Defective Flt3L driven DC development in the absence of Ikaros (111.35)

Abstract

Abstract Ikaros null (Ik-) mice have impaired dendritic cell (DC) development. This defect is recapitulated when Ik- bone marrow (BM) is cultured with Flt3L, a DC growth factor. Ik- BM cultures generate significantly fewer DCs than their wild type (WT) counterparts. This phenotype is specific to Flt3L-driven DC developments as Ik- GM-CSF cultures generate normal numbers of DCs. Time course gene expression analyses of Flt3L-cultures show that genes important for DC development such as Irf4, Irf8 and Spib are variably under-expressed in both Ik- progenitors and mature DCs, with Spib being the most affected. These data demonstrate that low expression of DC genes is not solely due to decreased DC differentiation and suggest that Ikaros may regulate their expression, which we are now exploring. The DCs that develop in Ik- Flt3L cultures are also qualitatively different from their WT counterparts. They have an activated phenotype, implicating Ikaros in regulation of DC function as well. Enforced expression of full-length Ikaros (Ik1) in Ik- BM cannot restore Flt3L-driven DC development, suggesting a different Ikaros isoform may be needed for DC rescue. Studies now underway will define Ikaros isoform expression during DC development and determine if enforced expression of discrete Ikaros isoforms or the Flt3 receptor itself can restore Flt3L-driven DC development in Ik- BM. These studies will place Ikaros relative to Flt3 signals during DC development and define its molecular role.