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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- 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- 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.

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

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