Role of Ikaros in mast cell development and differentiation (138.21)

Abstract

Abstract The transcription factor Ikaros has been implicated in the regulation of hematopoiesis at the level of T, B, NK and dendritic cells. In this study we examine the role of Ikaros in the development and differentiation of mast cells, using mice lacking Ikaros (Iknull). In vitro derived bone marrow mast cells (BMMCs) from Iknull mice expressed decreased levels of mRNA encoding transcription factors required for optimal mast cell development (MITF, GATA1, GATA2 and STAT5a), and mast cell-specific proteases (chymase, tryptase and carboxypeptidase). Upon activation through FcεRI crosslinking, Iknull mast cells revealed a hyper-activation phenotype as assessed by increased degranulation, cytokine secretion and expression of co-stimulatory molecules including OX40 ligand. Furthermore, Iknull BMMCs expressed reduced levels of several cell surface adhesion molecules and integrins including CD49d (integrin alpha 4), which is required for homing of mast cell precursors to the intestine. Consistent with this observation, in vivo examination of Iknull mice for presence of mast cells in various tissues revealed a striking deficiency of mast cells in the peritoneal cavity, and limiting dilution analysis demonstrated severely reduced number of mast cell precursors in the intestine. Taken together, our data suggest that Ikaros plays an important role in mast cell development, differentiation and activation. This research has been supported by JDRF-3-2007-617 and NIH RO1 CA047992.