Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination

Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition even...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 113; no. 37; pp. E5454 - E5463
Main Authors Pageon, Sophie V., Tabarin, Thibault, Yamamoto, Yui, Ma, Yuanqing, Nicovich, Philip R., Bridgeman, John S., Cohnen, André, Benzing, Carola, Gao, Yijun, Crowther, Michael D., Tungatt, Katie, Dolton, Garry, Sewell, Andrew K., Price, David A., Acuto, Oreste, Parton, Robert G., Gooding, J. Justin, Rossy, Jérémie, Rossjohn, Jamie, Gaus, Katharina
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 13.09.2016
SeriesPNAS Plus
Subjects
Adaptive Immunity - genetics
Animals
Antigens
Antigens - genetics
Antigens - immunology
Biological Sciences
CD3 Complex - immunology
Humans
Immune system
Major Histocompatibility Complex - immunology
Mice
Molecules
Peptides
Peptides - immunology
Phosphorylation
Phosphorylation - immunology
PNAS Plus
Proteins
Receptors, Antigen, T-Cell - immunology
Signal Transduction
Single Molecule Imaging
T cell receptors
TCR triggering
signal transduction
single-molecule localization microscopy
Online AccessGet full text

Cover

More Information
Summary:Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. Here, we used singlemolecule localization microscopy to quantify the organization of TCR–CD3 complexes into nanoscale clusters and to distinguish between triggered and nontriggered TCR–CD3 complexes. We found that only TCR–CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. Moreover, both pMHC dose and TCR–pMHC affinity determined the density of TCR–CD3 clusters, which scaled with overall phosphorylation levels. Thus, TCR–CD3 clustering translates antigen recognition by the TCR into signal initiation by the CD3 complex, and the formation of dense signaling-competent clusters is a process of antigen discrimination.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Edited by Jennifer Lippincott-Schwartz, National Institutes of Science, Bethesda, MD, and approved July 26, 2016 (received for review May 9, 2016)
1S.V.P., T.T., and Y.Y. contributed equally to this work.
Author contributions: S.V.P., J. Rossy, J. Rossjohn, and K.G. designed research; S.V.P., Y.Y., Y.M., and Y.G. performed research; P.R.N., J.S.B., A.C., C.B., M.D.C., K.T., G.D., A.K.S., D.A.P., and O.A. contributed new reagents/analytic tools; S.V.P., T.T., and Y.Y. analyzed data; S.V.P., R.G.P., J.J.G., and K.G. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1607436113