Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function

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 BostonFollow
• 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

Document Type

Article

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.