Flt3 ligand generates morphologically distinct semimature dendritic cells in ovalbumin-sensitized mice

Abstract

Dendritic cells (DCs) are unique antigen presenting cells that are immature prior to their encounter with an antigen. Exposure to allergens induces the maturation of DCs with changes in morphology and presence of dendrites. Here, we demonstrate that the DCs in the lungs of ovalbumin (OVA)-sensitized and challenged mice are more mature owing to their pronounced dendrites than the DCs in the lungs and spleen of PBS-treated mice, which are immature and possess cytoplasmic veils. Intermediate to these two groups are the DCs in the Flt3 ligand-treated group that exhibit comparatively fewer dendrites and cytoplasmic veils and hence are classified as semimature. Presence of large numbers of well developed mitochondria and rough endoplasmic reticulum in myeloid DCs from both lungs and spleen of OVA-sensitized and challenged mice indicate greater functional activity. Additionally, DCs from the OVA-sensitized and challenged mice also exhibit fat and glycogen stores, which are indicative of a mature population. In addition, treatment of the animals with Flt3 ligand attenuated airway hyperresponsiveness to methacholine in OVA-sensitized and challenged mice. These data suggest that morphological features could be indicative of the maturation and distinct functional state of DCs, and this could be associated with underlying mechanisms of Flt3 ligand-induced immunomodulation in allergic asthma.

Fms-like tyrosine kinase 3 ligand increases a lung DC subset with regulatory properties in allergic airway inflammation

“…Sensitized and non-sensitized controls received the same volume of PBS i.p. OVA sensitization significantly expanded the CD11c + DC population in the lungs (data not shown), which was consistent with the data in our previous reports 17, 18. The frequency of each DC population demonstrated a dynamic change in response to OVA sensitization and Flt3-L treatment.…”

“…Earlier reports have suggested the expansion of both myeloid (CD11c + CD11b + CD8α − ) and lymphoid (CD11c + CD11b − CD8α + ) DC subsets following Flt-L administration 16. We observed an increase in the number of lung DCs following the administration of Flt3-L 17, 18 and Flt3-L prevented and reversed allergic airway inflammation and AHR in a mouse model of asthma 18–20. Additionally, the phenotype and function of DCs may be tissue-specific and they could vary depending on different isolation techniques employed 21.…”

Fms-Like Tyrosine Kinase 3 Ligand Regulates Migratory Pattern and Antigen Uptake of Lung Dendritic Cell Subsets in a Murine Model of Allergic Airway Inflammation

“…The inefficiency Ag uptake has been reported in spleen DCs in Flt3L-treated mice (12), and our group has reported that the Flt3L-generated lung and spleen DCs exhibit a semimature phenotype indicated by fewer dendrites and cytoplasmic veils (24). These findings somewhat contradict the traditional belief that Flt3L facilitates the DC maturation.…”

Pathogenesis of Allergic Airway Inflammation

“…The therapeutic effect of Flt3-L is achieved through facilitating the generation of regulatory CD11c high CD11b low lung DC subset, impairing migration of immunogenic CD11c low CD11b high DC subset to draining lymph node and antigen uptake in immunogenic CD11c low CD11b high DC subset (9, 90–92), and increasing the density of CD4 + CD25 + Foxp3 + ICOS + T-regulatory cells (93) in the lungs of asthmatic mice. Thus, Flt3-L may prove to be a novel adjuvant therapy in bronchial asthma.…”