MECHANISMS OF LYMPHOID LINEAGE COMMITMENT

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by the applicant): The objectives of this revised application are to define how signals derived from interactions between IL-7 and its receptor promote the development and differentiation of common lymphoid precursors (CLPs) into early B cell precursors. IL-7 signaling is thought to regulate several key aspects of early lymphocyte differentiation, and mutations in the genes encoding IL-7 or its receptor are associated with severe combined immunodeficiency. We will use a variety of approaches to investigate how IL-7 receptor signaling influences CLP differentiation and survival and how these signals guide CLPs to differentiate into B cells versus early dendritic cell precursors. In the course of these studies, we hope to elucidate signaling pathways that are responsible for differentiation versus survival of early lymphocyte progenitors, and uncover the mechanisms by which early lymphoid precursors differentiate into B cells versus dendritic cells. Thus in Aim 1, we will exploit our observation that IL-7 alone promotes CLP differentiation into early B cell precursors to determine whether IL-7 acts to increase CLP survival or induce differentiation. In Aim 2, we will further exploit this observation by identifying which signaling pathways associated with IL-7 receptor function mediate this effect. In Aim 3, we will exploit our additional observation that CLPs and a unique subset of early B cell precursors each differentiate into dendritic cells when exposed to the appropriate cytokines. We find that loss of IL-7 receptor expression correlates with the capacity of early B-lineage cells to give rise to dendritic cells, and therefore will investigate whether IL-7 receptor signaling is important for guiding precursor cells away from the dendritic cell lineage and towards the B cell lineage. We will also investigate the possibility that early B-lineage cells constitute a developmental branch point for B and dendritic cell development by employing retroviral marking to identify progeny cells derived from these cells. The basic principles resolved by these studies should have relevance for the mechanisms underlying basic cellular differentiation and transformation, as well as immunodeficiency syndromes resulting from disruptions in cytokine signaling.