Protein kinase C-θ mediates negative feedback on regulatory T cell function

Alexandra Zanin-Zhorov; Yi Ding; Sudha Kumari; Mukundan Attur; Keli L. Hippen; Maryanne Brown; Bruce R. Blazar; Steven B. Abramson; Juan J. Lafaille; Michael L. Dustin

doi:10.1126/science.1186068

Protein kinase C-θ mediates negative feedback on regulatory T cell function

Alexandra Zanin-Zhorov
, Yi Ding
, Sudha Kumari
, Mukundan Attur
, Keli L. Hippen
, Maryanne Brown
, Bruce R. Blazar
, Steven B. Abramson
, Juan J. Lafaille
, Michael L. Dustin

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

259 Scopus citations

Abstract

T cell receptor (TCR)-dependent regulatory T cell (T_reg) activity controls effector T cell (T_eff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-a (TNF-a Protein kinase C-θ (PKC-θ) recruitment to the immunological synapse is required for full T_eff activation. In contrast, PKC-6 was sequestered away from the T_reg immunological synapse. Furthermore, PKC-θ blockade enhanced T_reg function, demonstrating PKC-6 inhibits T _reg-mediated suppression. Inhibition of PKC-6 protected T _reg from inactivation by TNF-a, restored activity of defective T _reg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. T_reg freed of PKC-6-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.

Original language	English (US)
Pages (from-to)	372-376
Number of pages	5
Journal	Science
Volume	328
Issue number	5976
DOIs	https://doi.org/10.1126/science.1186068
State	Published - Apr 16 2010

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title = "Protein kinase C-θ mediates negative feedback on regulatory T cell function",

abstract = "T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-a (TNF-a Protein kinase C-θ (PKC-θ) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-6 was sequestered away from the Treg immunological synapse. Furthermore, PKC-θ blockade enhanced Treg function, demonstrating PKC-6 inhibits T reg-mediated suppression. Inhibition of PKC-6 protected T reg from inactivation by TNF-a, restored activity of defective T reg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-6-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.",

author = "Alexandra Zanin-Zhorov and Yi Ding and Sudha Kumari and Mukundan Attur and Hippen, \{Keli L.\} and Maryanne Brown and Blazar, \{Bruce R.\} and Abramson, \{Steven B.\} and Lafaille, \{Juan J.\} and Dustin, \{Michael L.\}",

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doi = "10.1126/science.1186068",

language = "English (US)",

volume = "328",

pages = "372--376",

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TY - JOUR

T1 - Protein kinase C-θ mediates negative feedback on regulatory T cell function

AU - Zanin-Zhorov, Alexandra

AU - Ding, Yi

AU - Kumari, Sudha

AU - Attur, Mukundan

AU - Hippen, Keli L.

AU - Brown, Maryanne

AU - Blazar, Bruce R.

AU - Abramson, Steven B.

AU - Lafaille, Juan J.

AU - Dustin, Michael L.

PY - 2010/4/16

Y1 - 2010/4/16

N2 - T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-a (TNF-a Protein kinase C-θ (PKC-θ) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-6 was sequestered away from the Treg immunological synapse. Furthermore, PKC-θ blockade enhanced Treg function, demonstrating PKC-6 inhibits T reg-mediated suppression. Inhibition of PKC-6 protected T reg from inactivation by TNF-a, restored activity of defective T reg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-6-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.

AB - T cell receptor (TCR)-dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-a (TNF-a Protein kinase C-θ (PKC-θ) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-6 was sequestered away from the Treg immunological synapse. Furthermore, PKC-θ blockade enhanced Treg function, demonstrating PKC-6 inhibits T reg-mediated suppression. Inhibition of PKC-6 protected T reg from inactivation by TNF-a, restored activity of defective T reg from rheumatoid arthritis patients, and enhanced protection of mice from inflammatory colitis. Treg freed of PKC-6-mediated inhibition can function in the presence of inflammatory cytokines and thus have therapeutic potential in control of inflammatory diseases.

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UR - https://www.scopus.com/pages/publications/77951158406#tab=citedBy

U2 - 10.1126/science.1186068

DO - 10.1126/science.1186068

M3 - Article

C2 - 20339032

AN - SCOPUS:77951158406

SN - 0036-8075

VL - 328

SP - 372

EP - 376

JO - Science

JF - Science

IS - 5976

ER -

Protein kinase C-θ mediates negative feedback on regulatory T cell function

Abstract

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