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J. Biol. Chem., Vol. 283, Issue 25, 17362-17369, June 20, 2008

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T-cell Development and Function Are Modulated by Dual Specificity Phosphatase DUSP5^*

Panu E. Kovanen¹², Jérôme Bernard¹, Amin Al-Shami, Chengyu Liu, Julie Bollenbacher-Reilley, Lynn Young^¶, Cynthia Pise-Masison^||, Rosanne Spolski, and Warren J. Leonard³

From the Laboratory of Molecular Immunology and Transgenic Mouse Core Facility, NHLBI, the ^¶Bioinformatics and Molecular Analysis Section, Computational Bioscience and Engineering Laboratory, CIT, and the ^||Laboratory of Cellular Oncology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892

Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte proliferation and peripheral tolerance. IL-2 activates mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, and signal transducer and activator of transcription (STAT) pathways and modulates expression of target genes. Systematic analysis of IL-2 target genes has revealed regulation of potential feedback inhibitors of IL-2 signaling, including several suppressor of cytokine signaling (SOCS) family members as well as MAPK pathway-regulating dual specificity phosphatases (DUSPs). Here we have evaluated the in vivo actions of DUSP5, an extracellular signal-regulated kinase 1/2 (ERK1/2)-specific phosphatase, by generating transgenic mice overexpressing DUSP5 within the lymphoid compartment. We show that transgenic DUSP5 expression results in a block in thymocyte development at the double positive stage. We also demonstrate that DUSP5-expressing mature T cells exhibit decreased IL-2-dependent proliferation and defective IL-2-mediated induction of genes. Finally, DUSP5 transgenic mice develop autoimmune symptoms, suggesting a role for the MAPK pathway in the regulation of tolerance. Thus, proper regulation of DUSP5 activity is critical for normal immune system development, IL-2 actions, and tolerance.

Received for publication, December 4, 2007 , and in revised form, April 14, 2008.

^* This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Programs of NHLBI, NCI, and CIT. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1–S3.

¹ Both authors contributed equally to this work.

² Funded in part by grants from the University of Helsinki, Academy of Finland, Sigrid Juselius Foundation, and HUSLAB. Current address: Haartman Inst., Dept. of Pathology, University of Helsinki, Finland.

³ To whom correspondence should be addressed: Bldg. 10, Rm. 7B05, Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, MD 20892-1674. Tel.: 301-496-0098; Fax: 301-402-0971; E-mail: wjl{at}helix.nih.gov.

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