A DNA-Based T Cell Receptor Reveals a Role for Receptor Clustering in Ligand Discrimination.
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.
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94143, USA; National Centre for Biological Sciences, Bangalore 560065, India; HHMI Summer Institute, Woods Hole, MA 02543, USA.
Marcus J
MJ
Taylor
National Centre for Biological Sciences, Bangalore 560065, India; The Simons Centre for the Study of Living Machines, Bangalore 560065, India.
Kabir
K
Husain
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143, USA.
Zev J
ZJ
Gartner
National Centre for Biological Sciences, Bangalore 560065, India; HHMI Summer Institute, Woods Hole, MA 02543, USA. Electronic address: mayor@ncbs.res.in.
Satyajit
S
Mayor
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143, USA; HHMI Summer Institute, Woods Hole, MA 02543, USA. Electronic address: ron.vale@ucsf.edu.
Ronald D
RD
Vale
D004247:DNA / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D000072760:Single Molecule Imaging; D013601:T-Lymphocytes / Q000378:metabolism*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000032:analysis
D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D004247:DNA; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human