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

Pageon, Sophie V., Tabarin, Thibault, Yamamoto, Yui, Ma, Yanqing, Nicovich, Philip R., Bridgeman, John S., Cohnen, Andre, Benzing, Carola, Gao, Yijun, Tungatt, Katie, Dolton, Garry, Sewell, Andrew K., Price, David A., Acuto, Oreste, Parton, Robert G., Gooding, J. Justin, Rossy, Jeremy, Rossjohn, Jamie, and Gaus, Katharina (2016) Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination. Proceedings of the National Academy of Sciences of the United States of America, 113 (44). E5454-E5463.

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Abstract

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.

Item ID: 55334
Item Type: Article (Research - C1)
ISSN: 1091-6490
Funders: National Health and Medical Research Council of Australia (NHMRC), Australian Research Council (ARC), Wellcome Trust
Projects and Grants: NHMRC Grant 1022182, NHMRC Grant 1037320, NHMRC Grant 1059278, ARC CE140100011
Date Deposited: 23 Oct 2018 03:55
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110704 Cellular Immunology @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 50%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 50%
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