title: The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum.
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.
authors.affiliation: Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Eszter
authors.initials: E
authors.lastname: Lázár-Molnár
authors.forename: Attila
authors.initials: A
authors.lastname: Gácser
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Nathenson
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Nosanchuk
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism*; D060890:B7-H1 Antigen; D006658:Histoplasma / Q000276:immunology / Q000472:pathogenicity*; D006660:Histoplasmosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000378:metabolism*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C556977:PDCD1LG2 protein, human; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor