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Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions

Jönsson, Peter, Southcombe, Jennifer H., Santos, Ana Mafalda, Huo, Jiandong, Fernandes, Ricardo A., McColl, James, Lever, Melissa, Evans, Edward J., Hudson, Alexander, Chang, Veronica T., Hanke, Tomá?, Godkin, Andrew ORCID:, Dunne, Paul D., Horrocks, Mathew H., Palayret, Matthieu, Screaton, Gavin R., Petersen, Jan, Rossjohn, Jamie ORCID:, Fugger, Lars, Dushek, Omer, Xu, Xiao-Ning, Davis, Simon J. and Klenerman, David 2016. Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions. Proceedings of the National Academy of Sciences of the United States of America 113 (20) , pp. 5682-5687. 10.1073/pnas.1513918113

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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/μm2. 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: National Academy of Sciences
ISSN: 0027-8424
Date of First Compliant Deposit: 5 July 2017
Date of Acceptance: 23 March 2016
Last Modified: 02 Nov 2022 11:27

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