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（申请人提供）：Bcl6在卵泡辅助性CD4 T细胞分化和功能中的作用免疫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B淋巴细胞产生的病原体中和抗体起作用。然而，如果没有其他免疫系统成分的帮助，这些B细胞无法正常工作。另一种类型的淋巴细胞，滤泡T辅助细胞（TFH），对产生抗体的B淋巴细胞和生发中心很重要，但TFH最近才被发现，其生物学尚不清楚。我们发现了两个转录因子，Bcl6和Blimp-1，它们在小鼠的TFH分化中起着中心调节作用（Science, 2009）。将这些发现转化为人类将弥合我们对CD4 T细胞谱系承诺和体液免疫的理解中的关键空白。通过加强我们对这些蛋白质如何控制人体内TFH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，并可能极大地惠及普通民众。此外，由于Bcl6在许多淋巴瘤中起着至关重要的致瘤作用，因此更全面地了解Bcl6/Blimp1如何控制谱系承诺可能会带来新的淋巴瘤治疗方法。本文的目的一是研究Bcl6如何调控人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。