Development and function of myeloid-derived suppressor cells generated from mouse embryonic and hematopoietic stem cells.
Emerging evidence suggests that myeloid-derived suppressor cells (MDSCs) have great potential as a novel immune intervention modality in the fields of transplantation and autoimmune diseases. Thus far, efforts to develop MDSC-based therapeutic strategies have been hampered by the lack of a reliable source of MDSCs. Here we show that functional MDSCs can be efficiently generated from mouse embryonic stem (ES) cells and bone marrow hematopoietic stem (HS) cells. In vitro-derived MDSCs encompass two homogenous subpopulations: CD115(+)Ly-6C(+) and CD115(+)Ly-6C(-) cells. The CD115(+)Ly-6C(+) subset is equivalent to the monocytic Gr-1(+)CD115(+)F4/80(+) MDSCs found in tumor-bearing mice. In contrast, the CD115(+)Ly-6C(-) cells, a previously unreported population of MDSCs, resemble the granulocyte/macrophage progenitors developmentally. In vitro, ES- and HS-MDSCs exhibit robust suppression against T-cell proliferation induced by polyclonal stimuli or alloantigens via multiple mechanisms involving nitric oxide synthase-mediated NO production and interleukin (IL)-10. Impressively, they display even stronger suppressive activity and significantly enhance ability to induce CD4(+)CD25(+)Foxp3(+) regulatory T-cell development compared with tumor-derived MDSCs. Furthermore, adoptive transfer of ES-MDSCs can effectively prevent alloreactive T-cell-mediated lethal graft-versus-host disease, leading to nearly 82% long-term survival among treated mice. The successful in vitro generation of MDSCs may represent a critical step toward potential clinical application of MDSCs.
Zhou
Zuping
Z
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
French
Deborah L
DL
Ma
Ge
G
Eisenstein
Samuel
S
Chen
Ying
Y
Divino
Celia M
CM
Keller
Gordon
G
Chen
Shu-Hsia
SH
Pan
Ping-Ying
PY
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control / Q000601:surgery; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000502:physiology*; D007111:Immunity, Cellular / Q000502:physiology; D007165:Immunosuppression Therapy / Q000379:methods*; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D033581:Stem Cell Transplantation / Q000379:methods*; D013601:T-Lymphocytes / Q000276:immunology
D000954:Antigens, Surface; D016753:Interleukin-10; D009569:Nitric Oxide