Distinct CD8 T Cell Functions Mediate Susceptibility to Histoplasmosis During Chronic Viral Infection

Wu-Hsieh, Betty A.; Whitmire, Jason K.; Fries, R de; Lin, Jr-Shiuan; Matloubian, Mehrdad; Ahmed, Rafi

doi:10.4049/jimmunol.167.8.4566

Cited by 12 publications

(8 citation statements)

References 44 publications

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“…Given the myriad roles of type I IFNs in the host, the possible effects of induction of IFN-␤ cells infected with H. capsulatum could include modulation of (i) downstream cytokine production, (ii) apoptosis of infected macrophages, or (iii) specific aspects of the adaptive immune response to H. capsulatum. Interestingly, it was previously observed that chronic infection of macrophages or mice with lymphocytic choriomeningitis virus (LCMV) clone 13, which induces type I IFNs, caused sensitization of the host to H. capsulatum infection (84,90). Although the possible interpretations of these data are complex, they are consistent with the model that increased levels of type I IFNs correlate with increased sensitivity to H. capsulatum infection.…”

Section: Vol 78 2010supporting

confidence: 76%

Conidia but Not Yeast Cells of the Fungal PathogenHistoplasma capsulatumTrigger a Type I Interferon Innate Immune Response in Murine Macrophages

Inglis¹,

Berkes²,

Murray³

et al. 2010

Infect Immun

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Histoplasma capsulatum is the most common cause of fungal respiratory infections and can lead to progressive disseminated infections, particularly in immunocompromised patients. Infection occurs upon inhalation of the aerosolized spores, known as conidia. Once inside the host, conidia are phagocytosed by alveolar macrophages. The conidia subsequently germinate and produce a budding yeast-like form that colonizes host macrophages and can disseminate throughout host organs and tissues. Even though conidia are the predominant infectious particle for H. capsulatum and are the first cell type encountered by the host during infection, very little is known at a molecular level about conidia or about their interaction with cells of the host immune system. We examined the interaction between conidia and host cells in a murine bone-marrow-derived macrophage model of infection. We used whole-genome expression profiling and quantitative reverse transcription-PCR (qRT-PCR) to monitor the macrophage signaling pathways that are modulated during infection with conidia. Our analysis revealed that type I interferon (IFN)-responsive genes and the beta type I IFN (IFN-␤) were induced in macrophages during infection with H. capsulatum conidia but not H. capsulatum yeast cells. Further analysis revealed that the type I IFN signature induced in macrophages in response to conidia is independent of Toll-like receptor (TLR) signaling and the cytosolic RNA sensor MAVS but is dependent on the transcription factor interferon regulatory factor 3 (IRF3). Interestingly, H. capsulatum growth was restricted in mice lacking the type I IFN receptor, indicating that an intact host type I IFN response is required for full virulence of H. capsulatum in mice.

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Section: Vol 78 2010supporting

confidence: 76%

Conidia but Not Yeast Cells of the Fungal PathogenHistoplasma capsulatumTrigger a Type I Interferon Innate Immune Response in Murine Macrophages

Inglis¹,

Berkes²,

Murray³

et al. 2010

Infect Immun

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“…Because PD-1 was shown to be upregulated on exhausted CD8 ϩ T cells in chronic viral infections such HIV, it is reasonable to suggest that blockade of the PD-1 pathway would benefit the host immune response against both pathogens through restoration of the antiviral function of CD8 ϩ T cells and abolishing T cell suppression mediated through Hc-infected antigen-presenting cells (APCs). This supposition is supported by the finding that sublethal Hc infection associated with persistent infection of LCMV clone 13 resulted in reduced immunity leading to increased fungal burdens and high mortality (33). Because LCMV has been shown to cause exhaustion of CD8 ϩ T cells through up-regulation of PD-1 (14), it is intriguing to consider that Hc can cause fatal disease in these mice by efficiently avoiding host immune responses in the setting of high expression of both PD-Ls and PD-1.…”

Section: Discussionmentioning

confidence: 81%

The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungusHistoplasma capsulatum

