The eosinophil is a central effector cell in allergic asthma. Differentiation and function of eosinophils is regulated by interleukin (IL)‐3, IL‐5 and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), which all signal through a common β receptor subunit (βc). Recent therapeutic approaches targeting IL‐5 alone have had limited effects on disease progression. By employing mice lacking the βc and βIL‐3 receptor subunits we were able to interrupt signalling through all three eosinophilopoietic cytokines and prevent allergen‐induced expansion and accumulation of eosinophils in the lung in a mouse model of allergic airways inflammation. Moreover, βc deficiency resulted in inhibition of hallmark features of asthma including airways hypersensitivity, mucus hypersecretion and antigen‐specific IgE. Surprisingly, we also identified a critical role for the βc in regulating type 2 immunity. Th2 cells in the lung of allergen‐challenged βc−/− mice were limited in their ability to proliferate, produce cytokines and migrate to effector sites, which was attributed to reduced numbers of myeloid dendritic cells in the lung compartment. Thus the βc subunit plays a critical role in allergen‐induced eosinophil responses and is pivotal in regulating molecules that promote both early and late phases of allergic inflammation, representing a novel target for therapy. (Supported by the NIH and NHMRC)

The ligand for flt-3 (FLT3L) exhibits striking structural homology with stem cell factor (SCF ) and monocyte colony-stimulating factor (M-CSF ) and also acts in synergy with a range of other hematopoietic growth factors (HGF ). In this study, we show that FLT3L responsive hematopoietic progenitor cells (HPC) are CD34+CD38−, rhodamine 123dull, and hydroperoxycyclophosphamide (4-HC) resistant. To investigate the basis for the capacity of FLT3L to augment the de novo generation of myeloid progenitors from CD34+CD38− cells, single bone marrow CD34+CD38− cells were sorted into Terasaki wells containing serum-free medium supplemented with interleukin-3 (IL-3), IL-6, granulocyte colony-stimulating factor (G-CSF ), SCF (4 HGF ) ± FLT3L. Under these conditions, FLT3L recruited approximately twofold more CD34+CD38− cells into division than 4 HGF alone. The enhanced proliferative response to FLT3L was evident by day 3 and was maintained at all subsequent time points examined. In accord with these findings, we also show that transduction of CD34+CD38− cells with the LAPSN retrovirus is enhanced by FLT3L. The results of these experiments therefore indicate that increased recruitment of primitive HPC into cell cycle underlies the ex vivo expansion potential of FLT3L and also its ability to improve retroviral transduction of HPC.

A direct interaction between the erythropoietin (EPOR) and the beta-common (βc) receptors to form an Innate Repair Receptor (IRR) is controversial. On one hand, studies have shown a functional link between EPOR and βc receptor in tissue protection while others have shown no involvement of the βc receptor in tissue repair. To date there is no biophysical evidence to confirm a direct association of the two receptors either in vitro or in vivo. We investigated the existence of an interaction between the extracellular regions of EPOR and the βc receptor in silico and in vitro (either in the presence or absence of EPO or EPO-derived peptide ARA290). Although a possible interaction between EPOR and βc was suggested by our computational and genomic studies, our in vitro biophysical analysis demonstrates that the extracellular regions of the two receptors do not specifically associate. We also explored the involvement of the βc receptor gene (Csf2rb) under anaemic stress conditions and found no requirement for the βc receptor in mice. In light of these studies, we conclude that the extracellular regions of the EPOR and the βc receptor do not directly interact and that the IRR is not involved in anaemic stress.