Immune regulatory activity of CD34+ progenitor cells: evidence for a deletion-based mechanism mediated by TNF-alpha.
Previous studies suggest that cells within the CD34(+) hematopoietic stem cell compartment are endowed with immune regulatory activity. Furthermore, it is possible to expand the human regulatory cells upon short-term culture of purified CD34+ cells with an early-acting cytokine cocktail. We now show that addition of anti-CD28, anti-CD2, interleukin-2 (IL-2), anti-IL-10, or IL-12 to the bulk mixed lymphocyte reaction (MLR) cannot reverse the inhibitory activity of the CD34+ cells, ruling out anergy-based mechanisms or mechanisms involving Th1-Th2 skewing. Furthermore, phenotyping of cells present after addition of CD34+ cells to the bulk MLR ruled out potential induction of plasmacytoid dendritic precursors, known to be endowed with regulatory activity. In contrast, the inhibitory activity of CD34+ cells could be reversed by adding the caspase inhibitor BD-FMK to the bulk MLR, indicating a deletion-based mechanism. The deletion can be inhibited by anti-tumor necrosis factor-alpha (anti-TNF-alpha) and not by anti-transforming growth factor-beta (anti-TGF-beta), suggesting a potential role for TNF-alpha in the regulatory activity of CD34+ cells.
Department of Immunology, Weizmann Institute of Science, POB 26, Rehovot 76100, Israel.
Hilit
H
Gur
Rita
R
Krauthgamer
Esther
E
Bachar-Lustig
Helena
H
Katchman
Rinat
R
Arbel-Goren
Alain
A
Berrebi
Tirza
T
Klein
Arnon
A
Nagler
Antonio
A
Tabilio
Massimo F
MF
Martelli
Yair
Y
Reisner
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018952:Antigens, CD34; D061945:Caspase Inhibitors; D020169:Caspases / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases