1. Department of Immunology, University of Washington, Seattle, Washington 98195-7650, USA
2. Howard Hughes Medical Institute, University of Massachusetts, Worcester, Massachusetts 01605, USA
3. Section of Immunobiology, Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06520, USA
4. These authors contributed equally to this work
5. Present address: Department of Immunology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA

Correspondence to: Richard A. Flavell^3,4Chen Dong^1,4,5 Email: richard.flavell@yale.edu
Email: cdong@mdanderson.org

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 conserved^{2, 3}. A number of mammalian MKPs have been identified so far^{2, 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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