Role and regulation of extracellular vesicles generated in response to stimulation of CD24 on B lymphocytes

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Extracellular vesicles (EVs) are a group of heterogenous lipid bilayer-bound vesicles that are released from all cells and classified based on biogenesis. Exosomes are released from multivesicular bodies while microvesicles bud off the plasma membrane. Both exosomes and microvesicles carry protein, lipid, and nucleic acid cargo that can be transferred from donor to recipient cells. This transfer can cause changes to recipient cell function, including, as we have found, a gain of apoptosis-inducing receptors that can promote cell death of recipient cells. B lymphocytes (B cells) are the antibody-producing cells of the immune system. B cells undergo a multi-stage developmental process in the bone marrow. The receptor CD24 (alias heat stable antigen) is highly expressed on B cells earlier in development (pro- and pre-B cells) followed by decreased expression when they mature. CD24 is known to induce apoptosis in developing B cells. My group was the first to show that stimulation of CD24 induces the release of EVs from B cells. We found that CD24 regulates the packaging of different surface receptors on EVs. We also found that both CD24 and IgM stimulation of B cells causes transfer of a functional B cell receptor (BCR) and functional CD24 to recipient cells via EVs. These data show that EVs released by stimulated B cells can create recipient cells with increased sensitivity to CD24-induced apoptosis. In addition, this transfer creates B cells that express BCRs with more than one antigen-binding specificity; a direct contradiction to the dogma that B cells can only express one BCR. The induction of apoptosis by transfer of functional receptors suggests that CD24 may be acting as a homeostatic regulator where increased activation of CD24 increases the level of pro-apoptotic receptors on bystander recipient cells. This would enhance the sensitivity of recipient cells to pro-apoptotic ligands. Thus, transfer of receptors by EVs is a potential mechanism to regulate cell abundance in the bone marrow. My long-term DG program is focused on understanding the role that EVs play in regulating B cell development in the bone marrow. In the next 5 years, I plan to address the following 3 objectives. 1. Elucidate the signaling pathways by which CD24 stimulates EV release. 2. Identify the co-receptor for CD24 on bone marrow B cells. 3. Identify the bone marrow cells that are affected by EVs released from B cells in response to CD24. This work will directly impact our understanding of how EVs are generated and how EVs may contribute to B cell development. Thus, increasing our global understanding of the role and regulation of EVs, which may influence many areas of cell biology as EVs are highly conserved mediators of cell-cell communication. In addition, undergraduate and graduate students will be trained in state-of-the-art cellular and molecular techniques positioning them for success in their future scientific careers.