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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708053
• 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淋巴细胞在免疫反应中非常重要，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很好地理解，但涉及关键替代B细胞功能的机制尚不明确，特别是细胞因子产生和抗原呈递。此外，B细胞有时会在各种环境刺激（应激、炎症等）的作用下浸润组织形成异位淋巴样结构（ALS，通常存在于专门的淋巴样器官），ALS在正常组织中的作用尚不清楚。ALS的形成是一种生物学现象，对于提高幼稚淋巴细胞的微生物取样效率很重要。迄今为止，B淋巴细胞的研究大多是在动物模型中进行的，需要在人体中进行表征。解决这一挑战代表了当前NSERC提案的目标。