ABSTRACT
Plasmacytoid dendritic cells (pDCs) play a key role in the innate immune response to viral infection, due largely to their ability to produce large quantities of type I IFNs. These cells are also notable for their ability to differentiate into conventional dendritic cells after appropriate stimulation. Here, we show that a splenic population of murine CD11c(+) cells expressing pDC markers Gr-1, B220, and PDCA-1 is preferentially parasitized after infection with the virulent RH strain of Toxoplasma gondii. Although these markers are closely associated with pDCs, the population we identified was unusual because the cells express CD11b and higher than expected levels of CD11c. By adoptive transfer of CD45.1-positive cells into CD45.2 congenic mice, we show that CD11c(+)Gr-1(+) cells migrate from the peritoneal cavity to the spleen. During infection, these cells accumulate in the marginal zone region. Recruitment of infected CD11c(+)Gr-1(+) cells to the spleen is partially dependent upon signaling through chemokine receptor CCR2. Intracellular cytokine staining demonstrates that infected, but not noninfected, splenic CD11c(+)Gr-1(+) dendritic cells are suppressed in their ability to respond to ex vivo TLR stimulation. We hypothesize that Toxoplasma exploits pDCs as Trojan horses, targeting them for early infection, suppressing their cytokine effector function, and using them for dissemination within the host.
Subject(s)
Antigens, Surface/biosynthesis , Dendritic Cells/immunology , Dendritic Cells/parasitology , Toxoplasmosis/immunology , Toxoplasmosis/parasitology , Animals , Antigens, Surface/genetics , Biomarkers/metabolism , CD11c Antigen/biosynthesis , CD11c Antigen/genetics , Cells, Cultured , Dendritic Cells/metabolism , Female , Immunophenotyping , Interleukin-12/antagonists & inhibitors , Interleukin-12/biosynthesis , Mice , Mice, Congenic , Mice, Inbred C57BL , Mice, Knockout , Peritoneum/immunology , Peritoneum/parasitology , Peritoneum/pathology , Receptors, Chemokine/biosynthesis , Receptors, Chemokine/genetics , Toxoplasma/genetics , Toxoplasma/growth & development , Toxoplasma/immunology , Toxoplasmosis/metabolismABSTRACT
The murine cell surface determinant Gr-1 is expressed at high level on neutrophils. Depletion of polymorphonuclear leukocytes with anti-Gr-1(+) monoclonal antibody results in increased susceptibility and dysregulated immunity to many microbial pathogens, a finding widely interpreted to indicate the importance of neutrophils during infection. Yet, in recent years it has become clear that additional cell types express the Gr-1 determinant, including dendritic cell and monocyte subpopulations. In this review, we evaluate current knowledge on the functional aspects of Gr-1(+) cell populations. We focus on infection with the opportunistic protozoan Toxoplasma gondii, a case where host survival depends on an intact Gr-1(+) cell population.
