Deciphering alternative functions of B lymphocytes

B淋巴细胞/细胞在免疫反应中非常重要，它们的主要作用是产生抗体。虽然调节B淋巴细胞激活导致抗体产生的机制已经很清楚，但涉及关键替代B细胞功能的机制还不清楚，特别是细胞因子的产生和抗原呈递。此外，B细胞有时会对各种环境刺激(应激、炎症等)做出反应，渗透到组织中并形成替代的淋巴结构(ALS；通常存在于特殊的淋巴器官中)，而ALS在正常组织中的作用尚不清楚。肌萎缩侧索硬化症的形成是一种生物现象，对于提高原始淋巴细胞的微生物采样效率具有重要意义。到目前为止，B淋巴细胞主要是在动物模型中进行研究，需要在人类身上进行表征。应对这一挑战代表了NSERC当前提案的目标。 利用NSERC之前的资助，我建立了我的计划，通过几个来源(CD40L/IL-4)激活B细胞，这些来源通常由激活的T细胞接收。此外，我们还研究了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。我们已经从激活的B细胞和从正常人类肾脏的ALS分离的B细胞中进行了转录图谱分析(评估1000个基因中所有基因的表达)。我们已经定义了三组基因，它们可能参与B细胞的激活和组织归巢。 由于对T细胞和微生物信号对B淋巴细胞组织归巢依赖功能的调节研究不足，我们将继续研究控制替代功能的新分子事件的特征，特别是来自组织驻留和激活的外周B细胞。我们假设，关键的B淋巴细胞替代功能的编程是由B细胞对环境提示(激活/抑制)及其解剖定位的反应决定的。在这个五年计划的短期目标中，我们建议： 目的1：鉴定表达调控基因的B细胞亚群。 目的#2：确定候选基因的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 到目前为止，B细胞的研究主要是为了抗体的产生和多样性，以及与抗体产生有关的B细胞的分化/发育。然而，在这一特定领域，尤其是在人类中，仍有许多需要了解。我们现在知道B细胞具有关键的替代功能，如抗原递呈和免疫调节，两者都可能在控制免疫反应中起关键作用。这个项目将集中在控制这种基本的替代B细胞功能的机制上。

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.