title: Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii.
abstract: Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor-alpha, Toll-like receptor, and G protein-coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-gamma production. Accordingly, Tpl2(-/-) mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-gamma production. Furthermore, reconstitution of Rag2(-/-) mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-gamma defect seen in the Tpl2-deficient mice, confirming a T cell-intrinsic defect. CD4(+) T cells isolated from Tpl2(-/-) mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses.
authors.affiliation: Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. watfordw@mail.nih.gov
authors.forename: Wendy T
authors.initials: WT
authors.lastname: Watford
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hissong
authors.forename: Lydia R
authors.initials: LR
authors.lastname: Durant
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Yamane
authors.forename: Linda M
authors.initials: LM
authors.lastname: Muul
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Tato
authors.forename: Haydeé L
authors.initials: HL
authors.lastname: Ramos
authors.forename: Alan E
authors.initials: AE
authors.lastname: Berger
authors.forename: Lisa
authors.initials: L
authors.lastname: Mielke
authors.forename: Marko
authors.initials: M
authors.lastname: Pesu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Solomon
authors.forename: David M
authors.initials: DM
authors.lastname: Frucht
authors.forename: William E
authors.initials: WE
authors.lastname: Paul
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
authors.forename: Dragana
authors.initials: D
authors.lastname: Jankovic
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
mesh_terms: D000818:Animals; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D050797:STAT4 Transcription Factor / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C499308:Rag2 protein, mouse; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; C489843:Map3k8 protein, mouse