Initiation of T cell signaling by CD45 segregation at 'close contacts'

Veronica T Chang; Ricardo A Fernandes; Kristina A Ganzinger; Steven F Lee; Christian Siebold; James McColl; Peter Jönsson; Matthieu Palayret; Karl Harlos; Charlotte H Coles; E Yvonne Jones; Yuan Lui; Elizabeth Huang; Robert J C Gilbert; David Klenerman; A Radu Aricescu; Simon J Davis

doi:10.1038/ni.3392

Initiation of T cell signaling by CD45 segregation at 'close contacts'

Veronica T Chang, Ricardo A Fernandes, Kristina A Ganzinger, Steven F Lee, Christian Siebold, James McColl, Peter Jönsson, Matthieu Palayret, Karl Harlos, Charlotte H Coles, E Yvonne Jones, Yuan Lui, Elizabeth Huang, Robert J C Gilbert, David Klenerman, A Radu Aricescu, Simon J Davis

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Abstract

It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.

Original language	English
Pages (from-to)	574-582
Number of pages	9
Journal	Nature Immunology
Volume	17
Issue number	5
DOIs	https://doi.org/10.1038/ni.3392
Publication status	Published - 2016 May
Externally published	Yes

Subject classification (UKÄ)

Immunology

Free keywords

Crystallography, X-Ray
HEK293 Cells
Humans
Jurkat Cells
Leukocyte Common Antigens
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Microscopy, Electron
Microscopy, Fluorescence
Models, Molecular
Protein Structure, Tertiary
Receptors, Antigen, T-Cell
Signal Transduction
T-Lymphocytes
Time Factors
ZAP-70 Protein-Tyrosine Kinase
Journal Article
Research Support, Non-U.S. Gov't

Access to Document

10.1038/ni.3392

Initiation_of_T_cell_signalingAccepted author manuscript, 1.24 MB

Intermolecular interactions between molecules on the surface of cells
Jönsson, P. (PI)
2015/01/01 → 2018/12/31
Project: Research

Cite this

Chang, V. T., Fernandes, R. A., Ganzinger, K. A., Lee, S. F., Siebold, C., McColl, J., Jönsson, P., Palayret, M., Harlos, K., Coles, C. H., Jones, E. Y., Lui, Y., Huang, E., Gilbert, R. J. C., Klenerman, D., Aricescu, A. R., & Davis, S. J. (2016). Initiation of T cell signaling by CD45 segregation at 'close contacts'. Nature Immunology, 17(5), 574-582. https://doi.org/10.1038/ni.3392

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abstract = "It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.",

keywords = "Crystallography, X-Ray, HEK293 Cells, Humans, Jurkat Cells, Leukocyte Common Antigens, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Microscopy, Electron, Microscopy, Fluorescence, Models, Molecular, Protein Structure, Tertiary, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Time Factors, ZAP-70 Protein-Tyrosine Kinase, Journal Article, Research Support, Non-U.S. Gov't",

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doi = "10.1038/ni.3392",

language = "English",

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AU - Chang, Veronica T

AU - Fernandes, Ricardo A

AU - Ganzinger, Kristina A

AU - Lee, Steven F

AU - Siebold, Christian

AU - McColl, James

AU - Jönsson, Peter

AU - Palayret, Matthieu

AU - Harlos, Karl

AU - Coles, Charlotte H

AU - Jones, E Yvonne

AU - Lui, Yuan

AU - Huang, Elizabeth

AU - Gilbert, Robert J C

AU - Klenerman, David

AU - Aricescu, A Radu

AU - Davis, Simon J

PY - 2016/5

Y1 - 2016/5

N2 - It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.

AB - It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.

KW - Crystallography, X-Ray

KW - HEK293 Cells

KW - Humans

KW - Jurkat Cells

KW - Leukocyte Common Antigens

KW - Lymphocyte Specific Protein Tyrosine Kinase p56(lck)

KW - Microscopy, Electron

KW - Microscopy, Fluorescence

KW - Models, Molecular

KW - Protein Structure, Tertiary

KW - Receptors, Antigen, T-Cell

KW - Signal Transduction

KW - T-Lymphocytes

KW - Time Factors

KW - ZAP-70 Protein-Tyrosine Kinase

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ni.3392

DO - 10.1038/ni.3392

M3 - Article

C2 - 26998761

SN - 1529-2908

VL - 17

SP - 574

EP - 582

JO - Nature Immunology

JF - Nature Immunology

IS - 5

ER -

Initiation of T cell signaling by CD45 segregation at 'close contacts'

Abstract

Subject classification (UKÄ)

Free keywords

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Intermolecular interactions between molecules on the surface of cells

Cite this