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

Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2008; 105(7):2658-63. DOI: 10.1073/pnas.0711918105
Source: PubMed


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.

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Available from: Eszter Lazar-Molnar
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    • "In addition to data that T cell exhaustion exists in patients with chronic viral infections and sepsis, there is evidence from animal studies that treatment with anti-PD-1 and anti-PD-L1 antibodies can reverse T cell dysfunction, increase pathogen clearance and improve survival. Four different investigative teams reported that blockade of the PD-1 pathway prevents apoptotic cell death, restores host immunity and decreases mortality in clinically-relevant models of bacterial and fungal sepsis [16-20]. Given that T cell exhaustion is postulated to occur after chronic antigen exposure, it is somewhat surprising that anti-PD-1 and anti-PD-L1 antibodies were effective in particular animal models of sepsis even though the antibodies were administered relatively quickly after sepsis began, that is, often within the first 24 to 48 h after sepsis onset. "
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    ABSTRACT: A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients. Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-gamma) and interleukin-2 (IL-2) production were quantitated by flow cytometry. Lymphocytes from septic patients produced decreased IFN-gamma and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P < 0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P < 0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-gamma, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-gamma and IL-2 production in septic patients; (P < 0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P < 0.01). In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.
    Full-text · Article · Jan 2014 · Critical care (London, England)
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    • "(C) C57Bl/6 mice infected with 1.25 × 10 7 opsonized yeast cells had a 100% survival whereas control infected mice died within 1 month after infection (p < 0.001 for mAbs 8H2, 6F12, and 7C7 vs. controls). altered the PD-L expression on macrophages, which resulted in a dysregulation of T cell activation (Lazar-Molnar et al., 2008). The PD-1/PD-L pathway is involved in maintenance of self-tolerance and T cell regulation. "
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    ABSTRACT: The endemic human pathogenic fungus Histoplasma capsulatum is a major fungal pathogen with a broad variety of clinical presentations, ranging from mild, focal pulmonary disease to life-threatening systemic infections. Although azoles, such as itraconazole and voriconazole, and amphotericin B have significant activity against H. capsulatum, about 1 in 10 patients hospitalized due to histoplasmosis die. Hence, new approaches for managing disease are being sought. Over the past 10 years, studies have demonstrated that monoclonal antibodies (mAbs) can modify the pathogenesis of histoplasmosis. Disease has been shown to be impacted by mAbs targeting either fungal cell surface proteins or host co-stimulatory molecules. This review will detail our current knowledge regarding the impact of antibody therapy on histoplasmosis.
    Preview · Article · Feb 2012 · Frontiers in Microbiology
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    • "Recent findings suggest that the PD-1/PD-L1 pathway plays an important role in the interaction between host and pathogenic microbes that evolved to resist immune responses. Those pathogens include viruses [21], certain bacteria [22], fungi [23], and some worms [24]. "
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    ABSTRACT: Studies on the role of programmed death-1(PD-1) and its main ligand (PD-L1) during experimental models of sepsis have shown that the PD-1/PD-L1 pathway plays a pathologic role in altering microbial clearance, the innate inflammatory response and accelerated apoptosis in sepsis. However, the expression of PD-1 and PD-L1 and their role during the development of immune suppression in septic patients have not been elucidated. The present study was designed to determine whether the expression of PD-1 and PD-L1 is upregulated in septic shock patients and to explore the role of this pathway in sepsis-induced immunosuppression. Nineteen septic shock patients and 22 sex-matched and age-matched healthy controls were prospectively enrolled. Apoptosis in lymphocyte subpopulations and PD-1/PD-L1 expression on peripheral T cells, B cells and monocytes were measured using flow cytometry. Apoptosis of T cells induced by TNFα or T-cell receptor ligation in vitro and effects of anti-PD-L1 antibody administration were measured by flow cytometry. CD14+ monocytes of septic shock patients were purified and incubated with either lipopolysaccharide, anti-PD-L1 antibody, isotype antibody, or a combination of lipopolysaccharide and anti-PD-L1 antibody or isotype antibody. Supernatants were harvested to examine production of cytokines by ELISA. Compared with healthy controls, septic shock induced a marked increase in apoptosis as detected by the annexin-V binding and active caspase-3 on CD4+ T cells, CD8+ T cells and CD19+ B cells. Expression of PD-1 on T cells and of PD-L1 on monocytes was dramatically upregulated in septic shock patients. PD-1/PD-L1 pathway blockade in vitro with anti-PD-L1 antibody decreased apoptosis of T cells induced by TNFα or T-cell receptor ligation. Meanwhile, this blockade potentiated the lipopolysaccharide-induced TNFα and IL-6 production and decreased IL-10 production by monocytes in vitro. The expression of PD-1 on T cells and PD-L1 on monocytes was upregulated in septic shock patients. The PD-1/PD-L1 pathway might play an essential role in sepsis-induced immunosuppression.
    Full-text · Article · Feb 2011 · Critical care (London, England)
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