RT Journal Article
SR Electronic
T1 A DNA-based T cell receptor reveals a role for receptor clustering in ligand discrimination
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 062877
DO 10.1101/062877
A1 Marcus J. Taylor
A1 Kabir Husain
A1 Zev J. Gartner
A1 Satyajit Mayor
A1 Ronald D. Vale
YR 2017
UL http://biorxiv.org/content/early/2017/01/17/062877.abstract
AB T cells mount 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.