Antigen and Chemoattractant Receptor Signaling in B Cell Biology

描述（由申请人提供）：摘要未成熟或成熟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。在骨髓中发育期间，未成熟B细胞的抗原受体信号传导决定了该细胞是否在骨髓微环境中耐受或被允许离开并加入外周淋巴细胞池。这些结果中的任一个的实际要求是未成熟B细胞抗原特异性决定对化学引诱物、粘附或两者的应答。然而，这一点尚未得到证实，也没有鉴定出促进未成熟B细胞从骨髓中退出的化学引诱物。脾中成熟B细胞的抗原受体信号传导也促进抗原活化细胞迁移到最适合针对该抗原的抗体应答的微环境，并且在鉴定参与该运动的化学引诱物方面已经取得了进展。然而，不同的抗原是否促进类似的迁移反应尚不清楚，我们也不了解抗原受体信号传导如何促进化学引诱物反应性的变化。此外，考虑到真正的病原体也存在被成熟B细胞上的toll样受体识别的配体，抗原受体和toll样受体信号传导如何一起影响迁移和抗体应答尚未确定。在这个建议中，我们概述了三个实验目的，探讨抗原受体和化学引诱物受体信号转导对B淋巴细胞的功能和机制之间的关系，以及这种调节对B细胞选择和抗体应答的后果。为了实现这些目标，我们使用抗原和化学引诱物受体信号传导和细胞粘附的体外模型，以及B细胞发育、耐受性和抗体应答的体内小鼠模型。在第一个具体的目标，我们问抗原受体反应性如何改变化学引诱物的反应和粘附的未成熟B细胞。这些发现在第二个目标中通过评估化学引诱物是否能够影响抗原受体信号传导以及哪些化学引诱物有助于未成熟的B细胞从骨髓中退出来扩展。在最后一个具体的目标，我们调查的性质，抗原如何调节成熟的边缘区B细胞的化学引诱物的反应，以及这种调节是否进一步受到Toll样受体信号转导。在整个研究中，我们使用生物化学和遗传学的方法来评估抗原和化学引诱物受体相互调节的分子机制以及这些信号通路交叉的点。总之，我们预期这些实验来确定如何B细胞抗原受体信号由B淋巴细胞支配随后的细胞运动和这种调节对B细胞发育，选择和体液免疫的影响。 公共卫生相关性：B淋巴细胞的适当发育和功能是在防止自身免疫的同时对外来抗原产生抗体应答所必需的。这两个过程，发育和功能，依赖于B淋巴细胞的能力，以迁移，以响应定义的线索。该应用程序研究了B淋巴细胞在其发育过程中以及随后在抗体应答过程中如何调节迁移。

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.