Murine Flt3 ligand expands distinct dendritic cells with both tolerogenic and immunogenic properties.
Human Flt3 ligand can expand dendritic cells (DC) and enhance immunogenicity in mice. However, little is known about the effects of murine Flt3 ligand (mFlt3L) on mouse DC development and function. We constructed a vector to transiently overexpress mFlt3L in mice. After a single treatment, up to 44% of splenocytes became CD11c(+) and the total number of DC increased 100-fold. DC expansion effects lasted for >35 days. mFlt3L DC were both phenotypically and functionally distinct. They had increased expression of MHC and costimulatory molecules and expressed elevated levels of B220 and DEC205 but had minimal CD4 staining. mFlt3L DC also had a markedly altered cytokine profile, including lowered secretion of IL-6, IL-10, IFN-gamma, and TNF-alpha, but had a slightly increased capacity to stimulate T cells in vitro. However, in a variety of in vivo models, DC expanded by mFlt3L induced tolerogenic effects on T cells. Adoptive transfer of Ag-pulsed mFlt3L splenic DC to naive mice actually caused faster rates of tumor growth and induced minimal CTL compared with control DC. mFlt3L also failed to protect against tumors in which human Flt3 ligand was protective, but depletion of CD4(+) T cells restored tumor protection. Our findings 1) demonstrate that mFlt3L has distinct effects on DC development, 2) suggest an important role for mFlt3L in generating DC that have tolerogenic effects on T cells, and 3) may have application in immunotherapy in generating massive numbers of DC for an extended duration.
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
DeMatteo
Ronald P
RP
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000502:physiology*; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D037181:Lectins, C-Type / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000276:immunology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D016827:CD8 Antigens; D007371:Interferon-gamma; D016753:Interleukin-10; D015850:Interleukin-6; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C431698:CD8alpha antigen; C093569:DEC-205 receptor; C084881:flt3 ligand protein