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

ABSTRACT: The ?? 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/?m(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.

SUBMITTER: Jonsson P

PROVIDER: S-EPMC4878507 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Jönsson Peter P Southcombe Jennifer H JH Santos Ana Mafalda AM Huo Jiandong J Fernandes Ricardo A RA McColl James J Lever Melissa M Evans Edward J EJ Hudson Alexander A Chang Veronica T VT Hanke Tomáš T Godkin Andrew A Dunne Paul D PD Horrocks Mathew H MH Palayret Matthieu M Screaton Gavin R GR Petersen Jan J Rossjohn Jamie J Fugger Lars L Dushek Omer O Xu Xiao-Ning XN Davis Simon J SJ Klenerman David D

Proceedings of the National Academy of Sciences of the United States of America 20160425 20

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 ...[more]

PMID: 27114505

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Dataset Information

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

Publications

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

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