Contribution of c-Maf to regulatory B cells and antibody-secreting cells

项目总结 调节性B细胞参与许多病理生理过程，如促进免疫耐受。 自身免疫和器官移植，但也降低了对癌症的免疫反应。总体而言，许多研究 表明调节性B细胞和调节性T细胞一样，在调节免疫系统方面起着至关重要的作用 很多情况下。越来越多的证据突显出强烈的异质性以及高度的 调节B细胞亚群的功能可塑性，这对唯一和稳定的定义提出了挑战。然而，a 调节性B细胞的常见功能是产生免疫调节性细胞因子IL-10。虽然意义重大 人们的注意力一直集中在定义调节性B细胞的多种表型上，仍然存在一个关键的 需要了解调控B细胞功能的分子触发因素。在对人类进行的实验中 血液B细胞，我们已经获得了指向特定分子驱动因素的初步数据，这些分子驱动因素控制着 产生IL-10的调节性B细胞。其中，我们注意到转录因子c-maf，a 属于激活蛋白-1(AP-1)超家族的因子，已知可调节T细胞产生细胞因子 细胞和巨噬细胞。到目前为止，c-MAF在B细胞中的功能还没有报道。结果来自我们的 分析表明，在人类中，c-MAF是产生IL-10的B细胞的早期调节因子 具有浆母细胞表型。此外，最近的一份出版物与公开可用的基因 转录数据表明，c-Maf可以与小鼠B细胞中的IL10基因启动子结合，其中 小鼠B细胞亚群，在浆母细胞中转录水平最高。本研究旨在使用一种组织-- 特异性基因敲除小鼠模型的建立及体内c-Maf在肿瘤发生中的作用 抗体分泌细胞和产生IL-10的浆母细胞。具体地说，我们建议使用现有的c-Maf- 用FLOXED小鼠和CD19-Cre小鼠产生B细胞条件性c-Maf基因敲除小鼠，以检测以下指标：1) C-Maf在浆母细胞稳态发育和抗体产生中的作用 免疫后的浆母细胞和浆细胞；2)c-Maf对IL-10产生的贡献 产生调节性B细胞和浆母细胞。此外，这些研究将使用沙门氏菌感染 模型测试c-Maf是否有助于功能调节性B细胞的发展 免疫反应。拟议中的研究具有重要意义，因为它们是第一次调查c-受体的作用。 MAF在B细胞生物学中的应用，因为它们将有助于更好地理解分子过程 一方面，调节浆母细胞和体液免疫的发展，另一方面， 导致免疫恶化或无效的调节性B细胞的产生。

PROJECT SUMMARY Regulatory B cells are involved in many pathophysiological processes, such as promoting tolerance in autoimmunity and organ transplantation, but also reducing immune responses to cancer. Overall, many studies indicate that regulatory B cells, like regulatory T cells, play a crucial role in regulating the immune system in many circumstances. A growing body of evidence highlights the strong heterogeneity as well as a high functional plasticity of regulatory B-cell subsets, which challenge a unique and stable definition. However, a common function of regulatory B cells is to produce the immunoregulatory cytokine IL-10. While significant attention has been focused on defining the multiple phenotypes of regulatory B cells, there remains a critical need to understand the molecular triggers of regulatory B-cell functions. In experiments performed with human blood B cells, we have obtained preliminary data pointing to specific molecular drivers that control the generation of IL-10-producing regulatory B cells. Among them, we noticed the transcription factor c-MAF, a factor belonging to the activator protein-1 (AP-1) superfamily and known to modulate cytokine production in T cells and macrophages. To date, a function of c-MAF in B cells has not been reported. Results from our analyses suggest that in humans, c-MAF acts as an early regulator of the generation of IL-10-producing B cells with a plasmablast phenotype. In addition, a recent publication together with publicly available gene transcription data indicate that c-Maf can bind the Il10 gene promoter in murine B cells and that, among all mouse B-cell subsets, is most highly transcribed in plasmablasts. The present study aims to use a tissue- specific gene knock-out mouse model to explore and establish in vivo the role of c-Maf in the generation of antibody-secreting cells and IL-10-producing plasmablasts. Specifically, we propose to use established c-Maf- floxed mice and CD19-Cre mice to generate B-cell conditional c-Maf knock-out mice to test the following: 1) the function of c-Maf in the steady-state development of plasmablasts and the generation of antibody-secreting plasmablasts and plasma cells after immunization; and 2) the contribution of c-Maf to the generation of IL-10- producing regulatory B cells and plasmablasts. Furthermore, these studies will use a Salmonella infection model to test whether c-Maf contributes to the development of functional regulatory B cells that reduce critical immune responses. The proposed studies are significant because they are the first to investigate the role of c- Maf in B-cell biology and because they will lead to a better understanding of the molecular processes regulating, on one side, the development of plasmablasts and humoral immunity, and on the other, the generation of regulatory B cells that contribute to exacerbated or ineffective immunity.