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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift


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.


  • Jennifer H. Southcombe
  • Ana Mafalda Santos
  • Jiandong Huo
  • Ricardo A. Fernandes
  • James McColl
  • Melissa Lever
  • Edward J. Evans
  • Alexander Hudson
  • Veronica T. Chang
  • Tomáš Hanke
  • Andrew Godkin
  • Paul D. Dunne
  • Mathew H. Horrocks
  • Matthieu Palayret
  • Gavin R. Screaton
  • Jan Petersen
  • Jamie Rossjohn
  • Lars Fugger
  • Omer Dushek
  • Xiao Ning Xu
  • Simon J. Davis
  • David Klenerman
Enheter & grupper
Externa organisationer
  • University of Cambridge
  • Cardiff University
  • University of Oxford
  • Monash University

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Biokemi och molekylärbiologi


Sidor (från-till)5682-5687
Antal sidor6
TidskriftProceedings of the National Academy of Sciences of the United States of America
StatusPublished - 2016 maj 17
Peer review utfördJa

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