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 Blood, 1 October 2005, Vol. 106, No. 7, pp. 2302-2310.
Prepublished online as a Blood First Edition Paper on June 23, 2005; DOI 10.1182/blood-2005-01-0064.

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HEMATOPOIESIS

Membrane-bound and soluble IL-15/IL-15R{alpha} complexes display differential signaling and functions on human hematopoietic progenitors

Julien Giron-Michel, Massimo Giuliani, Manuela Fogli, Danièle Brouty-Boyé, Silvano Ferrini, Florence Baychelier, Pierre Eid, Caroline Lebousse-Kerdilès, Deniz Durali, Roberto Biassoni, Bernard Charpentier, Aimé Vasquez, Salem Chouaib, Anne Caignard, Lorenzo Moretta, and Bruno Azzarone

From the Medicina Istituto Gaslini and the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; U 542 and U 602 Institut National de la Santé et de la Recherche Médical (INSERM) Hôpital Paul Brousse; Laboratoire d'Oncologie Virale, Unité Propre de Recherche (UPR) 9045, Centre National de la Recherche Scientifique (CNRS); and U 487 INSERM, Institut Gustave Roussy (IGR); Villejuif, France.

Membrane-bound and soluble interleukin-15 (IL-15)/IL-15 receptor {alpha} (R{alpha}) complexes trigger differential transcription factor activation and functions on human hematopoietic progenitors. Indeed, human spleen myofibroblasts (SMFs) are characterized by a novel mechanism of IL-15 trans-presentation (SMFmb [membrane-bound]-IL-15), based on the association of an endogenous IL-15/IL-15R{alpha} complex with the IL-15R{beta}{gamma}c chains. SMFmb-IL-15 (1) induces lineage-specific signaling pathways that differ from those controlled by soluble IL-15 in unprimed and committed normal progenitors; (2) triggers survival and proliferation of leukemic progenitors expressing low-affinity IL-15R (M07Sb cells); (3) causes only an antiapoptotic effect on leukemic cells expressing high-affinity receptors (TF1{beta} cells). This behavior is likely due to the IL-15R{alpha} chain present on these cells that interact with the SMFmb-IL-15, inhibiting signal transducer and transcriptional activator 5 (STAT5) activation. On the other hand, the soluble IL-15/IL-15R{alpha} complex (hyper IL-15) displays a dominant pattern of action, activating only those cells expressing low-affinity IL-15R (IL-15R{beta}{gamma}c). Thus, hyper IL-15 induces antiapoptotic effects on M075b cells and the up-regulation of STAT6 activation on adult peripheral blood (PB) pre-natural killer (NK) committed progenitors. The latter effect using 100-fold concentrations of recombinant (r)-IL-15. In conclusion, SMFmb-IL-15 and soluble IL-15R{alpha}/IL-15 complexes seem to play a pivotal role in the control of the survival, proliferation and differentiation of both normal and leukemic circulating progenitors, highlighting new functions of IL-15 and of IL-15R{alpha}.


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