PT  - JOURNAL ARTICLE
AU  - Marcus J. Taylor
AU  - Kabir Husain
AU  - Zev J. Gartner
AU  - Satyajit Mayor
AU  - Ronald D. Vale
TI  - Signal Transduction Through a DNA-Based T Cell Receptor
AID  - 10.1101/062877
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 062877
4099  - http://biorxiv.org/content/early/2016/07/08/062877.short
4100  - http://biorxiv.org/content/early/2016/07/08/062877.full
AB  - T cells mount an immune response based upon the strength of the interaction between its T cell receptor (TCR) and peptide-loaded MHCs (pMHC) on an antigen-presenting cell. How T cells become activated by some pMHCs, but not others with slightly shorter bound times, remains an unanswered question. Here, we developed a finely tunable synthetic receptor-ligand system in which the extracellular domains of the TCR and pMHC were replaced with two short hybridizing strands of DNA. Remarkably, the T cell signaling response can discriminate between DNA ligands differing by a single base pair. Single molecule imaging reveals that ligated receptors with longer bound times promote the binding of more ligands nearby to create clusters; stable clusters of 2-4 ligated receptors then trigger receptor phosphorylation and signaling. These results reveal how T cells convert the bound time of an extracellular receptor-ligand interaction into a physical reorganization of molecules in the membrane and intracellular signaling.