling pathway is critically involved in CD4+ T cell-mediated disease progression and suggest a new therapeutic target for inflammatory bowel diseases.

NKG2D; CD4+ T cells; chronic colitis; inflammatory bowel disease


Address for reprint requests and other correspondence: T. Kanai, MD, Dept. of Gastroenterology and Hepatology, Tokyo Medical and Dental Univ., 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan (e-mail: taka.gast{at}tmd.ac.jp)






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