Chemokines and Lymphoid Tissue Organization and Function

趋化因子和淋巴组织的组织和功能

• 批准号: 10686036
• 负责人: Jason G Cyster
• 金额: $ 47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686036
• 关键词: Acceleration; Adoptive Transfer; Affect; Affinity; Antibody Response; Automobile Driving; B lymphoid malignancy; B-Lymphocytes; CD4 Positive T Lymphocytes; Calcium; Cell Communication; Cell physiology; Cells; Cytoplasm; Cytoplasmic Tail; Data; Follicular Lymphoma; Genes; Grant; Growth; HIV-1; Helper-Inducer T-Lymphocyte; Human; ITIM; Influenza; Ligands; Lymphoid Tissue; Lymphoma; Lymphomagenesis; Modeling; Mus; Mutate; Mutation; NR0B2 gene; Nuclear; Oncogenic; Output; PTPN11 gene; Pathway interactions; Plasma Cells; Property; Protein Tyrosine Phosphatase; Regulation; Reporter; Role; Signal Transduction; Sphingosine-1-Phosphate Receptor; Structure of germinal center of lymph node; Surface; T cell response; T-Lymphocyte; Testing; Time; Transduction Gene; Tumor Immunity; Tumor Suppressor Proteins; Work; cell type; chemokine; exome sequencing; growth factor receptor-bound protein 2; herpesvirus entry mediator; high voltage electron microscopy; insight; intravital imaging; large cell Diffuse non-Hodgkin' s lymphoma; novel strategies; novel therapeutic intervention; overexpression; pathogen; receptor; response; restraint; success; transmission process; two photon microscopy

Project Summary/Abstract B cell selection in germinal centers (GCs) is important for the success of antibody responses against influenza, HIV-1 and many other pathogens. However, the full set of signals involved in mounting GC responses is not understood. Recent work highlights the importance of signals from T follicular helper (Tfh) cells in driving preferential outgrowth of higher affinity B cells. The factors determining the strength and quality of signaling between Tfh cells and B cells are incompletely defined and are a focus of this proposal. The surface receptor HVEM (TNFRSF14) is frequently mutated in human GC-derived lymphomas (follicular lymphoma and GCB-diffuse large B cell lymphoma). This finding suggests HVEM has an important role in normal GC function but this role has not been defined. We have found that HVEM deficiency gives B cells a competitive advantage over wild-type B cells during GC responses. Our preliminary data suggest that this advantage only occurs when T cells are capable of sensing HVEM through expression of BTLA. We therefore propose a model where HVEM engagement of BTLA on Tfh cells restrains the amount of T cell help delivered to the B cell. The first Aim will define how HVEM restrains the competitiveness of B cells for representation in the GC. Adoptive transfer and conditional deletion approaches will be used to determine the stage(s) of the B cell response at which HVEM acts. The function of the HVEM intracellular domain will be tested using retroviral gene transduction approaches and the effects of HVEM deficiency on plasma cell formation, affinity maturation and recall responses will be determined. The second Aim will define how BTLA within CD4 T cells determines the quality of help received by the B cell. We will use retroviral gene transduction to test the role of the BTLA cytoplasmic domain in Tfh cell function. Analysis of T cells lacking the tyrosine phosphatases, SHP1 and SHP2, will define their roles in BTLA function. The influence of HVEM-BTLA engagement on cell-cell contact and T cell signaling will be studied using intravital 2-photon microscopy combined with the Salsa6f calcium reporter. Erk signaling will be followed using a new nuclear-cytoplasmic translocation reporter mouse line. The final Aim will examine how loss of the HVEM-BTLA interaction contributes to GC-derived lymphomagenesis. We will test whether BTLA functions as an extrinsic tumor suppressor by testing for accelerated outgrowth of Bcl2-overexpressing GC B cells in mice lacking BTLA in T cells. We will test for possible co-oncogenic effects of combined HVEM- and Gna13-deficiency. By defining how HVEM and BTLA act to control T cell help of B cell responses, this work may point to new approaches for augmenting B cell diversification and affinity maturation in GCs. An understanding of how HVEM constrains GC B cell accumulation, including cells over-expressing Bcl2, will provide insights that may lead to new approaches for treatment of FL and GCB-DLBCL.

