Microbial sensing and innate immune activation in B cells

B 细胞中的微生物传感和先天免疫激活

基本信息

  • 批准号:
    RGPIN-2020-06330
  • 负责人:
  • 金额:
    $ 2.33万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2022
  • 资助国家:
    加拿大
  • 起止时间:
    2022-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

B-cells are mostly known for their capacity to produce antibodies. However, an increasing body of literature has now shown that they may also participate in the immune response by various antibody-independent mechanisms, such as cytokine production, co-stimulation, and antigen presentation. B-cells can be divided in three different subpopulations: follicular B cells , innate-like marginal zone B-cells (MZB), and B1 B-cells. Follicular B cells are the most prominent B-cell subpopulation and reside in lymphoid follicles of secondary and tertiary lymphoid organs. MZB are located in the marginal zone of the spleen and are endowed with the capacity to bind immune complexes, migrate towards the splenic white pulp, and transfer antigen to follicular dendritic cells. B1 B-cells are known for their secretion of natural antibodies. We have recently reported that B cells can capture the protozoan parasite Leishmania donovani. Upon exposure to the parasite, B cells form clusters and hold L. donovani in extracellular IgM-rich pockets. This close interaction results in polyclonal B cell activation and eventually in cell death after 24-48h. Interestingly, the parasite triggers endosomal Toll-Like Receptors (TLRs), although it is attached extracellularly on the cell surface of the B cell. Activation of endosomal TLRs was required to induce IL-10 and IFN-I expression and to promote hypergammaglobulinemia. The pathways up- and downstream of endosomal TLR activation in B-cells and the contribution of these pathways to the induction of hypergammaglobulinemia are as yet unknown. Definition of these steps will require a deeper understanding of how B cells interact with the parasite. The overall goal of our research is to understand how various B cell subpopulations recognize and react to microorganisms, and how this recognition affects their function. Our objective in this application is to characterize the interaction between L. donovani and B cells in order to understand pathways leading to polyclonal B cell activation. Particularly, we will investigate i) parasite capture and cell surface interaction between L. donovani and various B cell subpopulations; ii) parasite recognition by endosomal toll-like receptors and other microbial sensors (mainly cytosolic) and the downstream pathways they activate; and iii) cell-to-cell communication (e.g. tunnelling nanotubules; receptor/ligand interactions) and role of this communication in the induction of polyclonal B cell activation. Transgenic parasites, knock-out mice, confocal microscopy, flow cytometry, and several biochemical techniques will be used to dissect the various activation and cellular communication pathways in in vitro experiments. The pathways identified here could uncover novel strategies that may also be used by other microorganisms to activate B cells and modulate their functions.
B 细胞因其产生抗体的能力而闻名,但现在越来越多的文献表明,它们也可能通过各种不依赖于抗体的机制参与免疫反应,例如细胞因子产生、共刺激和抗原。 B 细胞可分为三个不同的亚群:滤泡 B 细胞、先天样边缘区 B 细胞 (MZB) 和 B1 B 细胞是最重要的 B 细胞亚群。 MZB 存在于二级和三级淋巴器官的淋巴滤泡中,位于脾脏的边缘区,具有结合免疫复合物、向脾白髓迁移并将抗原转移至滤泡树突状细胞的能力。细胞因其分泌天然抗体而闻名。我们最近报道,B 细胞可以捕获原生动物寄生虫杜氏利什曼原虫。这种紧密的相互作用导致多克隆 B 细胞激活,并最终在 24-48 小时后导致细胞死亡,虽然寄生虫是附着的,但它会触发内体 Toll 样受体 (TLR)。内体 TLR 的激活需要在 B 细胞的细胞表面诱导 IL-10 和 IFN-I 表达并促进。 B 细胞内体 TLR 激活的上游和下游途径以及这些途径对诱导高丙种球蛋白血症的作用尚不清楚,这些步骤的定义需要更深入地了解 B 细胞如何与寄生虫相互作用。我们研究的总体目标是了解各种 B 细胞亚群如何识别微生物并对其做出反应,以及这种识别如何影响其功能。我们在此应用中的目标是表征杜氏乳杆菌之间的相互作用。特别是,我们将研究 i) 杜氏乳杆菌和各种 B 细胞亚群之间的寄生虫捕获和细胞表面相互作用;ii) 内体 toll 样受体和其他受体对寄生虫的识别。微生物传感器(主要是细胞质)及其激活的下游途径;以及 iii)细胞间通讯(例如隧道纳米管;受体/配体相互作用)以及这种通讯在转基因寄生虫、基因敲除小鼠、共聚焦显微镜、流式细胞术和多种生化技术将用于剖析体外实验中的各种激活和细胞通讯途径。这里确定的途径可以揭示新的策略。其他微生物也可能使用它来激活 B 细胞并调节其功能。

