B Cell Memory Regulation by Bone Morphogenetic Protein Receptor 1A

 描述（由申请人提供）：对有效B细胞记忆形成、维持和功能的机制了解甚少。我们对这一领域有着长期的兴趣，并作出了重大贡献。在这里，我们描述了有趣的观察表明，骨形态发生蛋白受体1a（Bmpr 1a）的激活是至关重要的生发中心反应，并需要长寿命的骨髓浆细胞（BMPC）和记忆B细胞（MBC）的发展。由于Bmpr 1a是TGF-β家族受体，在几种干细胞群体中转导调节自我更新和分化决定的信号，我们假设它在GC B细胞（GCB）和MBC中也起类似的作用。该提案的第一部分涉及Bmpr 1a激活在GCB功能和BMPC形成中的作用。我们想知道Bmpr 1a的激活是否调节GCB的增殖或凋亡，以及它的激活是否是GBC分化为BMPC所直接需要的。我们还建议构建Bmpr 1a荧光报告小鼠，以询问Bmpr 1a表达是否是所有GCB或限制性子集的特征，表明Bmpr 1a + GCB的专门功能。该提案的第二部分讨论了Bmpr 1a激活在MBC和BMPC中的作用。我们将确定这种途径是否能够使MBC自我更新，以及它是否支持BMPC的长期生存。我们还将询问，在次级反应中，Bmpr 1a是否直接调节MBC分化为PC。最后，使用目标1中创建的Bmpr 1a报告小鼠，我们将询问Bmpr 1a表达是否仅限于MBC亚群。在MBC中限制表达的发现将是有趣的，这表明激活Bmpr 1a信号传导的能力赋予MBC特殊的特性，例如自我更新的潜力。或者，如果Bmpr 1a表达是MBC的一般特性，则Bmpr 1a表达和这些Bmpr1a.eGFP报告小鼠将特别是用于追踪和分离罕见MBC的有价值的工具。总之，我们建议调查的作用，一个保守的干细胞通路的形成，维持和功能的B细胞记忆。BMP信号在B细胞生物学中研究得很少，因此这项工作是新颖的。这一发现对于从根本上理解适应性免疫系统的功能具有潜在的重要意义，并可能影响疫苗的设计。生成的数据和创建的模型系统将为今后的工作奠定基础。

 DESCRIPTION (provided by applicant): 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-ß 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.