Endogenous granulocyte-macrophage colony-stimulating factor overexpression in vivo results in the long-term recruitment of a distinct dendritic cell population with enhanced immunostimulatory function.
GM-CSF is critical for dendritic cell (DC) survival and differentiation in vitro. To study its effect on DC development and function in vivo, we used a gene transfer vector to transiently overexpress GM-CSF in mice. We found that up to 24% of splenocytes became CD11c+ and the number of DC increased up to 260-fold to 3 x 10(8) cells. DC numbers remained substantially elevated even 75 days after treatment. The DC population was either CD8alpha+CD4- or CD8alpha-CD4- but not CD8alpha+CD4+ or CD8alpha-CD4+. This differs substantially from subsets recruited in normal or Flt3 ligand-treated mice or using GM-CSF protein injections. GM-CSF-recruited DC secreted extremely high levels of TNF-alpha compared with minimal amounts in DC from normal or Flt3 ligand-treated mice. Recruited DC also produced elevated levels of IL-6 but almost no IFN-gamma. GM-CSF DC had robust immune function compared with controls. They had an increased rate of Ag capture and caused greater allogeneic and Ag-specific T cell stimulation. Furthermore, GM-CSF-recruited DC increased NK cell lytic activity after coculture. The enhanced T cell and NK cell immunostimulation by GM-CSF DC was in part dependent on their secretion of TNF-alpha. Our findings show that GM-CSF can have an important role in DC development and recruitment in vivo and has potential application to immunotherapy in recruiting massive numbers of DC with enhanced ability to activate effector cells.
Miller
George
G
Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Pillarisetty
Venu G
VG
Shah
Alaap B
AB
Lahrs
Svenja
S
Xing
Zhou
Z
DeMatteo
Ronald P
RP
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology; D000818:Animals; D000941:Antigens / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000517:prevention & control; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005822:Genetic Vectors / Q000008:administration & dosage; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007275:Injections, Intravenous; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000033:anatomy & histology / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology
D000276:Adjuvants, Immunologic; D000941:Antigens; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor