Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules

J Leukoc Biol. 2016 Mar;99(3):475-82. doi: 10.1189/jlb.4A0115-003RR. Epub 2015 Oct 14.


The programmed death-1 receptor is expressed on a wide range of immune effector cells, including T cells, natural killer T cells, dendritic cells, macrophages, and natural killer cells. In malignancies and chronic viral infections, increased expression of programmed death-1 by T cells is generally associated with a poor prognosis. However, its role in early host microbial defense at the intestinal mucosa is not well understood. We report that programmed death-1 expression is increased on conventional natural killer cells but not on CD4(+), CD8(+) or natural killer T cells, or CD11b(+) or CD11c(+) macrophages or dendritic cells after infection with the mouse pathogen Citrobacter rodentium. Mice genetically deficient in programmed death-1 or treated with anti-programmed death-1 antibody were more susceptible to acute enteric and systemic infection with Citrobacter rodentium. Wild-type but not programmed death-1-deficient mice infected with Citrobacter rodentium showed significantly increased expression of the conventional mucosal NK cell effector molecules granzyme B and perforin. In contrast, natural killer cells from programmed death-1-deficient mice had impaired expression of those mediators. Consistent with programmed death-1 being important for intracellular expression of natural killer cell effector molecules, mice depleted of natural killer cells and perforin-deficient mice manifested increased susceptibility to acute enteric infection with Citrobacter rodentium. Our findings suggest that increased programmed death-1 signaling pathway expression by conventional natural killer cells promotes host protection at the intestinal mucosa during acute infection with a bacterial gut pathogen by enhancing the expression and production of important effectors of natural killer cell function.

Keywords: Citrobacter rodentium; PD-1; attaching/effacing bacteria; granzyme B; perforin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Citrobacter rodentium*
  • Colon / immunology
  • Enterobacteriaceae Infections / immunology*
  • Female
  • Granzymes / biosynthesis
  • Interferon-gamma / biosynthesis
  • Intestinal Mucosa / immunology*
  • Killer Cells, Natural / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Perforin / biosynthesis
  • Programmed Cell Death 1 Receptor / physiology*
  • Signal Transduction


  • Programmed Cell Death 1 Receptor
  • Perforin
  • Interferon-gamma
  • Granzymes
  • Gzmb protein, mouse