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Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5

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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Figure 1: Targeted disruption of the mouse Mkp5 gene results in increased JNK activity.
Figure 2: Increased innate immune responses in the absence of MKP5.
Figure 3: Defective CD4 T-cell responses by Mkp5-/- mice.
Figure 4: Enhanced T-cell responses in Mkp5-/- mice after secondary LCMV infection.

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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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Correspondence to Richard A. Flavell or Chen Dong.

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Supplementary information

Supplementary Figures

Here we showed that Mkp5 gene expression was regulated during immune activation. Overexpression of Mkp5 inhibited AP1 and AP1 mediated transcriptional activities. MKP5 is a negative regulator of cytokine production in the innate immune response and regulates T cell proliferation (PPT 370 kb)

Supplementary Figure Legends (DOC 20 kb)

Supplementary Methods

The methods described here include transient transfection, lucifierase assay, Toll-like receptor activation and Listeria infection, which are used to obtain the supplementary data shown in the figures (DOC 21 kb)

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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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