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

Eszter Lázár-Molnár, A. Gácser, Gordon J. Freeman, Steven C. Almo, Stanley G. Nathenson, Joshua D. Nosanchuk

Research output: Contribution to journalArticle

59 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2658-2663
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number7
DOIs
Publication statusPublished - Feb 19 2008

Fingerprint

Histoplasma
Fungi
Histoplasmosis
Programmed Cell Death 1 Receptor
Immunity
Infection
Macrophages
Self Tolerance
Blocking Antibodies
Critical Pathways
T-Cell Antigen Receptor
Immunotherapy
Ligands
T-Lymphocytes
Survival

Keywords

  • Costimulation
  • Fungal infection
  • Programmed death-1

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. / Lázár-Molnár, Eszter; Gácser, A.; Freeman, Gordon J.; Almo, Steven C.; Nathenson, Stanley G.; Nosanchuk, Joshua D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 7, 19.02.2008, p. 2658-2663.

Research output: Contribution to journalArticle

Lázár-Molnár, Eszter ; Gácser, A. ; Freeman, Gordon J. ; Almo, Steven C. ; Nathenson, Stanley G. ; Nosanchuk, Joshua D. / The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 7. pp. 2658-2663.
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