The role of Bcl6 in the differentiation and function of Tfh

Bcl6在Tfh分化和功能中的作用

• 批准号: 8125922
• 负责人: Mark Kroenke
• 金额: $ 1.71万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2011-05-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125922
• 关键词: Affect; Antibodies; Antigens; Autoimmune Process; B-Lymphocytes; BLR1 gene; Biology; Blood; CD4 Positive T Lymphocytes; Cancer Biology; Cancer Vaccines; Cell Lineage; Cells; Cellular biology; Data; Ensure; Gene Expression; General Population; Generations; Genes; Germinal Center B-Lymphocyte; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immune response; Immune system; Immunization; Immunoglobulin G; Individual; Interleukin-12; Intervention; Knowledge; LIF gene; Licensing; Lupus; Lymphocyte; Lymphoma; Malignant Neoplasms; Medical; Memory; Messenger RNA; Modeling; Mus; Nature; Oncogenic; Pattern; Play; Production; Proteins; Reporting; Rest; Rodent; Role; Science; Signal Transduction; Structure of germinal center of lymph node; T-Lymphocyte Subsets; TCR Activation; Testing; Therapeutic; Tonsil; Translations; Vaccine Design; Vaccines; Work; autocrine; base; cost effective; cytokine; design; neutralizing antibody; novel; novel therapeutic intervention; overexpression; pathogen; plasma cell differentiation; response; small hairpin RNA; stem; transcription factor; vector

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.

描述（由申请人提供）：BCl6在卵泡辅助CD4 T细胞免疫的分化和功能中的作用是最具成本效益的医疗干预措施之一。大多数疫苗通过B淋巴细胞产生的病原体中和抗体的产生。但是，如果没有其他免疫系统组件的帮助，这些B细胞无法正常运行。另一种类型的淋巴细胞，卵泡T辅助细胞（TFH）对于产生抗体产生B淋巴细胞和生发中心很重要，但是最近才发现TFH，其生物学并不充分了解。我们发现了两个转录因子Bcl6和Blimp-1，它们是小鼠TFH分化的中心调节剂（Science，2009）。这些发现向人类的翻译将弥合我们对CD4 T细胞谱系承诺和体液免疫力的理解。通过增强我们对这些蛋白质如何控制人类中TFH分化和功能的知识，我们可以确保设计疫苗，以便它们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。此外，由于BCL6在许多淋巴瘤中起着至关重要的致癌作用，因此对BCL6/Blimp1控制谱系承诺如何带来新的淋巴瘤疗法的更全面了解。该提案的目的将调查BCL6如何调节人类TFH分化。 AIM II将增强我们对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：绝大多数当前有执照的疫苗通过触发中和抗体的产生来保护人类。卵泡T辅助细胞是这种体液免疫反应的关键组成部分，我们对它们如何区分和功能的了解受到限制。更好地了解卵泡T辅助细胞生物学将允许对某些癌症和自身免疫性疾病的更合理的疫苗设计和新型治疗方法。