title: Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis.
abstract: The programmed death-1 (PD-1) costimulatory receptor inhibits T and B cell responses and plays a crucial role in peripheral tolerance. PD-1 has recently been shown to inhibit T cell responses during chronic viral infections such as HIV. In this study, we examined the role of PD-1 in infection with Mycobacterium tuberculosis, a common co-infection with HIV. PD-1-deficient mice showed dramatically reduced survival compared with wild-type mice. The lungs of the PD-1-/- mice showed uncontrolled bacterial proliferation and focal necrotic areas with predominantly neutrophilic infiltrates, but a lower number of infiltrating T and B cells. Proinflammatory cytokines, such as TNF-alpha, IL-1, and especially IL-6 and IL-17 were significantly increased in the lung and sera of infected PD-1-/- mice, consistent with an aberrant inflammation. Microarray analysis of the lungs infected with M. tuberculosis showed dramatic differences between PD-1-/- and control mice. Using high-stringency analysis criteria (changes of twofold or greater), 367 transcripts of genes were differentially expressed between infected PD-1-/- and wild-type mice, resulting in profoundly altered inflammatory responses with implications for both innate and adaptive immunity. Overall, our studies show that the PD-1 pathway is required to control excessive inflammatory responses after M. tuberculosis infection in the lungs.
authors.affiliation: Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Eszter
authors.initials: E
authors.lastname: Lázár-Molnár
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Kari A
authors.initials: KA
authors.lastname: Sweeney
authors.forename: Emilie J
authors.initials: EJ
authors.lastname: Wang
authors.forename: Weijun
authors.initials: W
authors.lastname: Liu
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Nathenson
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions / Q000276:immunology; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000502:physiology; D009336:Necrosis; D020411:Oligonucleotide Array Sequence Analysis; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D061026:Programmed Cell Death 1 Receptor; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D007375:Interleukin-1; D020381:Interleukin-17; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha