title: DUSP4 deficiency enhances CD25 expression and CD4+ T-cell proliferation without impeding T-cell development.
abstract: The differentiation and activation of T cells are critically modulated by MAP kinases, which are in turn feed-back regulated by dual-specificity phosphatases (DUSPs) to determine the duration and magnitude of MAP kinase activation. DUSP4 (also known as MKP2) is a MAP kinase-induced DUSP member that is dynamically expressed during thymocyte differentiation. We generated DUSP4-deficient mice to study the function of DUSP4 in T-cell development and activation. Our results show that thymocyte differentiation and activation-induced MAP kinase phosphorylation were comparable between DUSP4-deficient and WT mice. Interestingly, activated DUSP4(-/-)  CD4(+)  T cells were hyperproliferative while DUSP4(-/-)  CD8(+)  T cells proliferated normally. Further mechanistic studies suggested that the hyperproliferation of DUSP4(-/-)  CD4(+)  T cells resulted from enhanced CD25 expression and IL-2 signaling through increased STAT5 phosphorylation. Immunization of DUSP4(-/-)  mice recapitulated the T-cell hyperproliferation phenotype in antigen recall responses, while the profile of Th1/Th2-polarized antibody production was not altered. Overall, these results suggest that other DUSPs may compensate for DUSP4 deficiency in T-cell development, MAP kinase regulation, and Th1/Th2-mediated antibody responses. More importantly, our data indicate that DUSP4 suppresses CD4(+)  T-cell proliferation through novel regulations in STAT5 phosphorylation and IL-2 signaling.
authors.affiliation: Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli County, Taiwan. cyhuang@nhri.org.tw
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Huang
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.forename: Wan-Yi
authors.initials: WY
authors.lastname: Hsiao
authors.forename: Fang-Hsuean
authors.initials: FH
authors.lastname: Liao
authors.forename: Pau-Yi
authors.initials: PY
authors.lastname: Huang
authors.forename: Tse-Hua
authors.initials: TH
authors.lastname: Tan
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D002478:Cells, Cultured; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D050799:STAT5 Transcription Factor; C522186:Dusp4 protein, mouse; D017027:Protein Tyrosine Phosphatases
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