Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum

Allen, Holly L.; Deepe, George S.

doi:10.1172/jci25365

Cited by 40 publications

(47 citation statements)

References 71 publications

(57 reference statements)

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“…Others have suggested that Histoplasma-induced T cell apoptosis is a requirement for developing effective antifungal protection (38). Microscopic examination of Histoplasma-infected liver granulomas by H&E staining did not show frequent central necrosis in C57BL/6 mice.…”

Section: Apoptosis Of Granuloma-infiltrating Leukocytes In Histoplasmmentioning

confidence: 81%

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Characterization of theHistoplasma capsulatum-Induced Granuloma

Héninger

Hogan²,

Karman

et al. 2006

The Journal of Immunology

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Rising rates of Histoplasma capsulatum infection are an emerging problem among the rapidly growing population of immune-compromised individuals. Although there is a growing understanding of systemic immunity against Histoplasma, little is known about the local granulomatous response, which is an important component in the control of infection. The focus of this article is the characterization of Histoplasma-induced granulomas. Five days after i.p. infection, infected macrophage appear in the liver and lung; however, no granulomas are apparent. Two days later, well-formed sarcoid granulomas are abundant in the lung and liver of infected mice, which contain all visible Histoplasma. Granulomas are dominated by macrophage and lymphocytes. Most of the Histoplasma and most of the apoptotic cells are found in the center of the lesions. We isolated liver granulomas at multiple time points after infection and analyzed the cellular composition, TCR gene usage, and cytokine production of granuloma-infiltrating cells. The lesions contain both CD4+ and CD8+ T cell subsets, and T cells are the primary source of IFN-γ and IL-17. The main source of local TNF-α is macrophage. Chemokines are produced by both infiltrating macrophage and lymphocytes. Dendritic cells are present in granulomas; however, T cell expansion seems to occur systemically because TCR usage is very heterogeneous even at the level of individual lesions. This study is the first direct examination of host cellular responses in the Histoplasma-induced granuloma representing the specific interface between host and pathogen. Our studies will allow further analysis of key elements of host Histoplasma interactions at the site of chronic infection.

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Section: Apoptosis Of Granuloma-infiltrating Leukocytes In Histoplasmmentioning

confidence: 81%

“…It may also be important in the control of the yeast by clearing infected cells. An intriguing report (38) shows that apoptosis is a prerequisite for a successful immune response. Mycobacteria are also known to evade immune clearance by inhibiting apoptosis in the infected macrophage (49,50).…”

Section: Discussionmentioning

confidence: 99%

Characterization of theHistoplasma capsulatum-Induced Granuloma

Héninger

Hogan²,

Karman

et al. 2006

The Journal of Immunology

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“…Boc-D-FMK (pan-caspase inhibitor; SigmaAldrich) (0.2 mol) or Z-FA-FMK (control peptide; Sigma-Aldrich) (0.2 mol) was dissolved in 10 l of dimethyl sulfoxide (DMSO) for storage and diluted with 190 l of sterilized Dulbecco's PBS immediately before injection. Mice were injected intraperitoneally with Boc-D-FMK or Z-FA-FMK at the time of intratracheal infection with Histoplasma and daily afterwards until the day of the experiment (2).…”

Section: T Cell Activation Taken Together Our Results Revealed Thatmentioning

confidence: 99%

Immunization with Apoptotic Phagocytes Containing Histoplasma capsulatum Activates Functional CD8⁺T Cells To Protect against Histoplasmosis

et al. 2011

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We have previously revealed the protective role of CD8 ؉ T cells in host defense against Histoplasma capsulatum in animals with CD4؉ T cell deficiency and demonstrated that sensitized CD8 ؉ T cells are restimulated in vitro by dendritic cells that have ingested apoptotic macrophage-associated Histoplasma antigen. Here we show that immunization with apoptotic phagocytes containing heat-killed Histoplasma efficiently activated functional CD8 ؉ T cells whose contribution was equal to that of CD4 ؉ T cells in protection against Histoplasma challenge. Inhibition of macrophage apoptosis due to inducible nitric oxide synthase (iNOS) deficiency or by caspase inhibitor treatment dampened the CD8 ؉ T cell but not the CD4 ؉ T cell response to pulmonary Histoplasma infection. In mice subcutaneously immunized with viable Histoplasma yeasts whose CD8 ؉ T cells are protective against Histoplasma challenge, there was heavy granulocyte and macrophage infiltration and the infiltrating cells became apoptotic. In mice subcutaneously immunized with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled apoptotic macrophages containing heat-killed Histoplasma, the CFSE-labeled macrophage material was found to localize within dendritic cells in the draining lymph node. Moreover, depleting dendritic cells in immunized CD11c-DTR mice significantly reduced CD8 ؉ T cell activation. Taken together, our results revealed that phagocyte apoptosis in the Histoplasma-infected host is associated with CD8 ؉

