ArticleProceedings of the National Academy of Sciences of the United States of America2016
Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 60 citations in OpenAlex.
- Generation and characterization of humanized CD4 knock-in mice expressing chimeric mouse/human CD4 protein.Lab animal · 2026Article
- Signatures of pathogen-driven selection and Austronesian gene flow of Papua New Guinea HLA alleles.American journal of human genetics · 2026Article
- A naturally selected αβ T cell receptor binds HLA-DQ2 molecules without co-contacting the presented peptide.Nature communications · 2025Article
- Comparative Kinetics of Supported Lipid Bilayer Formation on Silica Coated Vertically Oriented Highly Curved Nanowires and Planar Silica Surfaces.Nano letters · 2025Article
- Utilizing CRISPR-based genetic modification for precise control of seed dormancy: progress, obstacles, and potential directions.Molecular biology reports · 2025Review
- The TCR and LCK: foundations for T-cell activation and therapeutic innovation.Frontiers in immunology · 2025Review
- Article
- CD4 and LAG-3 from sharks to humans: related molecules with motifs for opposing functions.Frontiers in immunology · 2023Article
- The kinase occupancy of T cell coreceptors reconsidered.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Discrete LAT condensates encode antigen information from single pMHC:TCR binding events.Nature communications · 2022Article
- Cooperative binding of T cell receptor and CD4 to peptide-MHC enhances antigen sensitivity.Nature communications · 2022Article
- Epigenetic Reprogramming Leads to Downregulation of CD4 and Functional Changes in African Green Monkey Memory CD4Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- CD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element.Nature communications · 2022Article
- Seven mysteries of LAG-3: a multi-faceted immune receptor of increasing complexity.Immunotherapy advances · 2022Review
- Supported Lipid Bilayers and the Study of Two-Dimensional Binding Kinetics.Frontiers in molecular biosciences · 2022Review
- Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors.Molecular therapy. Methods & clinical development · 2021Article
- Single-cell measurements of two-dimensional binding affinity across cell contacts.Biophysical journal · 2021Article
- Trapping or slowing the diffusion of T cell receptors at close contacts initiates T cell signaling.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- MHC class II tetramers engineered for enhanced binding to CD4 improve detection of antigen-specific T cells.Nature biotechnology · 2021Article
- Affinity-matured HLA class II dimers for robust staining of antigen-specific CD4Nature biotechnology · 2021Article
Corrections and comments
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Authors and funding
23 authors at 8 institutions in 3 countries.
Funding
Abstract
The αβ T-cell coreceptor CD4 enhances immune responses more than 1 million-fold in some assays, and yet the affinity of CD4 for its ligand, peptide-major histocompatibility class II (pMHC II) on antigen-presenting cells, is so weak that it was previously unquantifiable. Here, we report that a soluble form of CD4 failed to bind detectably to pMHC II in surface plasmon resonance-based assays, establishing a new upper limit for the solution affinity at 2.5 mM. However, when presented multivalently on magnetic beads, soluble CD4 bound pMHC II-expressing B cells, confirming that it is active and allowing mapping of the native coreceptor binding site on pMHC II. Whereas binding was undetectable in solution, the affinity of the CD4/pMHC II interaction could be measured in 2D using CD4- and adhesion molecule-functionalized, supported lipid bilayers, yielding a 2D Kd of ∼5,000 molecules/μm(2) This value is two to three orders of magnitude higher than previously measured 2D Kd values for interacting leukocyte surface proteins. Calculations indicated, however, that CD4/pMHC II binding would increase rates of T-cell receptor (TCR) complex phosphorylation by threefold via the recruitment of Lck, with only a small, 2-20% increase in the effective affinity of the TCR for pMHC II. The affinity of CD4/pMHC II therefore seems to be set at a value that increases T-cell sensitivity by enhancing phosphorylation, without compromising ligand discrimination.
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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.