title: Ablation of tumor progression locus 2 promotes a type 2 Th cell response in Ovalbumin-immunized mice.
abstract: The protein kinase encoded by the Tpl2 proto-oncogene regulates ERK activation and cytokine gene expression in macrophages in response to LPS and TNF-alpha. In this study we show that OVA-immunized Tpl2(-/-) mice express high levels of IgE and develop more severe bronchoalveolar eosinophilic inflammation than Tpl2(+/+) controls, when challenged with OVA intranasally. Bronchoalveolar exudates and supernatants of OVA-stimulated splenocytes from immunized Tpl2(-/-) mice express elevated levels of IL-4 and IL-5, suggesting that Tpl2 ablation promotes the Th2 polarization of the T cell response. Anti-CD3 stimulation of CD4(+) T cells of wild-type and Tpl2 knockout mice revealed that Tpl2 ablation gives rise to a cell autonomous T cell defect that is primarily responsible for the Th2 polarization of the T cell response to Ag. This observation was further supported by experiments addressing the expression of Th1 and Th2 cytokines in OVA-stimulated mixed cultures of CD4(+) T cells from Tpl2(+/+)/OT2 or Tpl2(-/-)/OT2 mice and dendritic cells from Tpl2(+/+) or Tpl2(-/-) mice. Further studies revealed that Th1 cells express significantly higher levels of Tpl2 than Th2 cells. As a result, Tpl2(-/-) Th1 cells exhibit a stronger defect in ERK activation by anti-CD3 than Th2 cells and express low levels of T-bet. Given that the development of Th1 and Th2 cells depends on positive feedback signals from the T cells, themselves, the functional defect of the Tpl2(-/-) Th1 cells provides a mechanistic explanation for the T cell autonomous Th2 polarization in Tpl2(-/-) mice.
authors: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Wendy T
authors: WT
authors: Watford
authors: Chun-Chi
authors: CC
authors: Wang
authors: Christos
authors: C
authors: Tsatsanis
authors: Lisa A
authors: LA
authors: Mielke
authors: Aristides G
authors: AG
authors: Eliopoulos
authors: Constantine
authors: C
authors: Daskalakis
authors: Nicolas
authors: N
authors: Charles
authors: Sandra
authors: S
authors: Odom
authors: Juan
authors: J
authors: Rivera
authors: John
authors: J
authors: O'Shea
authors: Philip N
authors: PN
authors: Tsichlis
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D015153:Blotting, Western; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology*; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D016207:Cytokines; D011518:Proto-Oncogene Proteins; D007073:Immunoglobulin E; D010047:Ovalbumin; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse