title: 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.
abstract: 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.
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA shahram.sm@nih.gov.
authors.forename: Shahram
authors.initials: S
authors.lastname: Solaymani-Mohammadi
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Lakhdari
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Ivelina
authors.initials: I
authors.lastname: Minev
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Shenouda
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Blake F
authors.initials: BF
authors.lastname: Frey
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Billeskov
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Singer
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.affiliation: *Laboratory of Mucosal Immunology and Department of Medicine, University of California, San Diego, La Jolla, California, USA; Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; and Department of Biology and Center for Infectious Disease, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kagnoff
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium; D003106:Colon / Q000276:immunology; D004756:Enterobacteriaceae Infections / Q000276:immunology*; D005260:Female; D053804:Granzymes / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054353:Perforin / Q000096:biosynthesis; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D061026:Programmed Cell Death 1 Receptor; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse
keywords: Citrobacter rodentium; PD-1; attaching/effacing bacteria; granzyme B; perforin