© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 22, 1724-1732,
November 21, 2001
© 2001 Oxford University Press
ARTICLE |
Interleukin 15-Mediated Induction of Cytotoxic Effector Cells Capable of Eliminating Epstein-Barr Virus-Transformed/Immortalized Lymphocytes in Culture
Affiliations of authors: Laboratory of Immunovirology, Department of Microbiology and Immunology, and Pediatric Research Center, University of Montreal and Sainte-Justine Hospital, Montreal, PQ, Canada.
Correspondence to: José Menezes, Ph.D., D.V.M., Laboratory of Immunovirology, Sainte-Justine Hospital 3175, Côte-Ste-Catherine Rd., Montreal, PQ, Canada H3T 1C5 (e-mail: jmenezes{at}justine.umontreal.ca).
Background: Interleukin 15 (IL-15) activates cytotoxic lymphocytes and drives the expansion of memory T cells. Its role in immune control of virus-transformed cells and other tumor cells remains to be elucidated. We investigated the role of IL-15 in controlling Epstein-Barr virus (EBV)-transformed/immortalized lymphocytes in culture. EBV is a highly potent lymphocyte-transforming and opportunistic oncogenic herpesvirus associated with several human tumors. Methods: Peripheral blood mononuclear cells (PBMCs) from healthy donors were infected with EBV and cultured with either IL-15 or IL-15 plus anti-IL-15 antibodies for 3–4 weeks. We monitored EBV-induced transformation by assessing the clearly visible cell clusters by microscopy and analyzing the expression of EBV-encoded latent membrane oncoprotein-1 (LMP-1) and the EBV nuclear antigen (EBNA) complex by immunoblotting and immunofluorescence techniques, respectively. We depleted EBV-infected cultures of PBMCs of specific effector cell populations to investigate the effector cells involved in mediating IL-15 effect. Results: The presence of IL-15 resulted in the complete elimination of EBV-transformed cells in PBMC cultures. Western blot and immunofluorescence analyses performed 3–4 weeks after infection showed no detectable levels of LMP-1 and EBNA in IL-15-treated EBV-infected cultures, whereas IL-15-untreated EBV-infected cultures and IL-15/anti-IL-15-treated cultures expressed both proteins. IL-15 mediated its anti-EBV effect through early and late response mechanisms, i.e., by first activating natural killer (NK) cells and subsequently inducing cytolytic NK-T cells. The presence of anti-IL-15 neutralizing antibodies abrogated IL-15's effect on both mechanisms. Conclusion: In vitro, IL-15 mediated complete elimination of EBV-infected/transformed lymphocytes via successive activation of NK and NK-T cytotoxic effectors. If these in vitro findings reflect in vivo mechanisms, then IL-15 might be considered for cytokine-based immunotherapy in patients with EBV-associated lymphoproliferative disorders/malignancies.
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