HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tomita, T. Articles by Watanabe, M. PubMed PubMed Citation Articles by Tomita, T. Articles by Watanabe, M.

MyD88-Dependent Pathway in T Cells Directly Modulates the Expansion of Colitogenic CD4⁺ T Cells in Chronic Colitis¹

Takayuki Tomita^*, Takanori Kanai^2,*, Toshimitsu Fujii^*, Yasuhiro Nemoto^*, Ryuichi Okamoto^*, Kiichiro Tsuchiya^*, Teruji Totsuka^*, Naoya Sakamoto^*, Shizuo Akira and Mamoru Watanabe^*

^* Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

TLRs that mediate the recognition of pathogen-associated molecular patterns are widely expressed on/in cells of the innate immune system. However, recent findings demonstrate that certain TLRs are also expressed in conventional TCRβ⁺ T cells that are critically involved in the acquired immune system, suggesting that TLR ligands can directly modulate T cell function in addition to various innate immune cells. In this study, we report that in a murine model of chronic colitis induced in RAG-2^–/– mice by adoptive transfer of CD4⁺CD45RB^high T cells, both CD4⁺CD45RB^high donor cells and the expanding colitogenic lamina propria CD4⁺CD44^high memory cells expresses a wide variety of TLRs along with MyD88, a key adaptor molecule required for signal transduction through TLRs. Although RAG-2^–/– mice transferred with MyD88^–/–CD4⁺CD45RB^high cells developed colitis, the severity was reduced with the delayed kinetics of clinical course, and the expansion of colitogenic CD4⁺ T cells was significantly impaired as compared with control mice transferred with MyD88^+/+CD4⁺CD45RB^high cells. When RAG-2^–/– mice were transferred with the same number of MyD88^+/+ (Ly5.1⁺) and MyD88^–/– (Ly5.2⁺) CD4⁺CD45RB^high cells, MyD88^–/–CD4⁺ T cells showed significantly lower proliferative responses assessed by in vivo CFSE division assay, and also lower expression of antiapoptotic Bcl-2/Bcl-x_L molecules and less production of IFN- and IL-17, compared with the paired MyD88^+/+CD4⁺ T cells. Collectively, the MyD88-dependent pathway that controls TLR signaling in T cells may directly promote the proliferation and survival of colitogenic CD4⁺ T cells to sustain chronic 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 work 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 Foundation for Advancement of International Science.

² Address correspondence and reprint requests to Dr. Takanori Kanai, Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: taka.gast{at}tmd.ac.jp

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; DC, dendritic cell; PAMP, pathogen-associated molecular pattern; PB, peripheral blood; SP, spleen; MLN, mesenteric lymph node; BM, bone marrow; WT, wild type; LP, lamina propria; IEL, intraepithelial cell; HPF, high-power field.