Antigen and Chemoattractant Receptor Signaling in B Cell Biology

描述(申请人提供)：未成熟或成熟B淋巴细胞上的抗原受体传递的信号对随后的细胞迁移有直接影响。在骨髓发育期间，未成熟的B细胞发出的抗原受体信号决定了该细胞是在骨髓微环境中耐受，还是被允许退出并加入外周淋巴细胞池。这两种结果的一个实际要求是，未成熟的B细胞抗原特异性决定了对化学诱导剂、黏附或两者的反应。然而，这一点还没有被证明，也没有发现促进未成熟B细胞从骨髓中退出的化学诱导剂。脾中成熟的B细胞的抗原受体信号也促进了抗原激活的细胞迁移到最适合针对该抗原的抗体反应的微环境中，并且在识别参与这一运动的趋化剂方面取得了进展。然而，不同的抗原是否促进相似的迁移反应尚不清楚，我们也不清楚抗原受体信号如何促进趋化反应性的变化。此外，鉴于真正的病原体也存在成熟B细胞上Toll样受体识别的配体，抗原受体和Toll样受体信号如何共同影响迁移和抗体反应尚未确定。在这项建议中，我们概述了三个实验目的，以探索B淋巴细胞上抗原受体和趋化受体信号之间的功能和机制关系，以及这种调节对B细胞选择和抗体应答的影响。为了实现这些目标，我们使用了抗原和化学吸引受体信号和细胞黏附的体外模型，以及B细胞发育、耐受和抗体反应的体内小鼠模型。在第一个特定目标中，我们询问抗原受体反应性如何改变未成熟B细胞的趋化反应和黏附。这些发现被扩展到第二个目的，通过评估趋化物质是否能够影响抗原受体信号，以及哪些趋化物质有助于未成熟的B细胞从骨髓中退出。在最后一个特定的目标中，我们研究了抗原的性质如何调节成熟的边缘带B细胞的趋化反应，以及这种调节是否进一步受到Toll样受体信号的影响。在整个研究过程中，我们使用生化和遗传学方法来评估抗原和趋化物质受体相互调节的分子机制，以及这些信号通路的交叉点。总之，我们预计这些实验将确定B细胞抗原受体信号如何通过B淋巴细胞决定随后的细胞运动，以及这一调控对B细胞发育、选择和体液免疫的影响。 公共卫生相关性：在防止自身免疫的同时，需要B淋巴细胞的适当发育和功能来提高对外来抗原的抗体反应。这两个过程，无论是发育还是功能，都依赖于B淋巴细胞对特定线索做出反应而迁移的能力。这项应用研究了B淋巴细胞在发育过程中以及随后的抗体反应中如何调节迁移。

DESCRIPTION (provided by applicant): Abstract Signals transmitted by the antigen receptor on immature or mature B lymphocytes have a direct impact on subsequent cell migration. During development in the bone marrow, antigen receptor signaling by an immature B cell determines whether the cell is rendered tolerant in the marrow microenvironment or is allowed to exit and join the peripheral lymphocyte pool. A practical requirement for either of these outcomes is that immature B cell antigen specificity dictates response to chemoattractants, adhesion, or both. However, this has not been demonstrated nor the chemoattractants identified that facilitate immature B cell exit from the marrow. Antigen receptor signaling by mature B cells in the spleen also promotes the migration of antigen-activated cells to the microenvironment best suited for the antibody response towards that antigen and progress has been made in identifying the chemoattractants participating in this movement. However, whether diverse antigens promote similar migratory responses is not clear nor do we understand how antigen receptor signaling facilitates changes in chemoattractant responsiveness. Furthermore, given that bona fide pathogens also present ligands recognized by toll-like receptors on mature B cells, how antigen receptor and toll-like receptor signaling together influence migration and antibody response has not been established. In this proposal we outline three experimental aims that explore the functional and mechanistic relationships between antigen receptor and chemoattractant receptor signaling on B lymphocytes and the consequence of this regulation on B cell selection and antibody response. To accomplish these goals we use in vitro models of antigen and chemoattractant receptor signaling and cell adhesion coupled with in vivo mouse models of B cell development, tolerance, and antibody response. In the first specific aim we ask how antigen receptor reactivity alters chemoattractant response and adhesion of immature B cells. These findings are extended in the second aim by assessing whether chemoattractants are able to influence antigen receptor signaling and which chemoattractants contribute to immature B cell exit from the bone marrow. In the last specific aim we investigate how the nature of antigen regulates the chemoattractant response of mature marginal zone B cells and whether this regulation is further influenced by toll-like receptor signaling. Throughout this study we use biochemical and genetic approaches to evaluate the molecular mechanisms by which antigen and chemoattractant receptors regulate each other and the points where these signaling pathways intersect. Together, we anticipate these experiments to define how B cell antigen receptor signaling by B lymphocytes dictates subsequent cell movement and the implications of this regulation on B cell development, selection, and humoral immunity. PUBLIC HEALTH RELEVANCE: The appropriate development and function of B lymphocytes is required for mounting antibody responses to foreign antigens while preventing autoimmunity. Both of these processes, development and function, rely on the ability of B lymphocytes to migrate in response to defined cues. This application studies how B lymphocytes regulate migration during their development and later during an antibody response.