HEMATOPOIETIC AND LUNG ABNORMALITIES IN MICE WITH A NULL MUTATION OF THE COMMON BETA-SUBUNIT OF THE RECEPTORS FOR GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AND INTERLEUKIN-3 AND INTERLEUKIN-5

Gene targeting was used to create mice with a null mutation of the gene encoding the common beta subunit (beta(C)) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3; multi-CSF), and interleukin 5 (IL-5) receptor complexes (beta(C)(-/-) mice). High-affinity binding of GM-CSF was abolished in beta(C)(-/-) bone marrow cells, while cells from heterozygous animals (beta(C)(+/-) mice) showed an intermediate number of high-affinity receptors, Binding of IL-3 was unaffected, confirming that the IL-3-specific beta chain remained intact, Eosinophil numbers in peripheral blood and bone marrow of beta(C)(-/-) animals were reduced, while other hematological parameters were normal, In clonal cultures of beta(C)(-/-) bone marrow cells, even high concentrations of GM-CSF and IL-5 failed to stimulate colony formation, but the cells exhibited normal quantitative responsiveness to stimulation by IL-3 and other growth factors, beta(C)(-/-) mice exhibited normal development and survived to young adult life, although they developed pulmonary peribronchovascular lymphoid infiltrates and areas resembling alveolar proteinosis. There was no detectable difference in the systemic clearance and distribution of GM-CSF between beta(C)(-/-) and wild-type littermates, The data establish that beta(C) is normally limiting for high-affinity binding of GM-CSF and demonstrate that systemic clearance of GM-CSF is not mediated via such high-affinity receptor complexes.