Lázár‐Molnár

Gácser²,

Freeman

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

107

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The PD-1 costimulatory receptor inhibits T cell receptor signaling upon interacting with its ligands PD-L1 and PD-L2. The PD-1/PD-L pathway is critical in maintaining self-tolerance. In this study, we examined the role of PD-1 in a mouse model of acute infection with Histoplasma capsulatum, a major human pathogenic fungus. In a lethal model of histoplasmosis, all PD-1-deficient mice survived infection, whereas the wild-type mice died with disseminated disease. PD-L expression on macrophages and splenocytes was up-regulated during infection, and macrophages from infected mice inhibited in vitro T cell activation. Of interest, antibody blocking of PD-1 significantly increased survival of lethally infected wild-type mice. Thus, our studies extend the role of the PD-1/PD-L pathway in regulating antimicrobial immunity to fungal pathogens. The results show that the PD-1/PD-L pathway has a key role in the regulation of antifungal immunity, and suggest that manipulation of this pathway represents a strategy of immunotherapy for histoplasmosis.costimulation ͉ fungal infection ͉ programmed death-1

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“…They might provide B cell help or serve an immunoregulatory role through secretion of cytokines; these activities would be limited to conditions of high peptide/class I MHC density, for example when the APC is infected with an intracellular pathogen or when Ag loads are high due to persistent infection. Alternatively, they might represent a feedback response to intense or prolonged IL-4 exposure whereby down-regulation of CD8 reduces sensitivity to Ag, dampening the effector response and reducing the immunopathology associated with prolonged T cell activation and function (46,47). Either outcome might be exploited by tumors or infectious agents to escape elimination by cytolytic CD8 high T cells.…”

Section: Discussionmentioning

confidence: 99%

Progressive Differentiation and Commitment of CD8+ T Cells to a Poorly Cytolytic CD8low Phenotype in the Presence of IL-4

Kienzle

Olver

Buttigieg

et al. 2005

The Journal of Immunology

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Exposure to IL-4 during activation of naive murine CD8+ T cells leads to generation of IL-4-producing effector cells with reduced surface CD8, low perforin, granzyme B and granzyme C mRNA, and poor cytolytic function. We show in this study that maximal development of these cells depended on exposure to IL-4 for the first 5 days of activation. Although IL-4 was not required at later times, CD8 T cell clones continued to lose surface CD8 expression with prolonged culture, suggesting commitment to the CD8low phenotype. This state was reversible in early differentiation. When single CD8low cells from 4-day cultures were cultured without IL-4, 65% gave rise to clones that partly or wholly comprised CD8high cells; the proportion of reverted clones was reduced or increased when the cells were cloned in the presence of IL-4 or anti-IL-4 Ab, respectively. CD8 expression positively correlated with perforin and granzyme A, B, and C mRNA, and negatively correlated with IL-4 mRNA levels among these clones. By contrast, most CD8low cells isolated at later time points maintained their phenotype, produced IL-4, and exhibited poor cytolytic function after many weeks in the absence of exogenous IL-4. We conclude that IL-4-dependent down-regulation of CD8 is associated with progressive differentiation and commitment to yield IL-4-producing cells with little cytolytic activity. These data suggest that the CD4−CD8− cells identified in some disease states may be the product of a previously unrecognized pathway of effector differentiation from conventional CD8+ T cells.

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Distinct CD8 T Cell Functions Mediate Susceptibility to Histoplasmosis During Chronic Viral Infection

Cited by 12 publications

References 44 publications

Conidia but Not Yeast Cells of the Fungal PathogenHistoplasma capsulatumTrigger a Type I Interferon Innate Immune Response in Murine Macrophages

Conidia but Not Yeast Cells of the Fungal PathogenHistoplasma capsulatumTrigger a Type I Interferon Innate Immune Response in Murine Macrophages

The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungusHistoplasma capsulatum

Progressive Differentiation and Commitment of CD8+ T Cells to a Poorly Cytolytic CD8low Phenotype in the Presence of IL-4

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