Tumor necrosis factor alpha cooperates with interleukin 3 in the recruitment of a primitive subset of human CD34+ progenitors.
We have recently demonstrated that tumor necrosis factor alpha (TNF-alpha) potentiates interleukin 3 (IL-3) and granulocyte/macrophage colony-stimulating factor-induced growth of CD34+ hematopoietic progenitor cells (HPC), and favors the generation of dendritic/Langerhans cells. The stimulatory effect of TNF-alpha was detailed in the present study. Thus, CD34+ HPC entering in cycle (S/G2M) after a 48-h pulse with IL-3 expressed the transferrin receptor (TfR), and fluorescence-activated cell sorter-separated TfR+ HPC, but not TfR-HPC, showed a high proliferative response to IL-3. In contrast, TfR-HPC were found to undergo strong proliferation in response to IL-3 + TNF-alpha. Limiting dilution experiments indicated that TNF-alpha increased both the frequency and the average size of clones generated from TfR-HPC as a result of the development of a higher number of large clones. In contrast, TNF-alpha did not enhance the IL-3-dependent proliferation of TfR+ HPC. Preculturing CD34+ HPC for 48 h with TNF-alpha enhanced the subsequent generation of IL-3-dependent colony-forming units. Precultures with TNF-alpha or cultures with suboptimal doses of TNF-alpha allowed the recruitment of cells with both granulocytic and monocytic differentiation potential. Taken together, our results indicate that TNF-alpha recruits a subpopulation of CD34+ HPC hyposensitive to IL-3, with high proliferative capacity and some features of multipotential progenitors, that are likely to be more primitive than those responding to IL-3 alone.
Caux
C
C
Laboratory for Immunological Research, Schering-Plough, Dardilly, France.
Durand
I
I
Moreau
I
I
Duvert
V
V
Saeland
S
S
Banchereau
J
J
D015703:Antigens, CD / Q000032:analysis*; D018952:Antigens, CD34; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D011990:Receptors, Transferrin / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D018952:Antigens, CD34; D007377:Interleukin-3; D011990:Receptors, Transferrin; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor