Cooperative binding of T cell receptor and CD4 to peptide-MHC enhances antigen sensitivity

Nat Commun. 2022 Nov 17;13(1):7055. doi: 10.1038/s41467-022-34587-w.


Antigen recognition by the T cell receptor (TCR) of CD4+ T cells can be greatly enhanced by the coreceptor CD4. Yet, understanding of the molecular mechanism is hindered by the ultra-low affinity of CD4 binding to class-II peptide-major histocompatibility complexes (pMHC). Here we show, using two-dimensional (2D) mechanical-based assays, that the affinity of CD4-pMHC interaction is 3-4 logs lower than that of cognate TCR-pMHC interactions, and it is more susceptible to increased dissociation by forces (slip bond). In contrast, CD4 binds TCR-pre-bound pMHC at 3-6 logs higher affinity, forming TCR-pMHC-CD4 tri-molecular bonds that are prolonged by force (catch bond), and modulated by protein mobility on the cell membrane, indicating profound TCR-CD4 cooperativity. Consistent with a tri-crystal structure, using DNA origami as a molecular ruler to titrate spacing between TCR and CD4 we show that 7-nm proximity optimizes TCR-pMHC-CD4 tri-molecular bond formation with pMHC. Our results thus provide deep mechanistic insight into CD4 enhancement of TCR antigen recognition.

MeSH terms

  • Antigens*
  • Histocompatibility Antigens
  • Major Histocompatibility Complex
  • Peptides / chemistry
  • Receptors, Antigen, T-Cell* / metabolism


  • Receptors, Antigen, T-Cell
  • Antigens
  • Histocompatibility Antigens
  • Peptides