IFN-beta mediates coordinate expression of antigen-processing genes in RSV-infected pulmonary epithelial cells

Major histocompatibility complex (MHC) class I-restricted cytotoxic T lymph ocytes (CTLs) clear respiratory tract infections caused by the pneumovirus respiratory syncytial virus (RSV) and also mediate vaccine-induced pulmonar y injury. Herein we examined the mechanism for RSV-induced MHC class I pres entation. Like infectious viruses, conditioned medium from RSV-infected cel ls (RSV-CM) induces naive cells to coordinately express a gene cluster enco ding the transporter associated with antigen presentation 1 (TAP1) and low molecular mass protein (LMP) 2 and LMP7. Neutralization of RSV-CM with anti bodies 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 w ith a competitive TAP1 inhibitor blocked inducible class I expression. We c onclude that RSV infection coordinately increases MHC class I expression an d proteasome activity through the paracrine action of IFN-beta to induce ex pression of the TAP1/LMP2/LMP7 locus, an event that may be important in the initiation of CTL-mediated lung injury.