Epstein-Barr virus (EBV)-encoded RNA promotes growth of EBV-infected T cells through interleukin-9 induction.
EBV associates with various T-cell-proliferating diseases such as chronic active EBV infection and nasal lymphoma. In contrast to B cells, which are highly susceptible to EBV infection in vitro, T cells are refractory to EBV infection in vitro, and it has been difficult to examine the effects of EBV infection on T cells. We recently generated EBV recombinants with a selectable marker, which made it possible to select EBV-infected cells even when the efficiency of infection was low. Using the recombinant virus, we found that a human T-cell line, MT-2, was susceptible to EBV infection, and we succeeded in isolating EBV-infected cell clones with type II EBV latency, which was identical with those seen in EBV-infected T cells in vivo. EBV-infected MT-2 cell clones had shorter cell doubling times and higher saturation density than non-EBV-infected counterparts. We found that EBV-positive MT-2 cells expressed higher levels of interleukin (IL)-9 than EBV-negative MT-2 cells at the transcriptional level. It was also demonstrated that EBV-encoded small RNA was responsible for IL-9 expression. Addition of recombinant IL-9 accelerated the growth of MT-2 cells, whereas growth of the EBV-converted MT-2 cells was blocked by treatment with an anti-IL-9 antibody. These results suggest that IL-9 induced by EBV-encoded small RNA acts as an autocrine growth factor for EBV-infected T cells. Analysis of nasal lymphoma biopsies indicated that three of four specimens expressed IL-9. The present findings suggest that EBV directly affects the pathogenesis of EBV-associated T-cell diseases.
Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan.
Lixin
L
Yang
Katsuyuki
K
Aozasa
Kazuo
K
Oshimi
Kenzo
K
Takada
D001706:Biopsy; D002455:Cell Division / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D016906:Interleukin-9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009297:Nasal Mucosa / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000821:virology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism* / Q000494:pharmacology; D017735:Virus Latency; D019892:eIF-2 Kinase / Q000378:metabolism
D016906:Interleukin-9; D016328:NF-kappa B; D012333:RNA, Messenger; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D019892:eIF-2 Kinase