The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20062498
The Journal of Experimental Medicine, Vol. 204, No. 7, 1691-1702
The Rockefeller University Press, 0022-1007 $30.00
© Xiao et al.
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ARTICLE

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

Sheng Xiao1, Nader Najafian2, Jay Reddy1, Monica Albin2, Chen Zhu1, Eric Jensen5, Jaime Imitola1, Thomas Korn1, Ana C. Anderson1, Zheng Zhang1, Cristina Gutierrez1, Thomas Moll5, Raymond A. Sobel6, Dale T. Umetsu3, Hideo Yagita7, Hisaya Akiba7, Terry Strom4, Mohamed H. Sayegh2, Rosemarie H. DeKruyff3, Samia J. Khoury1, and Vijay K. Kuchroo1

1 Center for Neurologic Diseases, 2 Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, 3 Division of Immunology, Children's Hospital, 4 Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
5 Telos Pharmaceuticals LLC, San Diego, CA 92131
6 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
7 Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan

CORRESPONDENCE Vijay K. Kuchroo: vkuchroo{at}rics.bwh.harvard.edu OR Samia J. Khoury: skhoury{at}rics.bwh.harvard.edu

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.

Abbreviations used: AAD, amino-actinomycin D; CHO, Chinese hamster ovary; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; PLP, proteolipid protein; Tim, T cell immunoglobulin mucin.

S. Xiao and N. Najafian, and S.J. Khoury and V.K. Kuchroo contributed equally to this work.


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