THE ROLE OF THE IKAROS GENE IN LYMPHOCYTE DEVELOPMENT AND HOMEOSTASIS

The Ikaros gene, which encodes a family of hemopoietic-specific zinc f inger proteins, is described as a central regulator of lymphocyte diff erentiation. During fetal development, it is required at the earliest stage of T cell and B cell specification. In the adult, however, lymph oid lineages rely on Ikaros at distinct phases of their development. I ts activity is essential for the generation of B cell but not of T cel l precursors, although the differentiation of the latter is not normal . A significant increase in CD4 thymocytes and their immediate precurs ors is detected, and because these cells lack markers that correlate w ith positive selection, a deregulation in their maturation process is suggested. Furthermore, Ikaros-null thymocytes hyperproliferate in res ponse to T cell receptor (TCR) signaling; within days after their appe arance in the thymus, clonally expanding populations are detected. Der egulated TCR-mediated responses and the fast kinetics of tumor develop ment in these mutant thymocytes implicate Ikaros as a central tumor su ppressor gene for the T cell lineage. In addition, lack of natural kil ler cells and selective defects in gamma delta T cells and dendritic a ntigen-presenting cells point to Ikaros as an essential factor for the establishment of early branchpoints of the T cell pathway. The domina nt interference activity of Ikaros isoforms unable to bind DNA and the ir effects in lymphocyte development suggest that Ikaros works in conc ert with other factors. The role of Aiolos, a lymphoid-restricted and structurally related gene, in lymphoid differentiation is discussed. A model is proposed that defines Ikaros as the backbone of a complex re gulatory protein network that controls cell fate decisions and regulat es homeostasis in the hemo-lymphoid system. Changes in this regulatory network may reflect differentiation and proliferation adjustments mad e in hemo-lymphoid progenitors and precursors as they give rise to the cells of our immune system.