Detection of a Functional Hybrid Receptor gamma c/GM-CSFR beta in Human Hematopoietic CD34 super(+) Cells

A functional hybrid receptor associating the common gamma chain ( gamma c) with the granulocyte/macrophage colony-stimulating factor receptor beta (GM-CSFR beta ) chain is found in mobilized human peripheral blood (MPB) CD34 super(+) hematopoietic progenitors, SCF/Flt3-L primed cord blood (CB) precursors (CB super(Pr) CD34 super(+)/CD56 super(-)), and CD34 super(+) myeloid cell lines, but not in normal natural killer (NK) cells, the cytolytic NK-L cell line or nonhematopoietic cells. We demonstrated, using CD34 super(+) TF1 beta cells, which express an interleukin (IL)-15R alpha / beta / gamma c receptor, that within the hybrid receptor, the GM-CSFR beta chain inhibits the IL-15-triggered gamma c/JAK3-specific signaling controlling TF1 beta cell proliferation. However, the gamma c chain is part of a functional GM-CSFR, activating GM-CSF-dependent STAT5 nuclear translocation and the proliferation of TF1 beta 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-15R beta chain, nevertheless expresses both a functional hybrid receptor that controls JAK3 phosphorylation and a novel IL-15 alpha / gamma c/TRAF2 complex that triggers nuclear factor alpha 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.