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

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

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