The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
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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“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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Restoring function in exhausted CD8 T cells during chronic viral infection
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PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
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Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100643 · Cited by 2,072
Self-citationBlackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., Betts, M. R., Freeman, G. J., Vignali, D. A. A., & Wherry, E. J. (2009) · Nature Immunology · doi:10.1038/ni.1679 · Cited by 2,062
The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity
Zhu, C., Anderson, A. C., Schubart, A., Xiong, H., Imitola, J., Khoury, S. J., Zheng, X. X., Strom, T. B., & Kuchroo, V. K. (2005) · Nature Immunology · doi:10.1038/ni1271 · Cited by 2,057
Self-citationScansite 2.0: proteome-wide prediction of cell signaling interactions using short sequence motifs
Obenauer, J. C. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg584 · Cited by 1,609
Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.11.006 · Cited by 1,355
PD-1 and PD-1 ligands: from discovery to clinical application
Okazaki, T., & Honjo, T. (2007) · International Immunology · doi:10.1093/intimm/dxm057 · Cited by 1,310
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Research works printed but not linked: 1
- Obenauer J. C., 2004, Methods Mol. Biol, 261, 445
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Self-citationImmune checkpoint signaling and cancer immunotherapy
He, X., & Xu, C. (2020) · Cell Research · doi:10.1038/s41422-020-0343-4 · Cited by 1,431
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Wolf, Y., Anderson, A. C., & Kuchroo, V. K. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0224-6 · Cited by 959
Self-citationTim‐3 and its role in regulating anti‐tumor immunity
Das, M., Zhu, C., & Kuchroo, V. K. (2017) · Immunological Reviews · doi:10.1111/imr.12520 · Cited by 856
Self-citationNavigating metabolic pathways to enhance antitumour immunity and immunotherapy
Li, X., Wenes, M., Romero, P. J., Huang, S. C., Fendt, S., & Ho, P. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0203-7 · Cited by 750
Metadata
- 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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