Abstract
Major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTLs) clear respiratory tract infections caused by the pneumovirus respiratory syncytial virus (RSV) and also mediate vaccine-induced pulmonary injury. Herein we examined the mechanism for RSV-induced MHC class I presentation. Like infectious viruses, conditioned medium from RSV-infected cells (RSV-CM) induces naive cells to coordinately express a gene cluster encoding the transporter associated with antigen presentation 1 (TAP1) and low molecular mass protein (LMP) 2 and LMP7. Neutralization of RSV-CM with antibodies to interferon (IFN)-beta largely blocked TAP1/LMP2/LMP7 expression, whereas anti-interleukin-1 antibodies were without effect, and recombinant IFN-beta increased TAP1/LMP2/LMP7 expression to levels produced by RSV-CM. LMP2, LMP7, and TAP1 expression were required for MHC class I upregulation because the irreversible proteasome inhibitor lactacystin or transfection with a competitive TAP1 inhibitor blocked inducible class I expression. We conclude that RSV infection coordinately increases MHC class I expression and proteasome activity through the paracrine action of IFN-beta to induce expression of the TAP1/LMP2/LMP7 locus, an event that may be important in the initiation of CTL-mediated lung injury.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP-Binding Cassette Transporters / biosynthesis
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ATP-Binding Cassette Transporters / genetics
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Antibodies / pharmacology
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Antigen Presentation / drug effects
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Antigen Presentation / genetics
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Antigen Presentation / immunology*
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Cell Line
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Culture Media, Conditioned / metabolism
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Culture Media, Conditioned / pharmacology
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Cysteine Endopeptidases*
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Gene Expression Regulation / immunology*
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Genes, MHC Class I / immunology
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Genes, MHC Class II / immunology
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Humans
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Immediate-Early Proteins / metabolism
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Immediate-Early Proteins / pharmacology
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Interferon-beta / antagonists & inhibitors
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Interferon-beta / immunology*
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Interferon-beta / pharmacology
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / biosynthesis
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Major Histocompatibility Complex / genetics
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Major Histocompatibility Complex / immunology
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Multienzyme Complexes*
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Paracrine Communication / immunology
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Peptide Hydrolases / drug effects
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Peptide Hydrolases / metabolism
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Proteasome Endopeptidase Complex*
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Protein Biosynthesis
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Proteins / genetics
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RNA, Messenger / analysis
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RNA, Messenger / biosynthesis
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Respiratory Mucosa / cytology
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Respiratory Mucosa / immunology*
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Respiratory Mucosa / metabolism
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Respiratory Mucosa / virology
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Respiratory Syncytial Virus Infections / immunology*
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Respiratory Syncytial Virus Infections / metabolism
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Respiratory Syncytial Viruses / immunology
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Respiratory Syncytial Viruses / metabolism
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Viral Proteins*
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP-Binding Cassette Transporters
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Antibodies
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Culture Media, Conditioned
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ICP47 protein, Herpes simplex virus
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Immediate-Early Proteins
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Interleukin-1
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Multienzyme Complexes
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Proteins
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RNA, Messenger
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TAP1 protein, human
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Viral Proteins
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LMP-2 protein
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Interferon-beta
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Peptide Hydrolases
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Cysteine Endopeptidases
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LMP7 protein
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease