Loss of functionally redundant p38 isoforms in T cells enhances regulatory T cell induction

Morisada Hayakawa; Hiroko Hayakawa; Tsvetana Petrova; Patcharee Ritprajak; Ruhcha V. Sutavani; Guillermina Yanek Jimenez-Andrade; Yasuyo Sano; Min-Kyung Choo; John Seavitt; Ram K. C. Venigalla; Kinya Otsu; Katia Georgopoulos; J. Simon C. Arthur; Jin Mo Park

doi:10.1074/jbc.M116.764548

Loss of functionally redundant p38 isoforms in T cells enhances regulatory T cell induction

Morisada Hayakawa, Hiroko Hayakawa, Tsvetana Petrova, Patcharee Ritprajak, Ruhcha V. Sutavani, Guillermina Yanek Jimenez-Andrade, Yasuyo Sano, Min-Kyung Choo, John Seavitt, Ram K. C. Venigalla, Kinya Otsu, Katia Georgopoulos, J. Simon C. Arthur, Jin Mo Park (Lead / Corresponding author)

Cell Signalling and Immunology

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Abstract

The evolutionarily conserved protein kinase p38 mediates innate resistance to environmental stress and microbial infection. Four p38 isoforms exist in mammals and may have been co-opted for new roles in adaptive immunity. Murine T cells deficient in p38α, the ubiquitously expressed p38 isoform, showed no readily apparent cell-autonomous defects while expressing elevated amounts of another isoform, p38β. Mice with T cells simultaneously lacking p38α and p38β displayed lymphoid atrophy and elevated Foxp3+ regulatory T cell frequencies. Double deficiency of p38α and p38β in naïve CD4+ T cells resulted in an attenuation of MAPK-activated protein kinase (MK)-dependent mTOR signaling after T cell receptor engagement, and enhanced their differentiation into regulatory T cells under appropriate inducing conditions. Pharmacological inhibition of the p38-MK-mTOR signaling module produced similar effects, revealing potential for therapeutic applications.

Original language	English
Pages (from-to)	1762-1772
Number of pages	11
Journal	Journal of Biological Chemistry
Volume	292
Issue number	5
Early online date	23 Dec 2016
DOIs	https://doi.org/10.1074/jbc.M116.764548
Publication status	Published - 3 Feb 2017

Keywords

P-38
T-Cell
Signal transduction
Immunology
Mouse

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10.1074/jbc.M116.764548Licence: CC BY

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© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license.
Final published version, 3.59 MBLicence: CC BY

Arthur, Simon
- Cell Signalling and Immunology - Professor of Immune Signalling
Person: Academic

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Hayakawa, M., Hayakawa, H., Petrova, T., Ritprajak, P., Sutavani, R. V., Jimenez-Andrade, G. Y., Sano, Y., Choo, M.-K., Seavitt, J., Venigalla, R. K. C., Otsu, K., Georgopoulos, K., Arthur, J. S. C., & Park, J. M. (2017). Loss of functionally redundant p38 isoforms in T cells enhances regulatory T cell induction. Journal of Biological Chemistry, 292(5), 1762-1772. https://doi.org/10.1074/jbc.M116.764548

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title = "Loss of functionally redundant p38 isoforms in T cells enhances regulatory T cell induction",

abstract = "The evolutionarily conserved protein kinase p38 mediates innate resistance to environmental stress and microbial infection. Four p38 isoforms exist in mammals and may have been co-opted for new roles in adaptive immunity. Murine T cells deficient in p38α, the ubiquitously expressed p38 isoform, showed no readily apparent cell-autonomous defects while expressing elevated amounts of another isoform, p38β. Mice with T cells simultaneously lacking p38α and p38β displayed lymphoid atrophy and elevated Foxp3+ regulatory T cell frequencies. Double deficiency of p38α and p38β in na{\"i}ve CD4+ T cells resulted in an attenuation of MAPK-activated protein kinase (MK)-dependent mTOR signaling after T cell receptor engagement, and enhanced their differentiation into regulatory T cells under appropriate inducing conditions. Pharmacological inhibition of the p38-MK-mTOR signaling module produced similar effects, revealing potential for therapeutic applications.",

