The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma
Posted: Sat Nov 28, 2015 9:51 am
The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum
Eszter Lázár-Molnár,* Attila Gácser,† Gordon J. Freeman,‡ Steven C. Almo,§¶ Stanley G. Nathenson,*‖** and Joshua D. Nosanchuk*†**
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Abstract
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.
Keywords: costimulation, fungal infection, programmed death-1
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268192/
Eszter Lázár-Molnár,* Attila Gácser,† Gordon J. Freeman,‡ Steven C. Almo,§¶ Stanley G. Nathenson,*‖** and Joshua D. Nosanchuk*†**
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
Go to:
Abstract
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.
Keywords: costimulation, fungal infection, programmed death-1
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268192/