Murine Flt3 ligand expands distinct dendritic cells with both tolerogenic and immunogenic properties Journal Article

Authors: Miller, G.; Pillarisetty, V. G.; Shah, A. B.; Lahrs, S.; DeMatteo, R. P.
Article Title: Murine Flt3 ligand expands distinct dendritic cells with both tolerogenic and immunogenic properties
Abstract: Human Flt3 ligand can expand dendritic cells (DC)(DQ 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-γ and TNF-α, 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.
Keywords: controlled study; nonhuman; lymphocyte proliferation; t-lymphocytes; animal cell; mouse; phenotype; animals; mice; cells, cultured; cell division; gene overexpression; spleen; dendritic cell; interleukin 10; cell line; animal experiment; animal model; membrane proteins; cell differentiation; in vitro study; mice, inbred c57bl; genetic vectors; colorectal carcinoma; immunological tolerance; antigen presentation; lymphocyte activation; dendritic cells; immune tolerance; tumor necrosis factor alpha; immunotherapy; tumor necrosis factor-alpha; gamma interferon; immunogenicity; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; lymphoma; melanoma cell; interleukin 6; interleukin-6; natural killer cell; adoptive transfer; killer cells, natural; cytokine production; cytotoxicity, immunologic; adenovirus vector; cd4 antigen; antigens, cd; tumor growth; flt3 ligand; adjuvants, immunologic; cd45 antigen; injections, intravenous; adenoviridae; spleen cell; receptors, cell surface; interleukin-10; antigens, cd8; gene transfer techniques; antigens, cd45; lectins, c-type; major histocompatibility antigen; glycoprotein p 15095; interferon type ii; humans; male; priority journal; article
Journal Title: Journal of Immunology
Volume: 170
Issue: 7
ISSN: 0022-1767
Publisher: The American Association of Immunologists, Inc  
Date Published: 2003-04-01
Start Page: 3554
End Page: 3564
Language: English
PUBMED: 12646617
PROVIDER: scopus
DOI: 10.4049/jimmunol.170.7.3554
Notes: Export Date: 12 September 2014 -- Source: Scopus
Citation Impact
MSK Authors
  1. George Miller
    18 Miller
  2. Ronald P DeMatteo
    635 DeMatteo
  3. Alaap Shah
    20 Shah
  4. Svenja   Lahrs
    9 Lahrs