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- Title
Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function.
- Authors
Xiao, Sheng; Najafian, Nader; Reddy, Jay; Albin, Monica; Zhu, Chen; Jensen, Eric; Imitola, Jaime; Korn, Thomas; Anderson, Ana C; Zhang, Zheng; Gutierrez, Cristina; Moll, Thomas; Sobel, Raymond A; Umetsu, Dale T; Yagita, Hideo; Akiba, Hisaya; Strom, Terry; Sayegh, Mohamed H; DeKruyff, Rosemarie H; Khoury, Samia J; Kuchroo, Vijay K
- 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 specific for Tim-1 and identified two antibodies that showed opposite functional effects. One anti-Tim-1 antibody increased the frequency of antigen-specific T cells, the production of the proinflammatory cytokines IFN-gamma and IL-17, and the severity of experimental autoimmune encephalomyelitis. In contrast, another anti-Tim-1 antibody inhibited the generation of antigen-specific T cells, production of IFN-gamma 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 affinity/avidity with which it is engaged.
- Publication
The Journal of experimental medicine, 2007, Vol 204, Issue 7, p1691
- ISSN
0022-1007
- Publication type
Journal Article
- DOI
10.1084/jem.20062498