Phosphotyrosine-Dependent Coupling of Tim-3 to T-Cell Receptor Signaling Pathways
Open accessAbstract
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.
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Tyrosine kinase FYN and human leukocyte antigen B (HLA-B)-associated transcript 3 (BAT3) were suggested to inhibit the cytoplasmic tail of TIM-3 signaling.
“Nevertheless, tyrosine kinase FYN and human leukocyte antigen B (HLA‐B)‐associated transcript 3 (BAT3) were suggested to inhibit the cytoplasmic tail of TIM‐3 signaling [307, 308, 309].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [309]
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TIM-3 pathway dysregulation and targeting in cancer
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Beyond T cell exhaustion: TIM-3 regulation of myeloid cells
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A cellular platform for the evaluation of immune checkpoint molecules
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TIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives
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New Checkpoint Inhibitors on the Road: Targeting TIM-3 in Solid Tumors
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Immune Checkpoint Receptors Signaling in T Cells
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Characterizing Functional Domains for TIM-Mediated Enveloped Virus Entry
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TIM-3 in Leukemia; Immune Response and Beyond
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Phosphatidylserine binding directly regulates TIM-3 function
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PD-1 and TIM-3 differentially regulate subsets of mouse IL-17A–producing γδ T cells
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- Authors
- Lee, J., Su, E. W., Zhu, C., Hainline, S., Phuah, J., Moroco, J. A., Smithgall, T. E., Kuchroo, V. K., & Kane, L. P.
- Affiliations
- University of Pittsburgh (US)
- Brigham and Women's Hospital (US)
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2011-10-01
- Volume
- 31
- Issue
- 19
- Pages
- 3963-3974
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3187355
- OpenAlex
- W2107777135
- Cited by
- 285
- References
- 39
- Citations by year
- 2026: 11 · 2025: 26 · 2024: 28 · 2023: 18 · 2022: 24 · 2021: 32 · 2020: 26 · 2019: 21 · 2018: 23 · 2017: 19 · 2016: 14 · 2015: 11 · 2014: 13 · 2013: 6 · 2012: 13
- FWCI
- 4.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM077629, GM077629)
- National Institute of Allergy and Infectious Diseases (R56AI067544, P01AI073748, AI067544, AI073748, R01AI067544)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Keywords
- TIM-3, T cell receptor signaling, phosphotyrosine, immune exhaustion, T cell activation, Fyn, PI3K p85, chronic viral infection, agonistic antibodies
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Amino Acid Sequence, Animals, Humans, Lymphocyte Activation, Membrane Proteins, Molecular Sequence Data, Phosphoproteins, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, NF-kappa B, Transcription Factor AP-1, Phosphotyrosine, src-Family Kinases, Jurkat Cells, Adaptor Proteins, Signal Transducing, NFATC Transcription Factors, Proto-Oncogene Proteins c-fyn, Mice, ZAP-70 Protein-Tyrosine Kinase, HEK293 Cells
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