项目总结/摘要 生殖中心（GC）中的B细胞选择对于成功进行抗 流感、HIV-1和许多其他病原体。但是，安装GC所涉及的全套信号 答案不理解。最近的工作强调了来自T滤泡辅助细胞（Tfh）的信号的重要性 细胞驱动高亲和力B细胞的优先生长。决定强度和质量的因素 Tfh细胞和B细胞之间的信号传导的不完全定义并且是该提议的焦点。 表面受体HVEM（TNFRSF 14）在人GC源性淋巴瘤中频繁突变 （滤泡性淋巴瘤和GCB-弥漫性大B细胞淋巴瘤）。这一发现表明HVEM具有重要的 在正常GC功能中的角色，但此角色尚未定义。我们已经发现HVEM缺陷产生B 在GC反应期间，细胞比野生型B细胞具有竞争优势。我们的初步数据显示， 只有当T细胞能够通过BTLA的表达感受HVEM时，才出现这种优势。我们 因此，提出了一种模型，其中BTLA在Tfh细胞上的HVEM接合抑制了T细胞辅助的量， 递送到B细胞。第一个目标将定义HVEM如何抑制B细胞的竞争力， 在GC中的代表性。连续转移和条件删除方法将用于确定 HVEM作用的B细胞应答阶段。HVEM胞内结构域的功能将是 使用逆转录病毒基因转导方法和HVEM缺陷对浆细胞的影响进行了测试， 将确定亲和力形成、亲和力成熟和回忆响应。 第二个目标将定义CD 4 T细胞内的BTLA如何决定患者接受的帮助的质量。 B细胞。我们将利用逆转录病毒基因转导技术来检测BTLA胞浆区在Tfh细胞中的作用 功能对缺乏酪氨酸磷酸酶SHP 1和SHP 2的T细胞的分析将确定它们在BTLA中的作用 功能将研究HVEM-BTLA接合对细胞-细胞接触和T细胞信号传导的影响 使用活体双光子显微镜结合Salsa 6 f钙报告基因。Erk信号将被跟踪 使用新的核质易位报告小鼠系。 最后的目的将检查HVEM-BTLA相互作用的损失如何有助于GC衍生的 淋巴瘤形成我们将测试BTLA是否作为一种外源性肿瘤抑制因子， 在T细胞中缺乏BTLA的小鼠中，Bcl 2过表达GC B细胞的生长加速。我们将测试 HVEM和Gna 13联合缺乏可能的共致癌作用。 通过定义HVEM和BTLA如何控制T细胞帮助B细胞应答，这项工作可能指向 增加GC中B细胞多样化和亲和力成熟的新方法。了解如何 HVEM抑制GC B细胞积累，包括过表达Bcl 2的细胞，将提供可能 为FL和GCB-DLBCL的治疗提供了新的方法。

项目成果

Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit.

• DOI: 10.1084/jem.20041509
• 发表时间: 2005-01-17
• 期刊: The Journal of experimental medicine
• 作者: Lo CG;Xu Y;Proia RL;Cyster JG
• 通讯作者: Cyster JG

Peyer's patches: organizing B-cell responses at the intestinal frontier.

• DOI: 10.1111/imr.12400
• 发表时间: 2016-05
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Reboldi A;Cyster JG
• 通讯作者: Cyster JG

Deficiency in IL-17-committed Vγ4(+) γδ T cells in a spontaneous Sox13-mutant CD45.1(+) congenic mouse substrain provides protection from dermatitis.

• DOI: 10.1038/ni.2585
• 发表时间: 2013-06
• 期刊: Nature immunology
• 影响因子: 30.5

Chemokine requirements for B cell entry to lymph nodes and Peyer's patches.

B细胞进入淋巴结和Peyer斑块的趋化因子要求。

• DOI: 10.1084/jem.20020201
• 发表时间: 2002-07-01
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Okada, Takaharu;Ngo, Vu N;Ekland, Eric H;Forster, Reinhold;Lipp, Martin;Littman, Dan R;Cyster, Jason G
• 通讯作者: Cyster, Jason G

T follicular helper cells in germinal center B cell selection and lymphomagenesis.

• DOI: 10.1111/imr.12860
• 发表时间: 2020-07
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Mintz MA;Cyster JG
• 通讯作者: Cyster JG