The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum
Published online on February 11, 2008
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0711918105
pnas.org
Eszter Lázár-Molnár*, Attila Gácser{dagger}, Gordon J. Freeman{ddagger}, Steven C. Almo§,¶, Stanley G. Nathenson*,||,**, and Joshua D. Nosanchuk*,{dagger},**
Departments of *Microbiology and Immunology, ||Cell Biology, {dagger}Medicine, §Biochemistry, and ¶Physiology and Biophysics, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461; and {ddagger}Department of Medical Oncology, Dana–Farber Cancer Institute, Department of Medicine, Harvard Medical School, 44 Binney Street, Boston, MA 02115
Contributed by Stanley G. Nathenson, December 20, 2007 (sent for review November 30, 2007)
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.
costimulation | fungal infection | programmed death-1
Footnotes
Author contributions: E.l.-M. and A.G. contributed equally to this work: S.C.A., S.G.N., and J.D.N. contributed equally to this work; E.L.-M., A.G., S.C.A., S.G.N., and J.D.N. designed research; E.L.-M. and A.G. performed research; G.J.F. contributed new reagents/analytic tools; E.L.-M., A.G., G.J.F., S.C.A., S.G.N., and J.D.N. analyzed data; and E.L.-M. wrote the paper.
The authors declare no conflict of interest.
**To whom correspondence may be addressed. E-mail: nathenso@aecom.yu.edu or nosanchu@aecom.yu.edu |
