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

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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/