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 journalArticle

42 Citations (Scopus)

Abstract

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
JournalImmunity
Volume43
Issue number2
DOIs
StatePublished - Aug 18 2015

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T-Cell Antigen Receptor
CD3 Antigens
Cell Membrane
T-Lymphocytes
Cytoplasm
Ligands
Membranes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Cite this

Lee, M. S., Glassman, C. R., Deshpande, N. R., Badgandi, H. B., Parrish, H. L., Uttamapinant, C., ... Kuhns, M. S. (2015). A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ. Immunity, 43(2), 227-239. [3145]. https://doi.org/10.1016/j.immuni.2015.06.018

A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ. / Lee, Mark S.; Glassman, Caleb R.; Deshpande, Neha R.; Badgandi, Hemant B.; Parrish, Heather L.; Uttamapinant, Chayasith; Stawski, Philipp S.; Ting, Alice Y.; Kuhns, Michael S.

In: Immunity, Vol. 43, No. 2, 3145, 18.08.2015, p. 227-239.

Research output: Contribution to journalArticle

Lee, MS, Glassman, CR, Deshpande, NR, Badgandi, HB, Parrish, HL, Uttamapinant, C, Stawski, PS, Ting, AY & Kuhns, MS 2015, 'A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ', Immunity, vol. 43, no. 2, 3145, pp. 227-239. https://doi.org/10.1016/j.immuni.2015.06.018
Lee MS, Glassman CR, Deshpande NR, Badgandi HB, Parrish HL, Uttamapinant C et al. A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ. Immunity. 2015 Aug 18;43(2):227-239. 3145. https://doi.org/10.1016/j.immuni.2015.06.018
Lee, Mark S. ; Glassman, Caleb R. ; Deshpande, Neha R. ; Badgandi, Hemant B. ; Parrish, Heather L. ; Uttamapinant, Chayasith ; Stawski, Philipp S. ; Ting, Alice Y. ; Kuhns, Michael S. / A Mechanical Switch Couples T Cell Receptor Triggering to the Cytoplasmic Juxtamembrane Regions of CD3ζζ. In: Immunity. 2015 ; Vol. 43, No. 2. pp. 227-239.
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