Immunology Under Cover

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

T cell activation occurs when a T cell receptor (TCR) is exposed to antigen bound to a major histocompatability complex (MHC) on the surface of an antigen-presenting cell. The TCR is noncovalently associated with the , , , and subunits of CD3, which among them contain 10 cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs). Binding of antigen to the TCR triggers the tyrosine phosphorylation of these ITAMs, which results in downstream signaling events, but how ITAM phosphorylation is initiated is unclear. This led Xu et al. to investigate the role of the transmembrane CD3 subunit in T cell activation. They first showed that a fluorescently labeled peptide corresponding to the cytoplasmic domain of CD3 (CD3_CD) bound to phospholipid vesicles and that this interaction depended on a segment of basic (positively charged) residues of CD3_CD but not on its ITAM motif. Fluorescence resonance energy transfer (FRET) between labeled CD3 and the membrane demonstrated that wild-type CD3, but not a mutant CD3 in which six basic residues were mutated to serines, bound to the plasma membrane of a transfected human T cell line. Analysis of the CD3_CD in complex with a phospholipid bicelle structure by nuclear magnetic resonance (NMR) spectroscopy revealed that lipid-binding induced a fold in the structure of the CD3_CD such that its ITAM motif was embedded in the hydrophobic region of the bilayer, which made it inaccessible to the tyrosine kinase Lck in vitro. As Kuhns and Davis discuss, binding of CD3 to phospholipids in the plasma membrane shields its ITAM from tyrosine kinases, which implies that some other signal, perhaps mechanical, is required to enable ITAM-mediated signaling events to occur upon engagement of the TCR.

C. Xu, E. Gagnon, M. E. Call, J. R. Schnell, C. D. Schwieters, C. V. Carman, J. J. Chou, K. W. Wucherpfennig, Regulation of T cell receptor activation by dynamic membrane binding of the CD3 cytoplasmic tyrosine-based motif. Cell 135, 702–713 (2008). [PubMed]

M. S. Kuhns, M. M. Davis, The safety on the TCR trigger. Cell 135, 594–596 (2008). [PubMed]

The editors suggest the following Related Resources on Science sites:

In Science Signaling

PODCASTS
Immunology
Science Signaling Podcast: 16 December 2008

John F. Foley and Annalisa M. VanHook (16 December 2008)
Sci. Signal. 1 (50), pc14. [DOI: 10.1126/scisignal.150pc14]
 |  Abstract »  |  Full Text »  |  Podcast »

EDITORS' CHOICE
Immunology
Getting the Numbers Right

John F. Foley (27 May 2008)
Sci. Signal. 1 (21), ec194. [DOI: 10.1126/stke.121ec194]
 |  Abstract »

PERSPECTIVES
Receptors
TCR Triggering by the pMHC Complex: Valency, Affinity, and Dynamics

Rajat Varma (13 May 2008)
Sci. Signal. 1 (19), pe21. [DOI: 10.1126/stke.119pe21]
 |  Abstract »  |  Full Text »  |  PDF »

REVIEWS
Immunology
The Expanding Role for ITAM-Based Signaling Pathways in Immune Cells

Clare L. Abram and Clifford A. Lowell (13 March 2007)
Sci. STKE 2007 (377), re2. [DOI: 10.1126/stke.3772007re2]
 |  Gloss »  |  Abstract »  |  Full Text »  |  PDF »

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES: