Flt3 ligand and granulocyte-macrophage colony-stimulating factor preferentially expand and stimulate different dendritic and T-cell subsets.
OBJECTIVE
Mechanisms of T-cell stimulation by Flt3 ligand (Flt3L) and granulocyte-macrophage colony-stimulating factor (GM-CSF) remain unclear. Herein, we compared the effects of Flt3L and GM-CSF on the expansion of dendritic cells (DC) and T-cell subsets and cytokine expression.


METHODS
Naïve and effector/memory T cells were analyzed by flow cytometry (FC). CD4(+) and CD8(+) T cells and CD11c(+)CD11b(dull/-)(DC1) and CD11c(+)CD11b(+) (DC2) subsets were isolated and the frequency of IFN-gamma-, IL-12- (type 1) and IL-4-, IL-10 (type 2)-producing cells and cytokine mRNA expression evaluated.


RESULTS
Flt3L expanded both DC1 and DC2 subsets with a significantly higher percentage and number of DC1 than DC2, while GM-CSF preferentially expanded the DC2 subset. Isolated DC1 from Flt3L-injected mice had significantly higher levels of IL-12 (p40) than IL-10, while the converse occurred with DC2. The numbers of naïve and memory T cells were elevated in mice that received Flt3L or GM-CSF. However, the number of memory CD4(+) and CD8(+) T cells was significantly increased in Flt3L as compared to GM-CSF cohorts. While GM-CSF increased the frequency of both type 1 and type 2 cytokine-producing cells, Flt3L significantly augmented the frequency of type 1 T cells.


CONCLUSIONS
In contrast to GM-CSF, Flt3L preferentially induces the expansion of type 1 T cells. The mechanism of Flt3L-induced T-cell stimulation is associated with the expansion of the IL-12 (p40)-producing DC1 and memory T cells.
Parajuli
P
P
Wayne State University School of Medicine, Karmanos Cancer Institute, Dept. of Neurologic Surgery, Detroit, Mich., USA.
Mosley
R L
RL
Pisarev
V
V
Chavez
J
J
Ulrich
A
A
Varney
M
M
Singh
R K
RK
Talmadge
J E
JE
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation / Q000379:methods; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000145:classification / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D019089:Stem Cell Factor / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D016207:Cytokines; D008565:Membrane Proteins; D012333:RNA, Messenger; D019089:Stem Cell Factor; C084881:flt3 ligand protein; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor