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Mol. Cell. Biol. 31 (19): 3963-3974

Copyright © 2011 by the American Society for Microbiology. All rights reserved.

Phosphotyrosine-Dependent Coupling of Tim-3 to T-Cell Receptor Signaling Pathways{triangledown}

Judong Lee,1,3,{dagger} Ee Wern Su,1,3,{dagger} Chen Zhu,4 Sarah Hainline,1 Jiayao Phuah,1,3 Jamie A. Moroco,2 Thomas E. Smithgall,2 Vijay K. Kuchroo,4, and Lawrence P. Kane1*

Department of Immunology,1 Department of Microbiology and Molecular Genetics,2 Graduate Program in Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,3 Center for Neurologic Disease, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 021154

Received for publication 7 March 2011. Revision received 31 March 2011. Accepted for publication 22 July 2011.

Abstract: The transmembrane protein Tim-3 has been shown to negatively regulate T-cell-dependent immune responses and was recently demonstrated to be associated with the phenomenon of immune exhaustion, which can occur as a consequence of chronic viral infection. Unlike other negative regulators of T-cell function (e.g., PD-1), Tim-3 does not contain any obvious inhibitory signaling motifs. We have found that ectopic expression of Tim-3 in T cells leads to enhancement of T-cell receptor (TCR)-dependent signaling pathways, which was observed at the level of transcriptional reporters and endogenous cytokine production. We have exploited this observation to dissect what elements within the cytoplasmic tail of Tim-3 are required for coupling to downstream signaling pathways. Here we have demonstrated that two of the more membrane-proximal cytoplasmic tail tyrosines are required for Tim-3 signaling to T-cell activation pathways in a redundant fashion. Furthermore, we show that Tim-3 can directly bind to the Src family tyrosine kinase Fyn and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor. Thus, at least under conditions of short-term stimulation, Tim-3 can augment T-cell activation, although this effect can be blocked by the inclusion of an agonistic antibody to Tim-3. These findings should help further the study of Tim-3 function in other physiological settings, such as those that lead to immune exhaustion.

* Corresponding author. Mailing address: Department of Immunology, University of Pittsburgh School of Medicine, BST E-1056, 200 Lothrop St., Pittsburgh, PA 15261. Phone: (412) 648-8947. Fax: (412) 383-8096. E-mail: lkane{at}pitt.edu.

{dagger} These two authors contributed equally.

{triangledown} Published ahead of print on 1 August 2011.

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