Flt3-ligand and granulocyte colony-stimulating factor mobilize distinct human dendritic cell subsets in vivo.
Dendritic cells (DCs) have a unique ability to stimulate naive T cells. Recent evidence suggests that distinct DC subsets direct different classes of immune responses in vitro and in vivo. In humans, the monocyte-derived CD11c+ DCs induce T cells to produce Th1 cytokines in vitro, whereas the CD11c- plasmacytoid T cell-derived DCs elicit the production of Th2 cytokines. In this paper we report that administration of either Flt3-ligand (FL) or G-CSF to healthy human volunteers dramatically increases distinct DC subsets, or DC precursors, in the blood. FL increases both the CD11c+ DC subset (48-fold) and the CD11c- IL-3R+ DC precursors (13-fold). In contrast, G-CSF only increases the CD11c- precursors (>7-fold). Freshly sorted CD11c+ but not CD11c- cells stimulate CD4+ T cells in an allogeneic MLR, whereas only the CD11c- cells can be induced to secrete high levels of IFN-alpha, in response to influenza virus. CD11c+ and CD11c- cells can mature in vitro with GM-CSF + TNF-alpha or with IL-3 + CD40 ligand, respectively. These two subsets up-regulate MHC class II costimulatory molecules as well as the DC maturation marker DC-lysosome-associated membrane protein, and they stimulate naive, allogeneic CD4+ T cells efficiently. These two DC subsets elicit distinct cytokine profiles in CD4+ T cells, with the CD11c- subset inducing higher levels of the Th2 cytokine IL-10. The differential mobilization of distinct DC subsets or DC precursors by in vivo administration of FL and G-CSF offers a novel strategy to manipulate immune responses in humans.
Pulendran
B
B
Baylor Institute for Immunology Research, Dallas, TX 75204, USA.
Banchereau
J
J
Burkeholder
S
S
Kraus
E
E
Guinet
E
E
Chalouni
C
C
Caron
D
D
Maliszewski
C
C
Davoust
J
J
Fay
J
J
Palucka
K
K
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000502:physiology*; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D016167:Integrin alphaXbeta2 / Q000096:biosynthesis; D016898:Interferon-alpha / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D016207:Cytokines; D016167:Integrin alphaXbeta2; D016898:Interferon-alpha; D008024:Ligands; D008565:Membrane Proteins; C084881:flt3 ligand protein; D016179:Granulocyte Colony-Stimulating Factor