A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ

Mark S. Lee, Caleb R. Glassman, Neha R. Deshpande, Hemant B. Badgandi, Heather L. Parrish, Chayasith Uttamapinant, Philipp S. Stawski, Alice Y. Ting, Michael S. Kuhns

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


The eight-subunit T cell receptor (TCR)-CD3 complex is the primary determinant for T cell fate decisions. Yet how it relays ligand-specific information across the cell membrane for conversion to chemical signals remains unresolved. We hypothesized that TCR engagement triggers a change in the spatial relationship between the associated CD3ζζ subunits at the junction where they emerge from the membrane into the cytoplasm. Using three in situ proximity assays based on ID-PRIME, FRET, and EPOR activity, we determined that the cytosolic juxtamembrane regions of the CD3ζζ subunits are spread apart upon assembly into the TCR-CD3 complex. TCR engagement then triggered their apposition. This mechanical switch resides upstream of the CD3ζζ intracellular motifs that initiate chemical signaling, as well as the polybasic stretches that regulate signal potentiation. These findings provide a framework from which to examine triggering events for activating immune receptors and other complex molecular machines. Despite detailed insights into TCR-pMHC interactions and intracellular signaling, how pMHC-specific information crosses the T cell membrane is unclear. Kuhns and colleagues report that the juxtamembrane regions of the CD3ζζ signaling module are divaricated within the TCR-CD3 complex until TCR engagement triggers their juxtaposition, transferring information across the cell membrane.

Original languageEnglish (US)
Article number3145
Pages (from-to)227-239
Number of pages13
Issue number2
StatePublished - Aug 18 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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