International Immunology Advance Access originally published online on March 26, 2008
International Immunology 2008 20(5):695-708; doi:10.1093/intimm/dxn029
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Bimodal regulation of T cell-mediated immune responses by TIM-4
1 Department of Molecular Immunology
2 The 21st Century Center of Excellence Program, Combined Program on Microbiology and Immunology
3 Department of Immunochemistry
4 Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
5 World Premier International Immunology Frontier Research Center, Osaka University, Yamada-oka, Suita, Osaka 565-0871, Japan
6 Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
7 Biogen-Idec Inc., 12 Cambridge Center, Cambridge, MA 01746, USA
8 Present address: Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, 55 Lake Avenue, Worcester, MA 01655, USA
9 Present address: Department of Microbiology and Immunology, University of California, San Francisco, 513 Parnassus Avenue, HSE 1001, San Francisco, CA 94143, USA
Correspondence to: A. Kumanogoh; E-mail: kumanogo{at}ragtime.biken.osaka-u.ac.jp and H. Kikutani; E-mail: kikutani{at}ragtime.biken.osaka-u.ac.jp
T cell Ig and mucin domain (TIM)-4 is preferentially expressed on antigen-presenting cells, and its counter-ligand, TIM-1, is thought to deliver co-stimulating signals to T cells. However, the physiological functions of TIM-4 remain unclear. Here, we demonstrate that TIM-4 inhibits naive T cell activation through a ligand other than TIM-1. The inhibitory effect of TIM-4 was specific to naive T cells which do not express TIM-1, and the effect disappeared in pre-activated T cells. Conversely, antibody-mediated blockade of TIM-4 in vivo substantially suppressed T cell-mediated inflammatory responses despite enhanced generation of antigen-specific T cells. Furthermore, treatment with anti-TIM-4 reduced the inflammatory responses developed in mice that were adoptively transferred with antigen-primed T cells. These results suggest that TIM-4 exerts bimodal functions depending on the activation status of T cells.
Keywords: TIM gene family, TIM-4, TIM-1, antigen-presenting cells, T cell activation
Transmitting editor: K. Inaba
Received 17 October 2007, accepted 19 February 2008.