Deciphering alternative functions of B lymphocytes

破译 B 淋巴细胞的替代功能

• 批准号: RGPIN-2016-05376
• 负责人: Lapointe, Réjean
• 金额: $ 2.26万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683806
• 关键词: Deciphering; alternative; functions; lymphocytes

B lymphocytes/cells are very important in the immune response and their main role is to produce antibodies. While the mechanisms regulating B lymphocyte activation leading to antibody production are well understood, those involved in key alternative B cell functions are poorly defined, particularly cytokine production and antigenic presentation. Also, B cells sometimes infiltrate tissues and form alternative lymphoid structures (ALS; normally found in specialized lymphoid organs) in response to various environmental stimuli (stress, inflammation, etc.), and the roles of ALS in normal tissues are unclear. ALS formation is a biological phenomenon, important for increasing the efficiency of microbe sampling by naive lymphocytes. To date, B lymphocytes have been studied mostly in animal models and need to be characterized in humans. Addressing this challenge represents the objective in the current NSERC proposal. ***Using previous NSERC funding, I established my program on B cell activation by several sources (CD40L/IL-4), which are normally received by activated T cells. Additionally, we have studied the importance of signals from microbiobes on B cells and have reported that some viral-based ligands trigger a process called autophagy, which in turn enhance antigenic presentation. We have performed transcriptomic profiling (evaluate the expression of all genes among the many 1000) from activated B cells, and from B cells isolated from ALS of the normal human kidney. We have defined 3 groups of genes, potentially involved in B cell activation and tissue-homing.***Since the regulation of B lymphocyte tissue-homing-dependent functions in response to T cell and microbial signals is understudied, we will pursue the characterization of novel molecular events controlling alternative functions, specifically from tissue-resident and activated peripheral B cells. We hypothesize that programming of key B lymphocyte alternative functions is dictated by the response of B cell to environmental cues (activation/suppression) and to their anatomical localization. In this five-year short-term objectives, we propose to: ***AIM #1: Identify B cell subsets expressing modulated genes. ***AIM #2: Define the cytokine profile and capacity of antigenic presentation from the candidate genes***AIM #3: Develop 3D culture system to better model normal B lymphocyte biology ***Impact of this research program***So far, B cells have been studied mainly for antibody generation and diversity, and in their differentiation/development linked to antibody production. However, much remains to be understood in this specific field, especially in humans. We now know that B cells have key alternative functions such as antigenic presentation and immune modulation, both may be crucial in the control of immune responses. This project will focus on mechanisms controlling such essential alternative B cell functions. *****

B淋巴细胞/细胞在免疫应答中非常重要，其主要作用是产生抗体。虽然调节B淋巴细胞活化导致抗体产生的机制已被充分理解，但参与关键替代B细胞功能的机制定义不清，特别是细胞因子产生和抗原呈递。此外，B细胞有时会浸润组织并形成替代性淋巴结构（ALS;通常见于专门的淋巴器官）以响应各种环境刺激（应激、炎症等），ALS在正常组织中的作用尚不清楚。ALS形成是一种生物学现象，对于通过幼稚淋巴细胞增加微生物取样的效率很重要。迄今为止，B淋巴细胞主要在动物模型中进行研究，需要在人体中进行表征。应对这一挑战是当前NSERC提案的目标。* 利用以前的NSERC资金，我建立了我的B细胞活化的几个来源（CD 40 L/IL-4），这是通常由活化的T细胞接收的程序。此外，我们还研究了来自B细胞上微生物的信号的重要性，并报道了一些基于病毒的配体触发了一种称为自噬的过程，这反过来又增强了抗原呈递。我们已经从活化的B细胞和从正常人肾的ALS分离的B细胞进行了转录组学分析（评估1000个基因中所有基因的表达）。我们已经定义了3组基因，可能参与B细胞活化和组织归巢。由于调节B淋巴细胞的组织归巢依赖功能的T细胞和微生物的信号是欠研究，我们将追求的新的分子事件控制替代功能的特性，特别是从组织驻留和激活的外周B细胞。我们假设，编程的关键B淋巴细胞的替代功能是由B细胞的反应环境线索（激活/抑制）和他们的解剖定位。在这个五年短期目标中，我们提出：* 目标#1：鉴定表达调节基因的B细胞亚群。* AIM#2：从候选基因中定义细胞因子谱和抗原呈递能力 * 目标#3：开发3D培养系统以更好地模拟正常B淋巴细胞生物学 * 本研究计划的影响 * 迄今为止，B细胞主要研究抗体产生和多样性，以及与抗体产生相关的分化/发育。然而，在这一特定领域，特别是人类领域，仍有许多问题有待了解。我们现在知道，B细胞具有关键的替代功能，如抗原呈递和免疫调节，两者都可能在控制免疫反应中至关重要。本项目将集中在控制这些基本的替代B细胞功能的机制。*****