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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

Proc Natl Acad Sci U S A

Publication Date

13/09/2016

Volume

113

Pages

E5454 - E5463

Keywords

TCR triggering, signal transduction, single-molecule localization microscopy, Adaptive Immunity, Animals, Antigens, CD3 Complex, Humans, Major Histocompatibility Complex, Mice, Peptides, Phosphorylation, Receptors, Antigen, T-Cell, Signal Transduction, Single Molecule Imaging