项目成果

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Stager, Simona其他文献

Posttranscriptional regulation of II10 gene expression allows natural killer cells to express immunoregulatory function.
  • DOI:
    10.1016/j.immuni.2008.06.012
  • 发表时间:
    2008-08-15
  • 期刊:
  • 影响因子:
    32.4
  • 作者:
    Maroof, Asher;Beattie, Lynette;Zubairi, Soombul;Svensson, Mattias;Stager, Simona;Kaye, Paul M.
  • 通讯作者:
    Kaye, Paul M.
The TLR7/IRF-5 axis sensitizes memory CD4+ T cells to Fas-mediated apoptosis during HIV-1 infection.
  • DOI:
    10.1172/jci.insight.167329
  • 发表时间:
    2023-07-10
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Carmona-Perez, Liseth;Dagenais-Lussier, Xavier;Mai, Linh T.;Stogerer, Tanja;Swaminathan, Sharada;Isnard, Stephane;Rice, Matthew R.;Barnes, Betsy J.;Routy, Jean-Pierre;van Grevenynghe, Julien;Stager, Simona
  • 通讯作者:
    Stager, Simona
IRF-5 Promotes Cell Death in CD4 T Cells during Chronic Infection
  • DOI:
    10.1016/j.celrep.2018.06.107
  • 发表时间:
    2018-07-31
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
    Fabie, Aymeric;Linh Thuy Mai;Stager, Simona
  • 通讯作者:
    Stager, Simona
Innate Immune B Cell Activation by Leishmania donovani Exacerbates Disease and Mediates Hypergammaglobulinemia
  • DOI:
    10.1016/j.celrep.2016.05.028
  • 发表时间:
    2016-06-14
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
    Silva-Barrios, Sasha;Smans, Melina;Stager, Simona
  • 通讯作者:
    Stager, Simona
Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10+ CD4+ T cells.
  • DOI:
    10.1002/eji.200635937
  • 发表时间:
    2006-07
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Stager, Simona;Maroof, Asher;Zubairi, Soombul;Sanos, Stephanie L;Kopf, Manfred;Kaye, Paul M
  • 通讯作者:
    Kaye, Paul M

Stager, Simona的其他文献

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{{ truncateString('Stager, Simona', 18)}}的其他基金

Microbial sensing and innate immune activation in B cells
B 细胞中的微生物传感和先天免疫激活
  • 批准号:
    RGPIN-2020-06330
  • 财政年份:
    2021
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
Microbial sensing and innate immune activation in B cells
B 细胞中的微生物传感和先天免疫激活
  • 批准号:
    RGPIN-2020-06330
  • 财政年份:
    2020
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
Antigen-presenting and phagocytic functions of B cell subsets
B 细胞亚群的抗原呈递和吞噬功能
  • 批准号:
    RGPIN-2015-04714
  • 财政年份:
    2019
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
Antigen-presenting and phagocytic functions of B cell subsets
B 细胞亚群的抗原呈递和吞噬功能
  • 批准号:
    RGPIN-2015-04714
  • 财政年份:
    2018
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
Antigen-presenting and phagocytic functions of B cell subsets
B 细胞亚群的抗原呈递和吞噬功能
  • 批准号:
    RGPIN-2015-04714
  • 财政年份:
    2017
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
Antigen-presenting and phagocytic functions of B cell subsets
B 细胞亚群的抗原呈递和吞噬功能
  • 批准号:
    RGPIN-2015-04714
  • 财政年份:
    2016
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual
Antigen-presenting and phagocytic functions of B cell subsets
B 细胞亚群的抗原呈递和吞噬功能
  • 批准号:
    RGPIN-2015-04714
  • 财政年份:
    2015
  • 资助金额:
    $ 2.33万
  • 项目类别:
    Discovery Grants Program - Individual

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