Deciphering alternative functions of B lymphocytes

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。***利用以前的NSERC资金，我建立了我的B细胞活化的几个来源（CD40L/IL-4）的项目，这些来源通常由活化的T细胞接收。此外，我们已经研究了B细胞上微生物信号的重要性，并报道了一些基于病毒的配体触发称为自噬的过程，这反过来增强了抗原呈递。我们从活化的B细胞和从正常人肾脏ALS分离的B细胞中进行了转录组分析（评估1000多个基因中的所有基因表达）。我们已经定义了三组基因，可能参与B细胞活化和组织归巢。***由于B淋巴细胞组织归巢依赖功能对T细胞和微生物信号的调节尚未得到充分研究，我们将继续研究控制其他功能的新分子事件，特别是来自组织驻留和活化的外周B细胞。我们假设关键B淋巴细胞替代功能的编程是由B细胞对环境信号（激活/抑制）及其解剖定位的反应决定的。在这个五年的短期目标中，我们提出：目标#1：鉴定表达调控基因的B细胞亚群。***目标#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，特别是在人类中，仍有许多有待了解的地方。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起关键作用。该项目将重点研究控制这些基本替代B细胞功能的机制。＊＊＊＊＊

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. *****