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

Sheng Xiao, Nader Najafian, Jay Reddy, Monica Albin, Chen Zhu, Eric Jensen, Jaime Imitola, Thomas Korn, Ana C. Anderson, Zheng Zhang, Cristina Gutierrez, Thomas Moll, Raymond A. Sobel, Dale T. Umetsu, Hideo Yagita, Hisaya Akiba, Terry Strom, Mohamed H. Sayegh, Rosemarie H. DeKruyff, Samia J. KhouryVijay K. Kuchroo

Research output: Contribution to journalArticle

99 Scopus citations

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-γ 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-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 affinity/avidity with which it is engaged. JEM

Original languageEnglish (US)
Pages (from-to)1691-1702
Number of pages12
JournalJournal of Experimental Medicine
Volume204
Issue number7
DOIs
StatePublished - Jul 9 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Xiao, S., Najafian, N., Reddy, J., Albin, M., Zhu, C., Jensen, E., Imitola, J., Korn, T., Anderson, A. C., Zhang, Z., Gutierrez, C., Moll, T., Sobel, R. A., Umetsu, D. T., Yagita, H., Akiba, H., Strom, T., Sayegh, M. H., DeKruyff, R. H., ... Kuchroo, V. K. (2007). Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function. Journal of Experimental Medicine, 204(7), 1691-1702. https://doi.org/10.1084/jem.20062498