ArticlePloS one2015
TIM-3 Suppresses Anti-CD3/CD28-Induced TCR Activation and IL-2 Expression through the NFAT Signaling Pathway.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 77 citations in OpenAlex.
- Triple-Negative Breast Cancer: Molecular Subtypes; Immune Escape; Limitations of Current Immunotherapy; and the BTLA/HVEM/CD160 Axis as an Emerging Target.Current issues in molecular biology · 2026Review
- TIM-3 in AML: a janus-faced orchestrator of immune exhaustion and leukemic self-renewal.Cancer cell international · 2026Review
- Diet and Medicinal Herbs as Adjunctive Approaches to Immune Homeostasis in Sjögren's Disease.International journal of molecular sciences · 2026Review
- Immune checkpoint molecules beyond PD-1 and CTLA-4: emerging targets in autoimmune diseases and cancer immunotherapy.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Comparable restimulation of human T cells activated with CD3/CD28 beads versus soluble antibody complexes.Scientific reports · 2026Article
- The role of the TIM-3 receptor in inflammatory bowel disease and autoimmunity: implications for TIM-3 and TCR crosstalk.Journal of molecular medicine (Berlin, Germany) · 2026Review
- UCP2 Identifies Immunosuppressive Tumor-Associated Macrophages and Is Associated with Predicted Immunotherapy Resistance in Glioma.Oncology research · 2026Article
- Ligand-receptor interactions of V-domain Ig-containing suppressor of T cell activation and programmed death-1 suppress the anticancer activities of T cells.Immuno-oncology technology · 2025Article
- The concurrent silencing of Tim-3 and STAT-3 promotes tumor regression both in vitro and in ovo.BMC cancer · 2025Article
- Strategies to Overcome PD-1/PD-L1 Blockade Resistance: Focusing on Combination with Immune Checkpoint Blockades.Journal of Cancer · 2025Review
- A Luminescence-Based Method for In Vitro Screening of Immunomodulatory Checkpoints and Therapeutics.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Strategies to therapeutically modulate cytokine action.Nature reviews. Drug discovery · 2023Review
- A luminescence-based method to assess antigen presentation and antigen-specific T cell responses forFrontiers in immunology · 2023Article
- Exhaustion of CAR T cells: potential causes and solutions.Journal of translational medicine · 2022Review
- Immune Checkpoint Receptors Signaling in T Cells.International journal of molecular sciences · 2022Review
- The mechanism ofTranslational cancer research · 2022Article
- Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Phosphatidylserine binding directly regulates TIM-3 function.The Biochemical journal · 2021Article
- The PI3K pathway as a therapeutic intervention point in inflammatory bowel disease.Immunity, inflammation and disease · 2021Article
- Emerging Immunotherapy for Acute Myeloid Leukemia.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TIM-3 (T cell immunoglobulin and mucin-domain containing protein 3) is a member of the TIM family of proteins that is preferentially expressed on Th1 polarized CD4+ and CD8+ T cells. Recent studies indicate that TIM-3 serves as a negative regulator of T cell function (i.e. T cell dependent immune responses, proliferation, tolerance, and exhaustion). Despite having no recognizable inhibitory signaling motifs, the intracellular tail of TIM-3 is apparently indispensable for function. Specifically, the conserved residues Y265/Y272 and surrounding amino acids appear to be critical for function. Mechanistically, several studies suggest that TIM-3 can associate with interleukin inducible T cell kinase (ITK), the Src kinases Fyn and Lck, and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor protein to positively or negatively regulate IL-2 production via NF-κB/NFAT signaling pathways. To begin to address this discrepancy, we examined the effect of TIM-3 in two model systems. First, we generated several Jurkat T cell lines stably expressing human TIM-3 or murine CD28-ECD/human TIM-3 intracellular tail chimeras and examined the effects that TIM-3 exerts on T cell Receptor (TCR)-mediated activation, cytokine secretion, promoter activity, and protein kinase association. In this model, our results demonstrate that TIM-3 inhibits several TCR-mediated phenotypes: i) NF-kB/NFAT activation, ii) CD69 expression, and iii) suppression of IL-2 secretion. To confirm our Jurkat cell observations we developed a primary human CD8+ cell system that expresses endogenous levels of TIM-3. Upon TCR ligation, we observed the loss of NFAT reporter activity and IL-2 secretion, and identified the association of Src kinase Lck, and PLC-γ with TIM-3. Taken together, our results support the conclusion that TIM-3 is a negative regulator of TCR-function by attenuating activation signals mediated by CD3/CD28 co-stimulation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.