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“…The cell pellet was collected by centrifugation (450 ϫ g, 5 min, 4ЊC) and resuspended in HBSS. The lymphocyte population was then isolated using a 40-70% Percoll (Pharmacia, Uppsala, Sweden) gradient (23). Cells were incubated with allophyocyanin (APC) or fluorescein isothiocyanate-conjugated antibodies (1 g antibody per 20 l staining buffer) and isotype controls.…”

Section: Evaluation Of Airway and Tissue Cellular Recruitmentmentioning

confidence: 99%

Susceptibility of Hermansky-Pudlak Mice to Bleomycin-Induced Type II Cell Apoptosis and Fibrosis

Young

Pasula

Gulleman

et al. 2007

Am J Respir Cell Mol Biol

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Pulmonary inflammation, abnormalities in type II cell and macrophage morphology, and pulmonary fibrosis are features of Hermansky-Pudlak Syndrome (HPS), a recessive disorder associated with intracellular trafficking defects. We have previously reported that "Pearl" (HPS2) and "Pale Ear" (HPS1) mouse models have pulmonary inflammatory dysregulation and constitutive alveolar macrophage (AM) activation (Young LR et al., J Immunol 2006;176:4361-4368). In the current study, we used these HPS models to investigate mechanisms of lung fibrosis. Unchallenged HPS1 and HPS2 mice have subtle airspace enlargement and foamy AMs, but little or no histologic evidence of lung fibrosis. Seven days after intratracheal bleomycin (0.025 units), HPS1 and HPS2 mice exhibited increased mortality and diffuse pulmonary fibrosis compared to strain-matched C57BL/6J wildtype (WT) mice. HPS mice had significantly increased collagen deposition, and reduced quasi-static and static compliance consistent with a restrictive defect. The early airway and parenchymal cellular inflammatory responses to bleomycin were similar in HPS2 and WT mice. Greater elevations in levels of TGF-␤ and IL-12p40 were produced in the lungs and AMs from bleomycin-challenged HPS mice than in WT mice. TUNEL staining revealed apoptosis of type II cells as early as 5 h after low-dose bleomycin challenge in HPS mice, suggesting that type II cell susceptibility to apoptosis may play a role in the fibrotic response. We conclude that the trafficking abnormalities in HPS promote alveolar apoptosis and pulmonary fibrosis in response to bleomycin challenge.

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Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum

Cited by 40 publications

References 71 publications

Characterization of theHistoplasma capsulatum-Induced Granuloma

Characterization of theHistoplasma capsulatum-Induced Granuloma

Immunization with Apoptotic Phagocytes Containing Histoplasma capsulatum Activates Functional CD8⁺T Cells To Protect against Histoplasmosis

Susceptibility of Hermansky-Pudlak Mice to Bleomycin-Induced Type II Cell Apoptosis and Fibrosis

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Apoptosis modulates protective immunity to the pathogenic fungus Histoplasma capsulatum

Cited by 40 publications

References 71 publications

Characterization of theHistoplasma capsulatum-Induced Granuloma

Characterization of theHistoplasma capsulatum-Induced Granuloma

Immunization with Apoptotic Phagocytes Containing Histoplasma capsulatum Activates Functional CD8+T Cells To Protect against Histoplasmosis

Susceptibility of Hermansky-Pudlak Mice to Bleomycin-Induced Type II Cell Apoptosis and Fibrosis

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Immunization with Apoptotic Phagocytes Containing Histoplasma capsulatum Activates Functional CD8⁺T Cells To Protect against Histoplasmosis