Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5 (original) (raw)

Nature volume 430, pages 793–797 (2004) Cite this article

Abstract

Mitogen-activated protein (MAP) kinases are essential regulators in immune responses1, and their activities are modulated by kinases and phosphatases. MAP kinase phosphatase (MKP) is a family of dual-specificity phosphatases whose function is evolutionarily conserved2,3. A number of mammalian MKPs have been identified so far2,3, but their specific physiological functions in negative regulation of MAP kinases have not been genetically defined. Here we examine innate and adaptive immune responses in the absence of MKP5. JNK activity was selectively increased in Mkp5 (also known as Dusp10)-deficient mouse cells. _Mkp5_-deficient cells produced greatly enhanced levels of pro-inflammatory cytokines during innate immune responses and exhibited greater T-cell activation than their wild-type counterparts. However, _Mkp5_-deficient T cells proliferated poorly upon activation, which resulted in increased resistance to experimental autoimmune encephalomyelitis. By contrast, _Mkp5_-deficient CD4+ and CD8+ effector T cells produced significantly increased levels of cytokines compared with wild-type cells, which led to much more robust and rapidly fatal immune responses to secondary infection with lymphocytic choriomeningitis virus. Therefore, MKP5 has a principal function in both innate and adaptive immune responses, and represents a novel target for therapeutic intervention of immune diseases.

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Acknowledgements

We thank L. Evangelisti, C. Hughes and J. Stein for technical assistance; P. Leder for providing TC-1 ES cells; R. Alanis for his help with the Listeria infection experiment; A. Farr for his guidance in animal studies; and the entire Dong laboratory for their support and help. R.J.D. and R.A.F. are HHMI investigators, and C.D. is an Arthritis Investigator of the Arthritis Foundation.

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Author notes

  1. Yongliang Zhang & Chen Dong
    Present address: Department of Immunology, University of Texas, MD Anderson Cancer Center, Houston, Texas, 77030, USA
  2. Richard A. Flavell and Chen Dong: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Immunology, University of Washington, Seattle, Washington, 98195-7650, USA
    Yongliang Zhang, Joseph N. Blattman, Julie Duong, Thang Nguyen, Ying Wang, Philip D. Greenberg & Chen Dong
  2. Howard Hughes Medical Institute, University of Massachusetts, Worcester, Massachusetts, 01605, USA
    Norman J. Kennedy & Roger J. Davis
  3. Section of Immunobiology, Howard Hughes Medical Institute, Yale University, New Haven, Connecticut, 06520, USA
    Richard A. Flavell

Authors

  1. Yongliang Zhang
  2. Joseph N. Blattman
  3. Norman J. Kennedy
  4. Julie Duong
  5. Thang Nguyen
  6. Ying Wang
  7. Roger J. Davis
  8. Philip D. Greenberg
  9. Richard A. Flavell
  10. Chen Dong

Corresponding authors

Correspondence toRichard A. Flavell or Chen Dong.

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The authors declare that they have no competing financial interests.

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Zhang, Y., Blattman, J., Kennedy, N. et al. Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5.Nature 430, 793–797 (2004). https://doi.org/10.1038/nature02764

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