title: Type II Toxoplasma gondii induction of CD40 on infected macrophages enhances interleukin-12 responses.
abstract: Toxoplasma gondii is an obligate intracellular parasite that can cause severe neurological disease in infected humans. CD40 is a receptor on macrophages that plays a critical role in controlling T. gondii infection. We examined the regulation of CD40 on the surface of T. gondii-infected bone marrow-derived macrophages (BMdMs). T. gondii induced CD40 expression both at the transcript level and on the cell surface, and interestingly, the effect was parasite strain specific: CD40 levels were dramatically increased in type II T. gondii-infected BMdMs compared to type I- or type III-infected cells. Type II induction of CD40 was specific to cells harboring intracellular parasites and detectable as early as 6 h postinfection (hpi) at the transcript level. CD40 protein expression peaked at 18 hpi. Using forward genetics with progeny from a type II × type III cross, we found that CD40 induction mapped to a region of chromosome X that included the gene encoding the dense granule protein 15 (GRA15). Using type I parasites stably expressing the type II allele of GRA15 (GRA15II), we found that type I GRA15II parasites induced the expression of CD40 on infected cells in an NF-κB-dependent manner. In addition, stable expression of hemagglutinin-tagged GRA15II in THP-1 cells resulted in CD40 upregulation in the absence of infection. Since CD40 signaling contributes to interleukin-12 (IL-12) production, we examined IL-12 from infected macrophages and found that CD40L engagement of CD40 amplified the IL-12 response in type II-infected cells. These data indicate that GRA15II induction of CD40 promotes parasite immunity through the production of IL-12.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA Institute for Immunology, University of California, Irvine, Irvine, California, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Morgado
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA Institute for Immunology, University of California, Irvine, Irvine, California, USA.
authors.forename: Dattanand M
authors.initials: DM
authors.lastname: Sudarshana
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA Institute for Immunology, University of California, Irvine, Irvine, California, USA.
authors.forename: Lanny
authors.initials: L
authors.lastname: Gov
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA Institute for Immunology, University of California, Irvine, Irvine, California, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Harker
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA Institute for Immunology, University of California, Irvine, Irvine, California, USA Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California, USA.
authors.forename: Tonika
authors.initials: T
authors.lastname: Lam
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA Institute for Immunology, University of California, Irvine, Irvine, California, USA Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, California, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Casali
authors.affiliation: Department of Biological Sciences, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jon P
authors.initials: JP
authors.lastname: Boyle
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, USA Institute for Immunology, University of California, Irvine, Irvine, California, USA mlodoen@uci.edu.
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Lodoen
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis* / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology*; D015800:Protozoan Proteins / Q000276:immunology*; D014122:Toxoplasma / Q000276:immunology*
chemical_list: D000953:Antigens, Protozoan; D019013:CD40 Antigens; D015800:Protozoan Proteins; D018664:Interleukin-12