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-␥) 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 mitogenactivated 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.

AttenuatedToxoplasma gondiiStimulates Immunity to Pancreatic Cancer by Manipulation of Myeloid Cell Populations

“…CPS -invasion of tumor-associated myeloid cells activated these cell types in the TME, and could represent the predominant source of co-stimulation and IL12 production within the pancreatic tumor microenvironment. Our results in pancreatic tumor-bearing mice parallels recent results observed in naïve mice and ovarian cancer-bearing mice highlighting the critical importance of myeloid cell invasion by Toxoplasma in stimulating up-regulation of co-stimulatory molecules (20, 23, 50), and activation of T-cell immunity (20). …”

Comparative studies of macrophage-biased responses in mice to infection with Toxoplasma gondii ToxoDB #9 strains of different virulence isolated from China

“…Additionally, neither Wh3-Mφ nor Wh6-Mφ could up-regulate CD80 or CD86 expression, which differs from the reports stating that both molecules, or only CD80/CD86 expression, were up-regulated in Toxoplasma -infected cells [19,23]. This discrepancy might be the result of different cell types and parasite genotypes used in the studies.…”

CD200 modulates macrophage cytokine secretion and phagocytosis in response to poly(lactic-co-glycolic acid) microparticles and films

“…To isolate and differentiate BMDM, cells were treated with ACK lysis buffer (Invitrogen), centrifuged, and resuspended in D-10 media, which consists of Dulbecco’s modified Eagle medium (DMEM) supplemented with 2mM L-glutamine, 100 units /mL penicillin-streptomycin, 10% heat-inactivated FBS, and 10% media collected from the supernatant of CMG 12–14 cells ectopically expressing recombinant mouse macrophage colony stimulating factor (M-CSF). 30 BMDM were cultured at 37°C in a humidified incubator with 5% CO 2 . BMDM were dissociated using cell dissociation buffer (Invitrogen) on day 7, and seeded on the tissue culture plates (Olympus Plastics) in fresh D-10 culture media.…”