Control of Th2 and Th17 differentiation by BCL6

BCL6 控制 Th2 和 Th17 分化

• 批准号: 7662171
• 负责人: Alexander L Dent
• 金额: $ 19.25万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-08 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662171
• 关键词: Allergic; Asthma; Autoimmune Diseases; B-Cell Lymphomas; BCL6 gene; Biochemical Genetics; Biological Assay; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Development; Disease; Drug Delivery Systems; Gene Expression; Genes; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Human; Immunization; In Vitro; Inflammation; Inflammatory; Interleukin-17; Interleukin-4; Interleukin-6; Knowledge; Mediating; Microarray Analysis; Molecular; Mus; Oncogenes; Pathway interactions; Peripheral; Regulation; Repressor Proteins; Role; Signal Transduction; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Th2 Cells; Therapeutic Uses; Transcription Repressor/Corepressor; Work; cell type; cytokine; in vivo; inhibitor/antagonist; insight; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Allergic diseases, such as asthma, are promoted by abnormal differentiation of T helper type 2 (Th2) cells. A recently described T cell subset (termed "Th17" cells) has been found to promote inflammation and autoimmune disease, in large part due to their secretion of the cytokine IL-17. An important goal for the management of T cell-mediated diseases is to achieve a complete understanding of the regulatory mechanisms controlling the differentiation of Th2 and Th17 cell types. The BCL-6 gene, originally identified as an oncogene for B cell lymphoma, encodes a transcriptional repressor protein. We have shown previously that BCL-6 is a potent inhibitor of Th2 cell differentiation, and BCL-6-deficient mice develop greatly exaggerated Th2 responses and Th2-type inflammation. We have recently found that BCL-6-deficient T cells are severely impaired in their ability to undergo Th17 differentiation, indicating that BCL-6 function is required for normal Th17 differentiation. The cytokine IL-6 can promote Th17 differentiation, but the Th2 cytokine IL-4 strongly blocks Th17 differentiation. We have found that BCL-6 is necessary to repress IL-4 expression induced by IL-6 during Th17 differentiation. Further, we have found that BCL-6 is up-regulated in T cells stimulated under Th17 conditions, indicating a unique requirement for BCL-6 in Th17 differentiation. Our hypothesis is that BCL-6 is critically required for Th17 responses because BCL-6 represses IL-6-induced IL-4 and/or IL-4 signals that can block Th17 differentiation. We will test this hypothesis with four specific aims outlined below. The lethal Th2-type inflammatory disease that develops in BCL-6-deficient mice underscores the critical role of BCL-6 in T cell differentiation. Elucidating the molecular details of the role of BCL-6 in the Th2 and Th17 pathways will increase our understanding of how T helper cell differentiation is regulated and should promote the development of new drug targets for the treatment of human allergic and autoimmune diseases. Further, since BCL-6 is a major oncogene in human B cell lymphoma, increased knowledge of BCL-6 function will enhance our general understanding and treatment of B cell lymphoma. Public Health Relevance: Allergic diseases, inflammatory diseases and autoimmune diseases are promoted by abnormal differentiation of T helper cells. In this study, we wish to increase our understanding of how T helper cell differentiation is regulated. This work should promote the development of new drug targets for the treatment of human allergic and autoimmune diseases.

描述（由申请人提供）： 2 型辅助 T (Th2) 细胞的异常分化会促进过敏性疾病，例如哮喘。最近描述的 T 细胞亚群（称为“Th17”细胞）被发现可促进炎症和自身免疫性疾病，这在很大程度上是由于它们分泌细胞因子 IL-17。 T 细胞介导的疾病管理的一个重要目标是全面了解控制 Th2 和 Th17 细胞类型分化的调节机制。 BCL-6 基因最初被确定为 B 细胞淋巴瘤的癌基因，编码转录抑制蛋白。我们之前已经证明，BCL-6 是 Th2 细胞分化的有效抑制剂，BCL-6 缺陷的小鼠会出现严重夸大的 Th2 反应和 Th2 型炎症。我们最近发现BCL-6缺陷的T细胞进行Th17分化的能力严重受损，表明BCL-6功能是正常Th17分化所必需的。细胞因子IL-6可以促进Th17分化，但Th2细胞因子IL-4强烈阻断Th17分化。我们发现，BCL-6 对于抑制 Th17 分化过程中 IL-6 诱导的 IL-4 表达是必需的。此外，我们发现 BCL-6 在 Th17 条件下刺激的 T 细胞中上调，表明 Th17 分化中对 BCL-6 的独特需求。我们的假设是，BCL-6 对于 Th17 反应至关重要，因为 BCL-6 抑制 IL-6 诱导的 IL-4 和/或 IL-4 信号，从而阻止 Th17 分化。我们将通过下面列出的四个具体目标来检验这一假设。 BCL-6 缺陷小鼠中发生的致命 Th2 型炎症性疾病强调了 BCL-6 在 T 细胞分化中的关键作用。阐明 BCL-6 在 Th2 和 Th17 通路中作用的分子细节将增加我们对 T 辅助细胞分化如何调节的理解，并应促进治疗人类过敏和自身免疫性疾病的新药物靶点的开发。此外，由于BCL-6是人类B细胞淋巴瘤的主要癌基因，增加对BCL-6功能的了解将增强我们对B细胞淋巴瘤的总体了解和治疗。公共健康相关性：T 辅助细胞的异常分化会促进过敏性疾病、炎症性疾病和自身免疫性疾病。在这项研究中，我们希望加深对 T 辅助细胞分化如何调节的了解。这项工作应促进治疗人类过敏和自身免疫性疾病的新药物靶点的开发。