Detection of a Functional Hybrid Receptor γc/GM-CSFRβ in Human Hematopoietic CD34⁺ Cells

A functional hybrid receptor associating the common γ chain (γc) with the granulocyte/macrophage colony-stimulating factor receptor β (GM-CSFRβ) 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⁺ TF1β cells, which express an interleukin (IL)-15Rα/β/γc receptor, that within the hybrid receptor, the GM-CSFRβ chain inhibits the IL-15–triggered γc/JAK3-specific signaling controlling TF1β cell proliferation. However, the γc chain is part of a functional GM-CSFR, activating GM-CSF–dependent STAT5 nuclear translocation and the proliferation of TF1β 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-15Rβ chain, nevertheless expresses both a functional hybrid receptor that controls JAK3 phosphorylation and a novel IL-15α/γc/TRAF2 complex that triggers nuclear factor κB 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.