CD4+ T cell–independent vaccination against Pneumocystis carinii in mice

Zheng, Mingquan; Shellito, Judd E.; Marrero, Luis; Zhong, Qian; Julian, Stewart; Ye, Peng; Wallace, Virginia; Schwarzenberger, Paul; Kolls, Jay K.

doi:10.1172/jci13826

Cited by 100 publications

(108 citation statements)

References 31 publications

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“…Flow cytometry analysis indicated that 0.3 mg of the antibody achieved 95% depletion of CD4+ cells after a single injection. This result was consistent with that of Zheng et al [12] Immunosuppressed mice were transtracheally instilled with 2 × 10 6 P. murina organisms. Immunosuppressed, non-infected mice were used as controls.…”

Section: Mouse Model Of Pcpsupporting

confidence: 92%

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Decreased inflammatory response in Toll-like receptor 2 knockout mice is associated with exacerbated Pneumocystis pneumonia

Wang

Zhang

Lasbury

et al. 2008

Microbes and Infection

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Pneumocystis pneumonia (PcP) is marked by substantial inflammatory damage to the lung. We have found that Toll-like receptor 2 (TLR2) mediates macrophage inflammatory responses to Pneumocystis and hypothesized that TLR2 deficiency would lead to less severe inflammation and milder lung injury during PcP. Histopathology examination showed that TLR2−/− mice with PcP indeed exhibited milder pulmonary inflammation. TLR2−/− mouse lungs contained less TNF-α and displayed lower levels of NF-κB activation during PcP. However, TLR2−/− mice with PcP displayed increased severity in symptoms and organism burden. The increased organism burden is likely due to defects in protective mechanisms in TLR2−/− mice. mRNA levels of the inducible nitric oxide synthase and NADPH oxidase p47phox, as well as nitric oxide levels in the lungs, were decreased in TLR2−/− PcP mice. Taken together, this study shows that TLR2-mediated inflammatory responses contribute to a certain degree the clearance of Pneumocystis organism in mice.

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Section: Mouse Model Of Pcpsupporting

confidence: 92%

“…AF257179) using the method described by Zheng et al [12] A portion of the P. murina mitochondrial large subunit ribosomal RNA gene was cloned, and Pc rRNA was produced by in vitro transcription. A standard curve was generated with the known copy numbers of P. murina rRNA.…”

Section: Quantification Of P Murina Organism Burden By Real-time Rt-pcrmentioning

confidence: 99%

Decreased inflammatory response in Toll-like receptor 2 knockout mice is associated with exacerbated Pneumocystis pneumonia

Wang

Zhang

Lasbury

et al. 2008

Microbes and Infection

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“…As lymphocytic immunity wanes during the course of HIV infection or other immunosuppressive conditions, the DCs may also provide an alternate means to stimulate effective immunity against this organism. Intriguing studies by Zheng et al (28) have shown that murine bone marrow-derived DCs that express the murine CD40L can be stimulated ex vivo with Pneumocystis Ags. Such cells, when transferred to lymphocyte-depleted mice, confer protection against subsequent Pneumocystis pneumonia (28).…”

Section: Discussionmentioning

confidence: 98%

PneumocystisCell Wall β-Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism

Carmona

Vassallo

Vuk-Pavlović

et al. 2006

The Journal of Immunology

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Respiratory failure during Pneumocystis pneumonia is mainly a consequence of exaggerated inflammatory responses to the organism. Dendritic cells (DCs) are the most potent APCs in the lung and are key to the regulation of innate and adaptive immune responses. However, their participation in the inflammatory response directed against Pneumocystis infection has not been fully elucidated. Therefore, we studied the role of Pneumocystis carinii, as well as Saccharomyces cerevisiae, cell wall-derived β-glucans, in DC costimulatory molecule expression. We further studied the impact of β-glucans on subsequent T cell activation. Because cytokine secretion by DCs has recently been shown to be regulated by Fas ligand (FasL), its role in β-glucan activation of DCs was also investigated. β-Glucan-induced DC activation occurred in part through dectin-1 receptors. We demonstrated that DC activation by β-glucans elicits T cell activation and polarization into a Th1 patterned response, but with the conspicuous absence of IL-12. These observations differed from LPS-driven T cell polarization, suggesting that β-glucans and LPS signal DC activation through different mechanisms. We additionally determined that IL-1β and TNF-α secretion by β-glucan-stimulated DCs was partially regulated by Fas-FasL. This suggests that dysregulation of FasL could further enhance exuberant and prolonged cytokine production by DCs following DC-T cell interactions, further promoting lung inflammation typical of Pneumocystis pneumonia.

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“…The assay for determination of Pneumocystis copy number per whole lung has been previously described (14). Briefly, real-time PCR was conducted using one-step TaqMan RT-PCR reagents (Applied Biosystems).…”

Section: Rna Isolation and Taqman Probes And Primers For Pneumocystismentioning

confidence: 99%

Regulatory T Cells Dampen Pulmonary Inflammation and Lung Injury in an Animal Model ofPneumocystisPneumonia

McKinley

Logar

McAllister

et al. 2006

The Journal of Immunology

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103

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CD4+CD25+FoxP3+ regulatory T cells are decreased in patients infected with HIV and have been shown to be critical in mediating Ag tolerance in the lung. Because a subset of Pneumocystis-infected individuals develop substantial lung injury, which can be modeled in immune reconstituted scid mice, we used mouse models of Pneumocystis carinii to investigate the role of regulatory T cells in opportunistic infection and immune reconstitution. In this study, we show that CD4+CD25+FoxP3+ cells are part of the host response to Pneumocystis in CD4+ T cell-intact mice. Moreover, lung injury and proinflammatory Th1 and Th2 cytokine levels in the bronchoalveolar lavage fluid and lung homogenate were increased following CD4+CD25− immune reconstitution in Pneumocystis-infected SCID mice but not in CD4+CD25+ T cell-reconstituted animals. The ability of CD4+CD25+ T cells to control inflammation and injury during the course of Pneumocystis was confirmed by treatment of wild-type C57BL/6 mice with anti-CD25 mAb. These data show that CD4+CD25+ T cells control pulmonary inflammation and lung injury associated with Pneumocystis infection both in the setting of immune reconstitution as well as new acquisition of infection.

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CD4+ T cell–independent vaccination against Pneumocystis carinii in mice

Cited by 100 publications

References 31 publications

Decreased inflammatory response in Toll-like receptor 2 knockout mice is associated with exacerbated Pneumocystis pneumonia

Decreased inflammatory response in Toll-like receptor 2 knockout mice is associated with exacerbated Pneumocystis pneumonia

PneumocystisCell Wall β-Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism

Regulatory T Cells Dampen Pulmonary Inflammation and Lung Injury in an Animal Model ofPneumocystisPneumonia

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