IFN-beta mediates coordinate expression of antigen-processing genes in RSV-infected pulmonary epithelial cells.
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.
Jamaluddin
M
M
Department of Medicine, The University of Texas Medical Branch, Galveston, Texas 77555-1060, USA.
Wang
S
S
Garofalo
R P
RP
Elliott
T
T
Casola
A
A
Baron
S
S
Brasier
A R
AR
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000906:Antibodies / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D003546:Cysteine Endopeptidases; D005786:Gene Expression Regulation / Q000276:immunology*; D005805:Genes, MHC Class I / Q000276:immunology; D005802:Genes, MHC Class II / Q000276:immunology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism / Q000494:pharmacology; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D009097:Multienzyme Complexes; D019899:Paracrine Communication / Q000276:immunology; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000378:metabolism; D012136:Respiratory Syncytial Viruses / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000906:Antibodies; D017077:Culture Media, Conditioned; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D009097:Multienzyme Complexes; D011506:Proteins; D012333:RNA, Messenger; C073119:TAP1 protein, human; D014764:Viral Proteins; C071313:LMP-2 protein; D016899:Interferon-beta; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease