Dendritic cells (DC) are versatile immune cells that can promote protective anti-pathogen immunity or dampen destructive autoimmune responses. Fms-like tyrosine kinase 3-ligand (FLT3L) signals through the FLT3 receptor to drive DC differentiation and proliferation. We generated a novel mouse-FLT3L—human-FC-domain (FLT3L-FC) fusion construct that, when combined with hydrodynamic gene delivery (HDT), induces robust DC expansion in vivo. In particular, FLT3L-FC HDT induced expansion of surface marker-defined tolerogenic DC subsets. Given the central role of DC in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), we investigated the action of FLT3L-FC in EAE. Prophylactic treatment of mice with FLT3L-FC HDT (a single i.v. injection of 10 ug of plasmid DNA) significantly suppressed the onset and clinical severity of EAE, and significantly reduced the number of inflammatory foci in CNS parenchyma. FLT3L-FC HDT in EAE mice induced expansion of peripheral (spleen) and CNS-infiltrating tolerogenic DC, as well as peripheral CD4+ regulatory T cells (Tregs), which we speculate underlies the cellular mechanism of EAE suppression by FLT3L. Our results therefore support the emerging paradigm that the fundamental action of FLT3L in vivo is immune suppression.
- Copyright © 2013 by The American Association of Immunologists, Inc.