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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 and G Semenzato
Department of Clinical and Experimental Medicine, Padua University School
of Medicine, Italy.
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 (beta)
and the p64 (gamma) 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 beta and gamma 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 gamma-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 alpha 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 beta and
gamma chains of the IL-2R, providing further suggestions for the
interpretation of the mechanisms that lead to cell expansion in patients
with LDGL.
Volume 89,
Issue 1,
pp. 201-211,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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