keywords = "P-38, T-Cell, Signal transduction, Immunology, Mouse",

author = "Morisada Hayakawa and Hiroko Hayakawa and Tsvetana Petrova and Patcharee Ritprajak and Sutavani, \{Ruhcha V.\} and Jimenez-Andrade, \{Guillermina Yanek\} and Yasuyo Sano and Min-Kyung Choo and John Seavitt and Venigalla, \{Ram K. C.\} and Kinya Otsu and Katia Georgopoulos and Arthur, \{J. Simon C.\} and Park, \{Jin Mo\}",

note = "Wellcome (90\%): 105309/Z/14/A MRC (10\%): MR/L008785/1",

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doi = "10.1074/jbc.M116.764548",

language = "English",

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Hayakawa, M, Hayakawa, H, Petrova, T, Ritprajak, P, Sutavani, RV, Jimenez-Andrade, GY, Sano, Y, Choo, M-K, Seavitt, J, Venigalla, RKC, Otsu, K, Georgopoulos, K, Arthur, JSC & Park, JM 2017, 'Loss of functionally redundant p38 isoforms in T cells enhances regulatory T cell induction', Journal of Biological Chemistry, vol. 292, no. 5, pp. 1762-1772. https://doi.org/10.1074/jbc.M116.764548

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T1 - Loss of functionally redundant p38 isoforms in T cells enhances regulatory T cell induction

AU - Hayakawa, Morisada

AU - Hayakawa, Hiroko

AU - Petrova, Tsvetana

AU - Ritprajak, Patcharee

AU - Sutavani, Ruhcha V.

AU - Jimenez-Andrade, Guillermina Yanek

AU - Sano, Yasuyo

AU - Choo, Min-Kyung

AU - Seavitt, John

AU - Venigalla, Ram K. C.

AU - Otsu, Kinya

AU - Georgopoulos, Katia

AU - Arthur, J. Simon C.

AU - Park, Jin Mo

N1 - Wellcome (90%): 105309/Z/14/A MRC (10%): MR/L008785/1

PY - 2017/2/3

Y1 - 2017/2/3

N2 - The evolutionarily conserved protein kinase p38 mediates innate resistance to environmental stress and microbial infection. Four p38 isoforms exist in mammals and may have been co-opted for new roles in adaptive immunity. Murine T cells deficient in p38α, the ubiquitously expressed p38 isoform, showed no readily apparent cell-autonomous defects while expressing elevated amounts of another isoform, p38β. Mice with T cells simultaneously lacking p38α and p38β displayed lymphoid atrophy and elevated Foxp3+ regulatory T cell frequencies. Double deficiency of p38α and p38β in naïve CD4+ T cells resulted in an attenuation of MAPK-activated protein kinase (MK)-dependent mTOR signaling after T cell receptor engagement, and enhanced their differentiation into regulatory T cells under appropriate inducing conditions. Pharmacological inhibition of the p38-MK-mTOR signaling module produced similar effects, revealing potential for therapeutic applications.

AB - The evolutionarily conserved protein kinase p38 mediates innate resistance to environmental stress and microbial infection. Four p38 isoforms exist in mammals and may have been co-opted for new roles in adaptive immunity. Murine T cells deficient in p38α, the ubiquitously expressed p38 isoform, showed no readily apparent cell-autonomous defects while expressing elevated amounts of another isoform, p38β. Mice with T cells simultaneously lacking p38α and p38β displayed lymphoid atrophy and elevated Foxp3+ regulatory T cell frequencies. Double deficiency of p38α and p38β in naïve CD4+ T cells resulted in an attenuation of MAPK-activated protein kinase (MK)-dependent mTOR signaling after T cell receptor engagement, and enhanced their differentiation into regulatory T cells under appropriate inducing conditions. Pharmacological inhibition of the p38-MK-mTOR signaling module produced similar effects, revealing potential for therapeutic applications.

KW - P-38

KW - T-Cell

KW - Signal transduction

KW - Immunology

KW - Mouse

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DO - 10.1074/jbc.M116.764548

M3 - Article

C2 - 28011639

SN - 0021-9258

VL - 292

SP - 1762

EP - 1772

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 5

ER -

Loss of functionally redundant p38 isoforms in T cells enhances regulatory T cell induction

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Arthur, Simon

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