Hedgehog signaling controls T cell killing at the immunological synapse

Maike de la Roche; Alex T Ritter; Karen L Angus; Colin Dinsmore; Charles H Earnshaw; Jeremy F Reiter; Gillian M Griffiths

doi:10.1126/science.1244689

Hedgehog signaling controls T cell killing at the immunological synapse

Maike de la Roche, Alex T Ritter, Karen L Angus, Colin Dinsmore, Charles H Earnshaw, Jeremy F Reiter, Gillian M Griffiths

Department of Education

Research output: Contribution to journal › Article › peer-review

112 Citations (SciVal)

Abstract

The centrosome is essential for cytotoxic T lymphocyte (CTL) function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunological synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog (Hh) signaling. Lymphocytes do not form primary cilia, but we found and describe here that Hh signaling played an important role in CTL killing. T cell receptor activation, which "prearms" CTLs with cytotoxic granules, also initiated Hh signaling. Hh pathway activation occurred intracellularly and triggered Rac1 synthesis. These events "prearmed" CTLs for action by promoting the actin remodeling required for centrosome polarization and granule release. Thus, Hh signaling plays a role in CTL function, and the immunological synapse may represent a modified cilium.

Original language	English
Pages (from-to)	1247-50
Number of pages	4
Journal	Science (New York, N.Y.)
Volume	342
Issue number	6163
DOIs	https://doi.org/10.1126/science.1244689
Publication status	Published - 6 Dec 2013

Bibliographical note

Funding information:
This work was supported by a Wellcome Trust Principal Research Fellowship to G.M.G. (075880), a Wellcome Trust Strategic Award for core facilities at the CIMR (100140), NIH (R01AR05439 and R01GM095941), the Burroughs Wellcome Fund, the David and Lucile F. Packard Foundation, and the Sandler Family Supporting Foundation to J.R.

Keywords

Animals
CD8-Positive T-Lymphocytes/immunology
Cell Polarity
Cells, Cultured
Centrosome/metabolism
Cytotoxicity, Immunologic
Hedgehog Proteins/metabolism
Immunological Synapses
Kruppel-Like Transcription Factors/genetics
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Models, Immunological
Neuropeptides/genetics
Patched Receptors
Receptors, Antigen, T-Cell/immunology
Receptors, Cell Surface/metabolism
Receptors, G-Protein-Coupled/metabolism
Signal Transduction
Smoothened Receptor
T-Lymphocytes, Cytotoxic/immunology
Zinc Finger Protein GLI1
rac1 GTP-Binding Protein/genetics

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10.1126/science.1244689

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title = "Hedgehog signaling controls T cell killing at the immunological synapse",

abstract = "The centrosome is essential for cytotoxic T lymphocyte (CTL) function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunological synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog (Hh) signaling. Lymphocytes do not form primary cilia, but we found and describe here that Hh signaling played an important role in CTL killing. T cell receptor activation, which {"}prearms{"} CTLs with cytotoxic granules, also initiated Hh signaling. Hh pathway activation occurred intracellularly and triggered Rac1 synthesis. These events {"}prearmed{"} CTLs for action by promoting the actin remodeling required for centrosome polarization and granule release. Thus, Hh signaling plays a role in CTL function, and the immunological synapse may represent a modified cilium.",

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author = "{de la Roche}, Maike and Ritter, {Alex T} and Angus, {Karen L} and Colin Dinsmore and Earnshaw, {Charles H} and Reiter, {Jeremy F} and Griffiths, {Gillian M}",

note = "Funding information: This work was supported by a Wellcome Trust Principal Research Fellowship to G.M.G. (075880), a Wellcome Trust Strategic Award for core facilities at the CIMR (100140), NIH (R01AR05439 and R01GM095941), the Burroughs Wellcome Fund, the David and Lucile F. Packard Foundation, and the Sandler Family Supporting Foundation to J.R. ",

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month = dec,

day = "6",

doi = "10.1126/science.1244689",

language = "English",

volume = "342",

pages = "1247--50",

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T1 - Hedgehog signaling controls T cell killing at the immunological synapse

AU - de la Roche, Maike

AU - Ritter, Alex T

AU - Angus, Karen L

AU - Dinsmore, Colin

AU - Earnshaw, Charles H

AU - Reiter, Jeremy F

AU - Griffiths, Gillian M

N1 - Funding information: This work was supported by a Wellcome Trust Principal Research Fellowship to G.M.G. (075880), a Wellcome Trust Strategic Award for core facilities at the CIMR (100140), NIH (R01AR05439 and R01GM095941), the Burroughs Wellcome Fund, the David and Lucile F. Packard Foundation, and the Sandler Family Supporting Foundation to J.R.

PY - 2013/12/6

Y1 - 2013/12/6

N2 - The centrosome is essential for cytotoxic T lymphocyte (CTL) function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunological synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog (Hh) signaling. Lymphocytes do not form primary cilia, but we found and describe here that Hh signaling played an important role in CTL killing. T cell receptor activation, which "prearms" CTLs with cytotoxic granules, also initiated Hh signaling. Hh pathway activation occurred intracellularly and triggered Rac1 synthesis. These events "prearmed" CTLs for action by promoting the actin remodeling required for centrosome polarization and granule release. Thus, Hh signaling plays a role in CTL function, and the immunological synapse may represent a modified cilium.

AB - The centrosome is essential for cytotoxic T lymphocyte (CTL) function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunological synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog (Hh) signaling. Lymphocytes do not form primary cilia, but we found and describe here that Hh signaling played an important role in CTL killing. T cell receptor activation, which "prearms" CTLs with cytotoxic granules, also initiated Hh signaling. Hh pathway activation occurred intracellularly and triggered Rac1 synthesis. These events "prearmed" CTLs for action by promoting the actin remodeling required for centrosome polarization and granule release. Thus, Hh signaling plays a role in CTL function, and the immunological synapse may represent a modified cilium.

KW - Animals

KW - CD8-Positive T-Lymphocytes/immunology

KW - Cell Polarity

KW - Cells, Cultured

KW - Centrosome/metabolism

KW - Cytotoxicity, Immunologic

KW - Hedgehog Proteins/metabolism

KW - Immunological Synapses

KW - Kruppel-Like Transcription Factors/genetics

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Models, Immunological

KW - Neuropeptides/genetics

KW - Patched Receptors

KW - Receptors, Antigen, T-Cell/immunology

KW - Receptors, Cell Surface/metabolism

KW - Receptors, G-Protein-Coupled/metabolism

KW - Signal Transduction

KW - Smoothened Receptor

KW - T-Lymphocytes, Cytotoxic/immunology

KW - Zinc Finger Protein GLI1

KW - rac1 GTP-Binding Protein/genetics

U2 - 10.1126/science.1244689

DO - 10.1126/science.1244689

M3 - Article

C2 - 24311692

SN - 0036-8075

VL - 342

SP - 1247

EP - 1250

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6163

ER -

Hedgehog signaling controls T cell killing at the immunological synapse

Abstract

Bibliographical note

Keywords

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