Interleukin-15 triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes

R. Zambello, M. Facco, L. Trentin, R. Sancetta, C. Tassinari, A. Perin, A. Milani, G. Pizzolo, F. Rodeghiero, C. Agostini, R. Meazza, S. Ferrini, G. Semenzato

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Abstract

The recently cloned cytokine interleukin-15 (IL-15) shares several functional activities with IL-2 in different cell systems. Although IL-15 does not show sequence homology with IL-2, it uses components of the IL-2 receptor (IL-2R) for binding and signal transduction, namely, p75 (β) and the p64 (γ) chains of IL-2R. To evaluate whether IL-15 is involved in the activation of granular lymphocytes (GL) in patients with lymphoproliferative disease of granular lymphocytes (LDGL), we evaluated the ability of IL-15 to stimulate GL proliferation, cytotoxic function, and the role of IL-2R β and γ molecules on relevant cells. Our results show that IL-15 stimulates cell proliferation and cytotoxic activity of GL in LDGL patients. Reverse- transcriptase polymerase chain reaction (RT-PCR) and phenotypic analyses using the anti-IL-2R γ-chain-specific TUGh4 monoclonal antibody (MoAb) indicate that both CD3+ and CD3- GL express the p64 IL-2R, a result previously unknown. IL-15 activity was inhibited by antibodies against p75 and p64 IL-2R chains, while no inhibitory effects are detectable with anti- p55 IL-2R antibody. The association of anti-p75 and anti-p64 IL-2R MoAbs resulted in a nearly complete (95%) inhibition of IL-15-induced GL proliferation. Using RT-PCR analysis, we demonstrated that highly purified CD3+ and CD3- GL did not express mRNA for IL-15 or IL-2. By contrast, a clear-cut IL-15 mRNA signal was detected by RT-PCR in patients' peripheral blood mononuclear cells, with monocytes likely accounting for the source of IL-15 in LDGL patients. However, even in concentrated supernatants from enriched monocyte populations, we could not demonstrate the presence of IL- 15 protein. Using anti-IL-15 specific MoAbs, a membrane-bound form of this cytokine was demonstrated both on CD3+ and CD3- LDGL cells. By RT-PCR analysis, purified GL from these patients were found to express the message for IL-15 receptor α chain. Taken together, these results indicate that both CD3+ and CD3- GL are stimulated by IL-15 and that this cytokine mediates its activity through the β and γ chains of the IL-2R, providing further suggestions for the interpretation of the mechanisms that lead to cell expansion in patients with LDGL.

Original languageEnglish
Pages (from-to)201-211
Number of pages11
JournalBlood
Volume89
Issue number1
Publication statusPublished - Jan 1 1997

ASJC Scopus subject areas

  • Hematology

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    Zambello, R., Facco, M., Trentin, L., Sancetta, R., Tassinari, C., Perin, A., Milani, A., Pizzolo, G., Rodeghiero, F., Agostini, C., Meazza, R., Ferrini, S., & Semenzato, G. (1997). Interleukin-15 triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. Blood, 89(1), 201-211.