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

Jönsson, Peter, Southcombe, Jennifer H., Mafalda Santos, Ana, Huo, Jiandong, Fernandes, Ricardo A., McColl, James, Lever, Melissa, Evans, Edward J., Hudson, Alexander, Chang, Veronica T., Hanke, Tomáš, Godkin, Andrew, Dunne, Paul D., Horrocks, Mathew H., Palayret, Matthieu, Screaton, Gavin R., Petersen, Jan, Rossjohn, Jamie, 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. ISSN 0027-8424

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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
Additional Information: Funding information: This work was supported by the Wellcome Trust, the UK Medical Research Council, and the Swedish Research Council Grants 623-2014-6387 and 621-2014-3907 (to P.J.). O.D. is supported by the Sir Henry Dale Fellowship Grant 098363 jointly funded by the Wellcome Trust and the Royal Society.
Faculty \ School: Faculty of Science
Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 15 Aug 2022 15:31
Last Modified: 22 Oct 2022 07:53
DOI: 10.1073/pnas.1513918113

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