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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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Submitted January 7, 2005
Accepted May 16, 2005
Membrane-bound and soluble IL-15/IL-15R complexes display differential signalling and functions on human haematopoietic progenitors
Julien Giron-Michel, Massimo Giuliani, Manuela Fogli, Daniele Brouty-Boye, Silvano Ferrini, Florence Baychelier, Pierre Eid, Caroline Lebousse Kerdiles, Deniz Durali, Roberto Biassoni, Bernard Charpentier, Aime Vasquez, Salem Chouaib, Anne Caignard, Lorenzo Moretta, and Bruno Azzarone*
Medicina molecolare, Istituto Gaslini, Genova, Italy
U 542, INSERM Hopital Paul Brousse, Villejuif, France
U 602, INSERM Hopital Paul Brousse, Villejuif, France
Istituto Nazionale per la Ricerca sul Cancro IST, Genova, Italy
Laboratoire d'Oncologie Virale, UPR 9045, CNRS, Villejuif, France
U 487, INSERM, IGR, Villejuif, France
* Corresponding author; email: bazzarone{at}hotmail.com.
Membrane-bound and soluble IL-15/IL-15R complexes trigger differential transcription factors activation and functions on human haematopoietic progenitors.
Indeed, human spleen myofibroblasts are characterized by a novel mechanism of IL-15 trans-presentation (SMFmb-IL-15), based on the association of an endogenous IL-15/IL-15R complex with the IL-15R  c chains. SMFmb-IL-15 1) induces lineage-specific signalling pathways that differ from those controlled by soluble IL-15 in unprimed and committed normal progenitors, 2) triggers survival and proliferation of leukaemic progenitors expressing low affinity IL-15R (M07Sb cells), 3) causes only an anti-apoptotic effect on leukaemic cells expressing high affinity receptors (TF1 cells). This behaviour is likely due to the IL-15R chain present on these cells that interacting with the SMFmb-IL-15, inhibits STAT5 activation.
On the other hand, the soluble IL-15/IL-15R complex displays a dominant pattern of action activating only cells expressing low affinity IL-15R (IL-15Rc). Thus, this soluble complex induces on M07Sb cells anti-apoptotic effects and on adult PB pre-NK committed progenitors the up-regulation of STAT6 activation that is obtained only using 100-fold concentrations of r-IL-15.
In conclusion, SMFmb-IL-15 and soluble IL-15R/IL-15 complexes seem to play a pivotal role in the control of the survival, proliferation and differentiation of both normal and leukaemic circulating progenitors, highlighting new functions of IL-15 and of IL-15R.
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