The mechanisms that underlie effective B cell memory formation, maintenance and function are poorly understood. We have a long-standing interest in this area and have made significant contributions. Here, we describe intriguing observations suggesting that activation of bone morphogenetic protein receptor 1a (Bmpr1a) is critical in the germinal center reaction and is required for the development of long-lived bone marrow plasma cells (BMPC) and memory B cells (MBC). As Bmpr1a, a TGF- family receptor, transduces signals that regulate self-renewal and differentiation decisions in several stem cell populations, we hypothesize that it plays analogous roles in GC B cells (GCB) and MBC as well. The first part of the proposal addresses the role of Bmpr1a activation in GCB function and in the formation of BMPC. We ask if Bmpr1a activation regulates proliferation or apoptosis of GCB and if its activation is directly required for differentiation of GBC to BMPC. We also propose construction of a Bmpr1a fluorescent reporter mouse to ask if Bmpr1a expression is a characteristic of all GCB or a restricted subset, suggesting a specialized function of Bmpr1a+ GCB. The second part of the proposal addresses the role of Bmpr1a activation in MBC and BMPC. We will determine if this pathway enables MBC to self-renew and if it supports the long-term survival of BMPC. We will also ask if, in the secondary response, Bmpr1a directly regulates MBC differentiation to PC. Finally, using the Bmpr1a reporter mouse created in Aim 1, we will ask if Bmpr1a expression is restricted to a subpopulation of MBC. The finding of restricted expression amongst MBC would be intriguing, suggesting that the ability to activate Bmpr1a signaling confers special properties to MBC, such as the potential to self-renew. Alternatively, if Bmpr1a expression is a general property of MBC, Bmpr1a expression and these Bmpr1a.eGFP reporter mice particularly will be valuable tools for tracking and isolating rare MBC. In summary, we propose to investigate the role of a conserved stem cell pathway in the formation, maintenance and function of B cell memory. Bmp signaling has been studied little in B cell biology, so this work is novel. The findings are of potentially high significance to the fundamental understanding of the function of the adaptive immune system and may influence vaccine design. The data generated and the model systems created will lay the foundation of future work.
The development of effective, durable immunity after vaccination or infection is critical for health of individuals and the community. The mechanisms that regulate the development and maintenance of this 'immunologic memory' are poorly understood. We have identified bone morphogenetic protein receptor 1a (Bmpr1a) as a putative regulator of these processes and propose studies to elucidate its role.
