ArticleNature immunology2023
CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides.
Article in Nature immunology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- The development of novel chimeric antigen receptor gamma-delta T cells against multiple myeloma and single-cell RNA sequencing analysis.British journal of haematology · 2026Article
- Weak SLP-76/PLC-γ1 interaction fine-tunes T cell receptor signal strength to optimize T cell responsiveness.Nature communications · 2026Article
- Leveraging mathematical models to predict and control T-cell activation.PLoS computational biology · 2026Article
- Re-imagining T-cell receptor signaling: parallel paths may be key to discriminatory power.Journal of biosciences · 2026Article
- Review
- Parallel reactions on a single T cell receptor offer a robust kinetic proofreading mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Ligand discrimination in immune cells: Signal processing insights into immune dysfunction in ER+ breast cancer.PLoS computational biology · 2025Article
- Weak SLP-76-PLC-γ1 interaction in the LAT-nucleated multi-protein complex fine-tunes TCR signal strength to optimize T cell responsiveness.bioRxiv : the preprint server for biology · 2025Article
- Characterization and comparative analysis of multifunctional natural killer cell engagers during antitumor responses.Cell reports. Medicine · 2025Article
- Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity.Cell · 2025Article
- Charge-based immunoreceptor signalling in health and disease.Nature reviews. Immunology · 2025Review
- Early events in TCR signaling - the evolving role of ITAMs.Frontiers in immunology · 2025Review
- The TCR and LCK: foundations for T-cell activation and therapeutic innovation.Frontiers in immunology · 2025Review
- Mathematical models of TCR initial triggering.Frontiers in immunology · 2024Review
- CD3ε of a pan T cell marker involved in mouseInternational journal of ophthalmology · 2024Article
- T-cell virtuosity in ''knowing thyself".Frontiers in immunology · 2024Review
Corrections and comments
- Erratum issued
Authors and funding
16 authors at 9 institutions in 3 countries.
Funding
Abstract
The T cell antigen receptor (TCR) contains ten immunoreceptor tyrosine-based activation motif (ITAM) signaling sequences distributed within six CD3 subunits; however, the reason for such structural complexity and multiplicity is unclear. Here we evaluated the effect of inactivating the three CD3ζ chain ITAMs on TCR signaling and T cell effector responses using a conditional 'switch' mouse model. Unexpectedly, we found that T cells expressing TCRs containing inactivated (non-signaling) CD3ζ ITAMs (6F-CD3ζ) exhibited reduced ability to discriminate between low- and high-affinity ligands, resulting in enhanced signaling and cytokine responses to low-affinity ligands because of a previously undetected inhibitory function of CD3ζ ITAMs. Also, 6F-CD3ζ TCRs were refractory to antagonism, as predicted by a new in silico adaptive kinetic proofreading model that revises the role of ITAM multiplicity in TCR signaling. Finally, T cells expressing 6F-CD3ζ displayed enhanced cytolytic activity against solid tumors expressing low-affinity ligands, identifying a new counterintuitive approach to TCR-mediated cancer immunotherapy.
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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.