Submitted on June 23, 2007
Accepted on October 17, 2007
Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis
Yumi Ito1, Takanori Kanai2*, Teruji Totsuka1, Ryuichi Okamoto1, Kiichiro Tsuchiya1, Yasuhiro Nemoto3, Atsushi Yoshioka1, Takayushi Tomita1, Takashi Nagaishi4, Naoya Sakamoto1, Tamami Sakanishi5, Ko Okumura5, Hideo Yagita5, and Mamoru Watanabe1
1 Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Tokyo, Japan
2 Gastroenterology and Hepatology, Toyko Medical and Dental University, Tokyo, Tokyo, Japan
3 Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
4 Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
5 Immunology, Juntendo University, Toyko, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: taka.gast{at}tmd.ac.jp.
It has been recently demonstrated that NKG2D is an activating co-stimulatory receptor on NK cells, NKT cells, activated CD8+ T cells, and 
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 non-depleting 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- 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.
