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

Sophie V. Pageon, Thibault Tabarin, Yui Yamamoto, Yuanqing Ma, Philip R. Nicovich, John S. Bridgeman, Andre Cohnen, Carola Benzing, Yijun Gao, Michael D. Crowther, Katie Tungatt, Garry Dolton, Andrew K. Sewell, David A. Price, Oreste Acuto, Robert G. Parton, J. Justin Gooding, Jeremie Rossy, Jamie Rossjohn, Katharina Gaus

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)E5454-E5463
Number of pages10
JournalProceedings of the National Academy of Sciences
Volume113
Issue number37
DOIs
Publication statusPublished - 13 Sep 2016

Keywords

  • Signal transduction
  • Single-molecule localization microscopy
  • Tcr triggering

Cite this

Pageon, S. V., Tabarin, T., Yamamoto, Y., Ma, Y., Nicovich, P. R., Bridgeman, J. S., ... Gaus, K. (2016). Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination. Proceedings of the National Academy of Sciences, 113(37), E5454-E5463. https://doi.org/10.1073/pnas.1607436113
Pageon, Sophie V. ; Tabarin, Thibault ; Yamamoto, Yui ; Ma, Yuanqing ; Nicovich, Philip R. ; Bridgeman, John S. ; Cohnen, Andre ; 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, Jeremie ; Rossjohn, Jamie ; Gaus, Katharina. / Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination. In: Proceedings of the National Academy of Sciences. 2016 ; Vol. 113, No. 37. pp. 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.",
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author = "Pageon, {Sophie V.} and Thibault Tabarin and Yui Yamamoto and Yuanqing Ma and Nicovich, {Philip R.} and Bridgeman, {John S.} and Andre Cohnen and Carola Benzing and Yijun Gao and Crowther, {Michael D.} and Katie Tungatt and Garry Dolton and Sewell, {Andrew K.} and Price, {David A.} and Oreste Acuto and Parton, {Robert G.} and Gooding, {J. Justin} and Jeremie Rossy and Jamie Rossjohn and Katharina Gaus",
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Pageon, SV, Tabarin, T, Yamamoto, Y, Ma, Y, Nicovich, PR, Bridgeman, JS, Cohnen, A, Benzing, C, Gao, Y, Crowther, MD, Tungatt, K, Dolton, G, Sewell, AK, Price, DA, Acuto, O, Parton, RG, Gooding, JJ, Rossy, J, Rossjohn, J & Gaus, K 2016, 'Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination' Proceedings of the National Academy of Sciences, vol. 113, no. 37, pp. E5454-E5463. https://doi.org/10.1073/pnas.1607436113

Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination. / Pageon, Sophie V.; Tabarin, Thibault; Yamamoto, Yui; Ma, Yuanqing; Nicovich, Philip R.; Bridgeman, John S.; Cohnen, Andre; 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, Jeremie; Rossjohn, Jamie; Gaus, Katharina.

In: Proceedings of the National Academy of Sciences, Vol. 113, No. 37, 13.09.2016, p. E5454-E5463.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination

AU - Pageon, Sophie V.

AU - Tabarin, Thibault

AU - Yamamoto, Yui

AU - Ma, Yuanqing

AU - Nicovich, Philip R.

AU - Bridgeman, John S.

AU - Cohnen, Andre

AU - Benzing, Carola

AU - Gao, Yijun

AU - Crowther, Michael D.

AU - Tungatt, Katie

AU - Dolton, Garry

AU - Sewell, Andrew K.

AU - Price, David A.

AU - Acuto, Oreste

AU - Parton, Robert G.

AU - Gooding, J. Justin

AU - Rossy, Jeremie

AU - Rossjohn, Jamie

AU - Gaus, Katharina

PY - 2016/9/13

Y1 - 2016/9/13

N2 - 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.

AB - 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.

KW - Signal transduction

KW - Single-molecule localization microscopy

KW - Tcr triggering

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U2 - 10.1073/pnas.1607436113

DO - 10.1073/pnas.1607436113

M3 - Article

VL - 113

SP - E5454-E5463

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

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

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