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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 single-molecule 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.

Original publication

DOI

10.1073/pnas.1607436113

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

09/2016

Volume

113

Pages

E5454 - E5463

Addresses

European Molecular Biology Laboratory (EMBL) Australia Node in Single Molecule Science, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of New South Wales, Sydney, NSW 2052, Australia;

Keywords

Animals, Humans, Mice, Peptides, Receptors, Antigen, T-Cell, Antigens, Signal Transduction, Major Histocompatibility Complex, Phosphorylation, Adaptive Immunity, Single Molecule Imaging, CD3 Complex