The role of Bcl6 in the differentiation and function of Tfh

描述（由申请人提供）：Bcl 6在滤泡辅助性CD 4 T细胞的分化和功能中的作用免疫接种是最具成本效益的医疗干预措施之一。大多数疫苗通过产生由B淋巴细胞产生的病原体中和抗体来起作用。然而，如果没有其他免疫系统成分的帮助，这些B细胞就不能正常发挥作用。另一种类型的淋巴细胞，滤泡性T辅助细胞（TFH），对于产生抗体的B淋巴细胞和生殖中心是重要的，然而TFH只是最近才被发现，并且它们的生物学还没有被很好地理解。我们已经发现了两种转录因子，Bcl 6和Blimp-1，其在小鼠中作为TFH分化的中心调节因子发挥作用（Science，2009）。将这些发现转化为人类将弥合我们对CD 4 T细胞谱系定型和体液免疫理解的关键差距。通过增强我们对这些蛋白质如何控制TFH在人体中的分化和功能的了解，我们可以确保疫苗的设计能够利用这些细胞来促进更有效的免疫反应。以更合理的方式设计免疫接种的能力将影响传统和癌症疫苗领域，并可能使普通人群受益匪浅。此外，由于Bcl 6在许多淋巴瘤中起着至关重要的致癌作用，因此更全面地了解Bcl 6/Blimp 1如何控制谱系定型可能会带来新的淋巴瘤治疗方法。本研究的目的一是探讨Bcl-6如何调控人TFH的分化。目的II将提高我们对LIF和其他TFH细胞因子如何影响TFH分化和功能的理解。 公共卫生相关性：目前获得许可的绝大多数疫苗通过触发病原体中和抗体的产生来保护人类。滤泡性T辅助细胞是这种体液免疫反应的关键组成部分，我们对它们如何分化和发挥功能的了解有限。更好地了解滤泡性T辅助细胞生物学将允许更合理的疫苗设计和新的治疗方法，以某些癌症和自身免疫性疾病。

DESCRIPTION (provided by applicant): The role of Bcl6 in the differentiation and function of follicular helper CD4 T cells Immunization is one of the most cost effective medical interventions. Most vaccines work through the generation of pathogen neutralizing antibodies made by B lymphocytes. However, these B cells cannot function properly without help from other immune system components. Another type of lymphocyte, the follicular T helper cell (TFH), is important for the generation of antibody producing B lymphocytes and germinal centers, yet TFH have only been recently discovered and their biology is not well understood. We have uncovered two transcription factors, Bcl6 and Blimp-1, that function as central regulators of TFH differentiation in mice (Science, 2009). Translation of these findings into humans will bridge critical gaps in our understanding of CD4 T cell lineage commitment and humoral immunity. By enhancing our knowledge of how these proteins control TFH differentiation and function in humans, we can ensure that vaccines are designed such that they utilize these cells to promote more effective immune responses. The ability to design immunizations in a more rational fashion will impact the traditional and cancer vaccine fields, and could enormously benefit the general population. Furthermore, because Bcl6 plays a crucial oncogenic role in many lymphomas, a more complete understanding of how Bcl6/Blimp1 control lineage commitment may bring about novel lymphoma therapies. Aim I of this proposal will investigate how Bcl6 regulates human TFH differentiation. Aim II will enhance our understanding of how LIF and other TFH cytokines affect TFH differentiation and function. PUBLIC HEALTH RELEVANCE: The vast majority of currently licensed vaccines protect humans by triggering the production of pathogen neutralizing antibodies. Follicular T helper cells are a critical component of this humoral immune response, and our knowledge of how they differentiate and function is limited. A better understanding of follicular T helper cell biology will allow for more rational vaccine design and novel therapeutic approaches to certain cancers and autoimmune conditions.