title: Jun NH2-terminal kinase is constitutively activated in T cells transformed by the intracellular parasite Theileria parva.
abstract: When T cells become infected by the parasite Theileria parva, they acquire a transformed phenotype and no longer require antigen-specific stimulation or exogenous growth factors. This is accompanied by constitutive interleukin 2 (IL-2) and IL-2 receptor expression. Transformation can be reversed entirely by elimination of the parasites using the specific drug BW720c. Extracellular signal-regulated kinase and jun NH2-terminal kinase (JNK) are members of the mitogen-activated protein kinase family, which play a central role in the regulation of cellular differentiation and proliferation and also participate in the regulation of IL-2 and IL-2 receptor gene expression. T. parva was found to induce an unorthodox pattern of mitogen-activated protein kinase expression in infected T cells. JNK-1 and JNK-2 are constitutively active in a parasite-dependent manner, but have altered properties. In contrast, extracellular signal-regulated kinase-2 is not activated even though its activation pathway is functionally intact. Different components of the T cell receptor (TCR)-dependent signal transduction pathways also were examined. The TCRzeta or CD3epsilon chains were found not to be phosphorylated and T. parva-transformed T cells were resistant to inhibitors that block the early steps of T cell activation. Compounds that inhibit the progression of T cells to proliferation, however, were inhibitory. Our data provide the first example, to our knowledge, for parasite-mediated JNK activation, and our findings strongly suggest that T. parva not only lifts the requirement for antigenic stimulation but also entirely bypasses early TCR-dependent signal transduction pathways to induce continuous proliferation.
authors.affiliation: Institute of Animal Pathology, University of Berne, Postfach 2735, CH-3001 Berne, Switzerland.
authors.forename: Y
authors.initials: Y
authors.lastname: Galley
authors.forename: G
authors.initials: G
authors.lastname: Hagens
authors.forename: I
authors.initials: I
authors.lastname: Glaser
authors.forename: W
authors.initials: W
authors.lastname: Davis
authors.forename: M
authors.initials: M
authors.lastname: Eichhorn
authors.forename: D
authors.initials: D
authors.lastname: Dobbelaere
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008301:Maleimides / Q000494:pharmacology; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D009285:Naphthoquinones / Q000494:pharmacology*; D011090:Polyenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000302:isolation & purification / Q000502:physiology; D020123:Sirolimus; D013601:T-Lymphocytes / Q000276:immunology / Q000469:parasitology* / Q000502:physiology*; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D016797:Theileria parva / Q000502:physiology*
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007211:Indoles; D008301:Maleimides; D009285:Naphthoquinones; D011090:Polyenes; D017260:Receptor-CD3 Complex, Antigen, T-Cell; C046326:buparvaquone; D015124:8-Bromo Cyclic Adenosine Monophosphate; C058028:immunomycin; D011494:Protein Kinases; D048056:Mitogen-Activated Protein Kinase 9; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C088060:bisindolylmaleimide; D020123:Sirolimus; D016559:Tacrolimus