Grant: Discovery Grants Program - Individual

Cells can respond to the their environment through interaction with proteins released from other cells as well as direct interactions with other cells. However, recently, it has been appreciated that cells can also communicate with each other through vesicles that are either secreted, called exosomes, or bud off from the plasma membrane, called microvesicles (MV). Collectively exosomes and MV are termed extracellular vesicles (EV). EV are coated with selected cellular proteins and filled with intracellular membrane and cytosolic proteins, as well as regulatory RNA and mRNA. The transfer of proteins and RNA from donor cells via EV can cause the recipient cells to take on new functions and characteristics. B lymphocytes (B cells) are the antibody-producing cells of the immune system. It is important that B cell development is properly regulated to acquire a properly functioning immune system. Recently, we found that immature B cells release MV when a cell surface receptor called CD24 is stimulated to mimic ligand-mediated clustering. These MV carry CD24 on their surface and caused a redistribution of CD24 among the B cell population. It is known that clustering of CD24 causes apoptosis of immature B cells however the function of the CD24-bearing MV is not known. In addition, the mechanisms that regulate MV release in general are poorly understood. Finally, it is not clear how CD24 can promote the generation of MV since it is anchored to the outside of the cell and it does not have a transmembrane domain through which to transmit signals into the cell. Thus, the goal of this proposal is to understand how these MV are generated and the role that they play in regulating cell-cell communication between B cells and target cells. Immature B cells develop in the bone marrow in close proximity to cells that support B cell development, which are called stromal cells. Therefore, we will first determine if MV can be taken up by stromal cells to affect their function. Next, we will identify the key pathways that regulate the generation of MV and determine if MV generation is a common response upon engagement of other receptors. Lastly, we will identify the key partners that allow CD24 to transmit signals into the cell. Overall, these studies will advance our understanding of how MV can regulate recipient cell function and significantly increase our understanding of how MV are generated. Moreover, this work may provide novel insights into how MV can contribute to B cell development. Understanding the role and regulation of MV will impact all areas of cell biology as EV are highly conserved mediators of cell-cell communication.