Abstract:
UNLABELLED:Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR(-/-)) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8(+) T cell response. HMPV-infected IFNAR(-/-) mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR(-/-) mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8(+) T cells of IFNAR(-/-) mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8(+) T cells of IFNAR(-/-) mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1(low) dendritic cells (DCs), but not PD-L1(high) alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8(+) T cell impairment. IMPORTANCE:Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8(+) T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8(+) T cell impairment via PD-1-PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8(+) T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8(+) T cell impairment.
journal_name
J Viroljournal_title
Journal of virologyauthors
Hastings AK,Erickson JJ,Schuster JE,Boyd KL,Tollefson SJ,Johnson M,Gilchuk P,Joyce S,Williams JVdoi
10.1128/JVI.03275-14subject
Has Abstractpub_date
2015-04-01 00:00:00pages
4405-20issue
8eissn
0022-538Xissn
1098-5514pii
JVI.03275-14journal_volume
89pub_type
杂志文章abstract::When short pulses of [(3)H]uracil were administered to Bacillus subtilis infected with phage 2C, the main species of labeled RNA was a 10S component that hybridized chiefly, but not exclusively, with the heavy strand of 2C DNA. After long pulses, most of the radioactivity was found in the 23S, 16S, and 5S rRNA's, whic...
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pub_type: 杂志文章
doi:10.1128/JVI.14.6.1482-1493.1974
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.6.4092-4096.1994
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doi:10.1128/JVI.22.3.694-701.1977
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.68.3.1350-1359.1994
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.63.6.2798-2812.1989
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.10.4.721-729.1972
更新日期:1972-10-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/JVI.67.12.7612-7617.1993
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更新日期:1983-05-01 00:00:00
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.3.1725-1730.1998
更新日期:1998-03-01 00:00:00
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pub_type: 杂志文章
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更新日期:1968-05-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/jvi.74.3.1200-1208.2000
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.67.2.933-942.1993
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journal_title:Journal of virology
pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2001-05-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:1977-01-01 00:00:00
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:1993-05-01 00:00:00
abstract::Major histocompatibility complex class I (MHC I)-restricted CD8(+) T-cell responses play a pivotal role in anti-human immunodeficiency virus (HIV) immunity and the control of viremia. The rhesus macaque is an important animal model for HIV-related research. Among the MHC I alleles of the rhesus macaque, Mamu-A 02 is p...
journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2011-07-01 00:00:00
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pub_type: 杂志文章
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更新日期:2013-07-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2020-08-31 00:00:00