title: Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways.
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.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Judong
authors.initials: J
authors.lastname: Lee
authors.forename: Ee Wern
authors.initials: EW
authors.lastname: Su
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.forename: Sarah
authors.initials: S
authors.lastname: Hainline
authors.forename: Jiayao
authors.initials: J
authors.lastname: Phuah
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Moroco
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Smithgall
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D057809:HEK293 Cells; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D018808:Transcription Factor AP-1; D019000:Phosphotyrosine; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D019061:src-Family Kinases