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

Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2658-63. doi: 10.1073/pnas.0711918105. Epub 2008 Feb 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism*
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • B7-1 Antigen / metabolism*
  • B7-H1 Antigen
  • Histoplasma / immunology
  • Histoplasma / pathogenicity*
  • Histoplasmosis / genetics
  • Histoplasmosis / immunology
  • Histoplasmosis / metabolism*
  • Histoplasmosis / prevention & control*
  • Lymphocyte Activation / immunology
  • Macrophages / metabolism
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptides / metabolism*
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Signal Transduction*
  • Survival Rate
  • T-Lymphocytes / immunology
  • Up-Regulation

Substances

  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Membrane Glycoproteins
  • PDCD1LG2 protein, human
  • Pdcd1 protein, mouse
  • Pdcd1lg2 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor