Veterinary and Biomedical Sciences, Department of

 

Authors

Vijay K. Kuchroo, Brigham and Women’s Hospital and Children’s Hospital BostonFollow
Sheng Xiao, Brigham and Women’s Hospital and Children’s Hospital Boston
Nader Najafian, Brigham and Women’s Hospital and Children’s Hospital Boston
Jay Reddy, Brigham and Women’s Hospital and Children’s Hospital Boston
Monica Albin, Brigham and Women’s Hospital and Children’s Hospital Boston
Chen Zhu, Brigham and Women’s Hospital and Children’s Hospital Boston
Eric Jensen, Telos Pharmaceuticals LLC
Jaimie Imitola, Brigham and Women’s Hospital and Children’s Hospital Boston
Thomas Korn, Brigham and Women’s Hospital and Children’s Hospital Boston
Ana C. Anderson, Brigham and Women’s Hospital and Children’s Hospital BostonFollow
Zheng Zhang, Brigham and Women’s Hospital and Children’s Hospital Boston
Cristina Gutierrez, Brigham and Women’s Hospital and Children’s Hospital Boston
Thomas Moll, Telos Pharmaceuticals LLC
Raymond A. Sobel, Stanford University School of Medicine
Dale T. Umetsu, Beth Israel Deaconess Medical Center, Harvard Medical School
Hideo Yagita, Juntendo University School of Medicine
Hisaya Akiba, Juntendo University School of Medicine
Terry Strom, Beth Israel Deaconess Medical Center, Harvard Medical School
Mohamed H. Sayegh, Brigham and Women’s Hospital and Children’s Hospital Boston
Rosemarie H. DeKruyff, Beth Israel Deaconess Medical Center, Harvard Medical School
Samia J. Khoury, Brigham and Women’s Hospital and Children’s Hospital Boston

Date of this Version

2007

Citation

The Journal of Experimental Medicine, Vol. 204, No. 7, July 9, 2007 1691-1702

Comments

Copyright 2014. Used by permission.

Abstract

It has been suggested that T cell immunoglobulin mucin (Tim)-1 expressed on T cells serves to positively costimulate T cell responses. However, crosslinking of Tim-1 by its ligand Tim-4 resulted in either activation or inhibition of T cell responses, thus raising the issue of whether Tim-1 can have a dual function as a costimulator. To resolve this issue, we tested a series of monoclonal antibodies specifi c for Tim-1 and identifi ed two antibodies that showed opposite functional effects. One anti–Tim-1 antibody increased the frequency of antigen-specifi c T cells, the production of the proinfl ammatory cytokines IFN-γ and IL-17, and the severity of experimental autoimmune encephalomyelitis. In contrast, another anti– Tim-1 antibody inhibited the generation of antigen-specifi c T cells, production of IFN-γ and IL-17, and development of autoimmunity, and it caused a strong Th2 response. Both antibodies bound to closely related epitopes in the IgV domain of the Tim-1 molecule, but the activating antibody had an avidity for Tim-1 that was 17 times higher than the inhibitory antibody. Although both anti–Tim-1 antibodies induced CD3 capping, only the activating antibody caused strong cytoskeletal reorganization and motility. These data indicate that Tim-1 regulates T cell responses and that Tim-1 engagement can alter T cell function depending on the affi nity/avidity with which it is engaged.

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