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Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

Biogen Idec, Cambridge, MA 02142

The T cell, Ig domain, and mucin domain-1 (TIM-1) gene is associated with Th2 T cell responses and human atopic diseases. The mechanism by which TIM-1 influences T cell responses remains unknown. We demonstrate that TIM-1 is recruited to the TCR-signaling complex via association with CD3. TIM-1 up-regulates TCR-associated signaling events, including phosphorylation of Zap70 and IL-2-inducible T cell kinase. This activity requires TIM-1 tyrosine phosphorylation. TIM-1 expression induces formation of a novel complex that includes PI3K and ITK. Finally, the consequences of TIM-1 activation include increased expression of effector cytokines. These results demonstrate that TIM-1 is a critical component of the human T cell response and provide a mechanistic hypothesis for the role of TIM-1 in disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Paul D. Rennert, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142. E-mail address: paul.rennert{at}biogenidec.com

² Abbreviations used in this paper: TIM, T cell, Ig domain, and mucin domain; TAPR, T cell and airway phenotype regulator; HAV, hepatitis A virus; CBA, cytometric bead array; ITK, IL-2-inducible T cell kinase.

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