title: Programmed death (PD)-1-deficient mice are extremely sensitive to murine hepatitis virus strain-3 (MHV-3) infection.
abstract: The inhibitory receptor programmed death-1 (PD-1) has the capacity to maintain peripheral tolerance and limit immunopathological damage; however, its precise role in fulminant viral hepatitis (FH) has yet to be described. Here, we investigated the functional mechanisms of PD-1 as related to FH pathogenesis induced by the murine hepatitis virus strain-3 (MHV-3). High levels of PD-1-positive CD4(+), CD8(+) T cells, NK cells and macrophages were observed in liver, spleen, lymph node and thymus tissues following MHV-3 infection. PD-1-deficient mice exhibited significantly higher expression of the effector molecule which initiates fibrinogen deposition, fibrinogen-like protein 2 (FGL2), than did their wild-type (WT) littermates. As a result, more severe tissue damage was produced and mortality rates were higher. Fluorescence double-staining revealed that FGL2 and PD-1 were not co-expressed on the same cells, while quantitative RT-PCR demonstrated that higher levels of IFN-γ and TNF-α mRNA transcription occurred in PD-1-deficient mice in response to MHV-3 infection. Conversely, in vivo blockade of IFN-γ and TNF-α led to efficient inhibition of FGL2 expression, greatly attenuated the development of tissue lesions, and ultimately reduced mortality. Thus, the up-regulation of FGL2 in PD-1-deficient mice was determined to be mediated by IFN-γ and TNF-α. Taken together, our results suggest that PD-1 signaling plays an essential role in decreasing the immunopathological damage induced by MHV-3 and that manipulation of this signal might be a useful strategy for FH immunotherapy.
authors.affiliation: Institute of Immunology, PLA, Third Military Medical University, Chongqing, P. R. China.
authors.forename: Yongwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Shengxi
authors.initials: S
authors.lastname: Wu
authors.forename: Guoning
authors.initials: G
authors.lastname: Guo
authors.forename: Lei
authors.initials: L
authors.lastname: Fei
authors.forename: Sheng
authors.initials: S
authors.lastname: Guo
authors.forename: Chengying
authors.initials: C
authors.lastname: Yang
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Fu
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005340:Fibrinogen / Q000378:metabolism; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D054884:Host-Pathogen Interactions; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000472:pathogenicity / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology*; D015398:Signal Transduction; D015996:Survival Rate; D046888:Tissue Array Analysis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; C490637:Fgl2 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005340:Fibrinogen