title: Toxoplasma gondii induces B7-2 expression through activation of JNK signal transduction.
abstract: Toxoplasma gondii is a globally distributed parasite pathogen that infects virtually all warm-blooded animals. A hallmark of immunity to acute infection is the production of gamma interferon (IFN-γ) and interleukin-12 (IL-12), followed by a protective T cell response that is critical for parasite control. Naïve T cell activation requires both T-cell receptor (TCR) stimulation and the engagement of costimulatory receptors. Because of their important function in activating T cells, the expression of costimulatory ligands is believed to be under tight control. The molecular mechanisms governing their induction during microbial stimulation, however, are not well understood. We found that all three strains of T. gondii (types I, II, and III) upregulated the expression of B7-2, but not B7-1, on the surface of mouse bone marrow-derived macrophages. Additionally, intraperitoneal infection of mice with green fluorescent protein (GFP)-expressing parasites resulted in enhanced B7-2 levels specifically on infected, GFP(+) CD11b(+) cells. B7-2 induction occurred at the transcript level, required active parasite invasion, and was not dependent on MyD88 or TRIF. Functional assays demonstrated that T. gondii-infected macrophages stimulated naïve T cell proliferation in a B7-2-dependent manner. Genome-wide transcriptional analysis comparing infected and uninfected macrophages revealed the activation of mitogen-activated protein kinase (MAPK) signaling in infected cells. Using specific inhibitors against MAPKs, we determined that parasite-induced B7-2 is dependent on Jun N-terminal protein kinase (JNK) but not extracellular signal-regulated kinase (ERK) or p38 signaling. We also observed that T. gondii-induced B7-2 expression on human peripheral blood monocytes is dependent on JNK signaling, indicating that a common mechanism of B7-2 regulation by T. gondii may exist in both humans and mice.
authors.affiliation: Department of Molecular Biology and Biochemistry, 3238 McGaugh Hall, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Morgado
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Ong
authors.forename: John C
authors.initials: JC
authors.lastname: Boothroyd
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Lodoen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000469:parasitology; D020869:Gene Expression Profiling; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D009000:Monocytes; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D040081:Protein Array Analysis; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000469:parasitology / Q000502:physiology; D014122:Toxoplasma / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051940:B7-2 Antigen; D039481:CD11b Antigen; D048670:MAP Kinase Kinase 4; D053594:Myeloid Differentiation Factor 88; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C470409:TICAM1 protein, human