Monomeric agonist peptide/MHCII complexes activate T‐cells in an autonomous fashion

Molecular crowding of agonist peptide/MHC class II complexes (pMHCIIs) with structurally similar, yet per se non-stimulatory endogenous pMHCIIs has been postulated to sensitize T-cells for the recognition of single antigens on the surface of dendritic cells and B-cells. When testing this premise with the use of advanced live cell microscopy, we observed pMHCIIs as monomeric, randomly distributed entities diffusing rapidly after entering the APC surface. Synaptic TCR-engagement of highly abundant endogenous pMHCIIs was low or non-existent and affected neither TCR-engagement of rare agonist pMHCII in early and advanced synapses nor agonist-induced TCR-proximal signaling. Our findings highlight the capacity of single freely diffusing agonist pMHCIIs to elicit the full T-cell response in an autonomous and peptide-specific fashion with consequences for adaptive immunity and immunotherapeutic approaches. SHORT SUMMARY Platzer et al. revealed via highly quantitative and single molecule live cell microscopy the nature of peptide-loaded MHC class II molecules (pMHCII) as monomeric, densely populating, randomly distributed and predominantly rapidly diffusing entities on the surface of B-cells and dendritic cells. Low abundant stimulatory agonist pMHCII acted as autonomous units with the highest chance of T-cell detection when equally spread on APCs. The presence of bystander-pMHCII previously termed “co-agonist pMHC” affected neither synaptic agonist -TCR-binding nor efficiencies of T-cell recognition. “Co-agonist”-TCR-binding resembled random molecular collisions. Findings inform the design of T-cell-based immunotherapies.

• Publication year

  2023

• Venue

  bioRxiv

• Publication date

  2023-03-14

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.15252/embr.202357842PMID 37768718PMCID 10626418
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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