A DNA-Based T Cell Receptor Reveals a Role for Receptor Clustering in Ligand Discrimination

TitleA DNA-Based T Cell Receptor Reveals a Role for Receptor Clustering in Ligand Discrimination
Publication TypeJournal Article
Year of Publication2017
AuthorsTaylor MJ, Husain K, Gartner ZJ, Mayor S, Vale RD
JournalCell
Volume169
Start Page108
Issue1
Pagination108-119
Abstract

A T cell mounts an immune response by measuring the binding strength of its T cell receptor (TCR) for peptide-loaded MHCs (pMHC) on an antigen-presenting cell. How T cells convert the lifetime of the extracellular TCR-pMHC interaction into an intracellular signal remains unknown. Here, we developed a synthetic signaling system in which the extracellular domains of the TCR and pMHC were replaced with short hybridizing strands of DNA. Remarkably, T cells can discriminate between DNA ligands differing by a single base pair. Single-molecule imaging reveals that signaling is initiated when single ligand-bound receptors are converted into clusters, a time-dependent process requiring ligands with longer bound times. A computation model reveals that receptor clustering serves a kinetic proofreading function, enabling ligands with longer bound times to have disproportionally greater signaling outputs. These results suggest that spatial reorganization of receptors plays an important role in ligand discrimination in T cell signaling.

URLhttp://www.sciencedirect.com/science/article/pii/S0092867417302854
DOI10.1016/j.cell.2017.03.006
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