Chemokines and Lymphoid Tissue Organization and Function

描述（由申请人提供）：机体突变的高亲和抗体反应的增加对于抵御一系列病原体的保护是重要的，也是大多数疫苗策略成功的基础。除了它们的有益功能外，GCs也是一类主要淋巴瘤的来源。GC - B细胞和基质细胞之间的相互作用支持GC - B细胞选择和存活所必需的事件，促进GC - B细胞生长调节和限制的机制也不完全清楚。本应用程序中提出的研究将推进这两个领域的知识。首先，我们将研究一种新发现的基质细胞类型，即表达cxcl12的网状细胞（CRCs），它存在于GCs中。研究人员将研究crc的表型和发育要求，利用活体双光子显微镜跟踪GC B细胞与GC生态位新组分相互作用的动力学，并探讨细胞的功能作用。它们在定位表达cxcr4的滤泡辅助性T细胞以及GC B细胞中的作用将被研究。其次，剖析g α13介导的GC B细胞生长和迁移调控机制。溶血磷脂鞘鞘醇-1-磷酸（S1P）与其受体S1PR2之间的相互作用对传递控制GC B细胞生长和约束的Gα13-信号具有重要意义。g α13和S1PR2在人GC - B细胞型弥漫性大B细胞淋巴瘤（GCB-DLBCL）中经常发生突变，其中任何一个基因的缺失都足以使小鼠易患这种恶性肿瘤。虽然GC - B细胞是非循环性的，但GCB-DLBCL表现为全身性疾病。初步数据显示，小鼠体内缺乏g α13足以使GC B细胞失去限制，使GC B细胞进入循环。然而，s1pr2缺乏并不会导致GC B细胞播散。这些观察结果导致发现GCB-DLBCL中经常突变的孤儿g蛋白偶联受体（GPCR） P2RY8也通过参与Gα13促进GCB细胞的生长调节和限制。本研究的主要目的是明确这种新型人GPCR的表达和功能，以及g α13介导的GC B细胞在GC中的作用机制。建立适当调节的免疫反应对人类健康至关重要。这项工作将确定一种新的基质细胞类型如何支持GC B细胞体细胞突变和选择事件，这些事件对于产生高度突变的抗体（如能够介导针对流感和HIV-1抗原的广泛中和反应的抗体）是必要的。本研究将从S1PR2和g α13在GCB-DLBCL的肿瘤抑制和传播抑制通路中发挥作用的证据出发，确定一个新的受体P2RY8在这一过程中的作用。这些研究预计将对这种恶性肿瘤的新治疗策略的发展产生影响。

DESCRIPTION (provided by applicant): The mounting of somatically mutated high affinity antibody responses is important in protection against a range of pathogens and underlies the success of most vaccine strategies. As well as their beneficial functions, GCs are the source of a major class of lymphoma. The interactions between GC B cells and stromal cells in the GC niche that support events necessary for GC B cell selection and survival are incompletely understood as are the mechanisms promoting GC B cell growth regulation and confinement. The research proposed in this application will advance knowledge in both of these areas. First, the properties of a newly identified stromal cell type, termed CXCL12-expressing reticular cells (CRCs), present within GCs will be investigated. The phenotype and developmental requirements of CRCs will be studied, the dynamics of GC B cell interaction with this new component of the GC niche tracked using intravital 2-photon microscopy, and the functional roles of the cells will be probed. Their role in positioning CXCR4-expressing follicular helper T cells, as well as GC B cells, will be investigated. Second, the mechanism of Gα13-mediated regulation of GC B cell growth and migration will be dissected. One receptor-ligand interaction important for transmitting Gα13- signals that control GC B cell growth and confinement is that between the lysophospholipid sphingosine-1-phosphate (S1P) and its receptor S1PR2. Both Gα13and S1PR2 are frequently mutated in human GC B cell-type diffuse large B cell lymphoma (GCB-DLBCL) and loss of either gene is sufficient to predispose mice to this malignancy. Although GC B cells are non-recirculatory, GCB-DLBCL presents as a systemic disease. Preliminary data show that Gα13-deficiency in mice is sufficient to cause a loss of GC B cell confinement and allow GC B cells to enter circulation. S1PR2-deficiency, however, does not lead to GC B cell dissemination. These observations have led to the discovery that an orphan G-protein coupled receptor (GPCR) that is frequently mutated in GCB-DLBCL, P2RY8, also promotes GC B cell growth regulation and confinement by engaging Gα13. A major goal of this proposal is to define the expression and function of this novel human GPCR, and the mechanism of Gα13-mediated GC B cell confinement in GCs. Mounting appropriately regulated immune responses is essential for human health. This work will define how a new stromal cell type supports GC B cell somatic mutation and selection events necessary for generating highly mutated antibodies such as those capable of mediating broadly neutralizing responses against influenza and HIV-1 antigens. The research will build from evidence that S1PR2 and Gα13function in a tumor suppressor and dissemination-inhibitory pathway in GCB-DLBCL to define the role of a new receptor, P2RY8, in this process. These studies are anticipated to have implications for development of new treatment strategies for this malignancy.