Murine Flt3 Ligand Expands Distinct Dendritic Cells with Both Tolerogenic and Immunogenic Properties

Abstract

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-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.

Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-α induction pathway

“…1A). Our results are consistent with studies with psoralen-UV-inactivated recombinant Ad (31,32), where transcriptionally inactive viral templates were found to induce BMDC maturation as efficiently as unmodified virus. Therefore, BMDC maturation in response to Ad exposure does not depend on efficient gene expression associated with the high affinity uptake pathway known to function with CAR-containing cell lines.…”

Immunostimulatory effect of Fms-like tyrosine kinase 3 ligand on peripheral monocyte-derived dendritic cells and natural killer cells: Utilization for ovarian cancer treatment

“…Previous reports suggested the risk that systemically administered FLT3L could induce immunotolerance in vivo by increasing immature DCs (17)(18)(19)(20)(21), although others reported contrary findings (4,15). These conflicting data suggest that FLT3L may give rise to immunotolerance if administered systemically, and the enhancement of tumor immunity mainly depends on the circumstances where local immune response is evoked.…”

Spleen but not tumor infiltration by dendritic and T cells is increased by intravenous adenovirus-Flt3 ligand injection

“…Instead, accelerated tumor growth occurred after challenge with a tumor expressing the relevant peptide. 24 These, as well as other studies, have suggested that Flt3L, like other cytokines, 25 can stimulate the expansion of immature myeloid suppressor cells (IMSCs). These cells have the potential to promote tumor escape from immune control by inhibiting adaptive immune responses, DC function, and infiltration of tumors with T cells, resulting in the suppression of T-cell control of tumor progression and growth.…”

“…20 Flt3L has been reported to exhibit a paradoxical profile; in some cases, it has been found to expand DCs in the absence of a therapeutic response and to induce tolerance. 24 Furthermore, in some studies when adenovirus-(Adv-) Flt3L-expanded DCs were loaded with tumor peptides and used as a vaccine, no protection was observed. Instead, accelerated tumor growth occurred after challenge with a tumor expressing the relevant peptide.…”