ArticlePloS one2014
T cell receptor signaling can directly enhance the avidity of CD28 ligand binding.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Clinical Efficacy and Safety of Pembrolizumab Therapy for B-cell Lymphoma: A Systematic Review and Meta-analysis.Anti-cancer agents in medicinal chemistry · 2025Pooled it
- Immune Checkpoint Inhibitors in Malignant Melanoma: Anti-PD-1, Anti-CTLA-4 and Anti-LAG-3 Therapies.Current oncology reports · 2026Review
- The homodimer interfaces of costimulatory receptors B7 and CD28 control their engagement and pro-inflammatory signaling.Journal of biomedical science · 2023Article
- Bivalent binding of staphylococcal superantigens to the TCR and CD28 triggers inflammatory signals independently of antigen presenting cells.Frontiers in immunology · 2023Article
- Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation.Cancer cell · 2021Article
- Binding of Staphylococcal Enterotoxin B (SEB) to B7 Receptors Triggers TCR- and CD28-Mediated Inflammatory Signals in the Absence of MHC Class II Molecules.Frontiers in immunology · 2021Article
- T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors.International journal of molecular sciences · 2020Review
- The CD28 Transmembrane Domain Contains an Essential Dimerization Motif.Frontiers in immunology · 2020Article
- Colorectal Cancer Immunotherapy: Options and Strategies.Frontiers in immunology · 2020Review
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- Staphylococcal and Streptococcal Superantigens Trigger B7/CD28 Costimulatory Receptor Engagement to Hyperinduce Inflammatory Cytokines.Frontiers in immunology · 2019Article
- A non-conserved amino acid variant regulates differential signalling between human and mouse CD28.Nature communications · 2018Article
- TCR and CD28 Concomitant Stimulation Elicits a Distinctive Calcium Response in Naive T Cells.Frontiers in immunology · 2018Article
- The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling.Frontiers in immunology · 2018Article
- Early T cell receptor signals globally modulate ligand:receptor affinities during antigen discrimination.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- BetaBiochimica et biophysica acta. Biomembranes · 2017Article
- Impact of Metabolism on T-Cell Differentiation and Function and Cross Talk with Tumor Microenvironment.Frontiers in immunology · 2017Review
- Superantigens hyperinduce inflammatory cytokines by enhancing the B7-2/CD28 costimulatory receptor interaction.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- CD28 Costimulation: From Mechanism to Therapy.Immunity · 2016Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
T cell activation takes place in the context of a spatial and kinetic reorganization of cell surface proteins and signaling molecules at the contact site with an antigen presenting cell, termed the immunological synapse. Coordination of the activation, recruitment, and signaling from T cell receptor (TCR) in conjunction with adhesion and costimulatory receptors regulates both the initiation and duration of signaling that is required for T cell activation. The costimulatory receptor, CD28, is an essential signaling molecule that determines the quality and quantity of T cell immune responses. Although the functional consequences of CD28 engagement are well described, the molecular mechanisms that regulate CD28 function are largely unknown. Using a micropipet adhesion frequency assay, we show that TCR signaling enhances the direct binding between CD28 and its ligand, CD80. Although CD28 is expressed as a homodimer, soluble recombinant CD28 can only bind ligand monovalently. Our data suggest that the increase in CD28-CD28 binding is mediated through a change in CD28 valency. Molecular dynamic simulations and in vitro mutagenesis indicate that mutations at the base of the CD28 homodimer interface, distal to the ligand-binding site, can induce a change in the orientation of the dimer that allows for bivalent ligand binding. When expressed in T cells, this mutation allows for high avidity CD28-CD80 interactions without TCR signaling. Molecular dynamic simulations also suggest that wild type CD28 can stably adopt a bivalent conformation. These results support a model whereby inside-out signaling from the TCR can enhance CD28 ligand interactions by inducing a change in the CD28 dimer interface to allow for bivalent ligand binding and ultimately the transduction of CD28 costimulatory signals that are required for T cell activation.
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Registered trials
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.