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Detection of a Functional Hybrid Receptor c/GM-CSFRß in Human Hematopoietic CD34⁺ Cells

J. Giron-Michel^1,9, M. Fogli², A. Gaggero³, S. Ferrini³, A. Caignard⁴, D. Brouty-Boyé⁵, S. Baouz¹, M.-C. Le Bousse-Kerdilès⁵, B. Péault¹, M. van Dijk⁶, S. Bulfone-Paus⁷, D. Durali⁸, S. Chouaib⁴ and B. Azzarone^1,9

¹ U 506 Institut National de la Sante et de la Recherche Medicale (INSERM), Hôpital Paul Brousse, 94807 Villejuif, France
² Istituto Gaslini, Largo Gerolamo Gaslini 516147 Genoa, Italy
³ Istituto Nazionale per la Ricerca sul Cancro, IST, Largo Rosanna Benzi 16132 Genoa, Italy
⁴ U 487 INSERM, IGR, 94800 Villejuif, France
⁵ U 268 INSERM, Hôpital Paul Brousse, 94807 Villejuif, France
⁶ GenMab B.V. University Medical Center Immunotherapy Laboratory, KC02.85.2 Lundlaan 6 3584 EA Utrecht, Netherlands
⁷ Forshungzentrum Borstel, Parkallee 22, D-23845 Borstel, Germany
⁸ INSERM E-0109, Bicêtre, France
⁹ U 542 INSERM, Hôpital Paul Brousse, 94807 Villejuif, France

Address correspondence to Dr. Bruno Azzarone, INSERM U542, Bâtiment Lavoisier, Hôpital Paul Brousse, 94807 Villejuif, France. Phone: 00-33-145595344; Fax: 00-33-145595343; E-mail: bazzarone{at}hotmail.com

A functional hybrid receptor associating the common chain (c) with the granulocyte/macrophage colony-stimulating factor receptor ß (GM-CSFRß) chain is found in mobilized human peripheral blood (MPB) CD34⁺ hematopoietic progenitors, SCF/Flt3-L primed cord blood (CB) precursors (CB^Pr CD34⁺/CD56^-), and CD34⁺ myeloid cell lines, but not in normal natural killer (NK) cells, the cytolytic NK-L cell line or nonhematopoietic cells. We demonstrated, using CD34⁺ TF1ß cells, which express an interleukin (IL)-15R/ß/c receptor, that within the hybrid receptor, the GM-CSFRß chain inhibits the IL-15–triggered c/JAK3-specific signaling controlling TF1ß cell proliferation. However, the c chain is part of a functional GM-CSFR, activating GM-CSF–dependent STAT5 nuclear translocation and the proliferation of TF1ß cells. The hybrid receptor is functional in normal hematopoietic progenitors in which both subunits control STAT5 activation. Finally, the parental TF1 cell line, which lacks the IL-15Rß chain, nevertheless expresses both a functional hybrid receptor that controls JAK3 phosphorylation and a novel IL-15/c/TRAF2 complex that triggers nuclear factor B activation. The lineage-dependent distribution and function of these receptors suggest that they are involved in hematopoiesis because they modify transduction pathways that play a major role in the differentiation of hematopoietic progenitors.

Key Words: IL-15 • GM-CSF • IL-15R • signal transduction • CD34⁺ cells

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