Control of Th2 and Th17 differentiation by BCL6

描述（由申请人提供）：过敏性疾病，如哮喘，是由辅助性T细胞2型（Th 2）细胞的异常分化促进的。已经发现最近描述的T细胞亚群（称为“Th 17”细胞）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。管理T细胞介导的疾病的一个重要目标是实现对控制Th 2和Th 17细胞类型分化的调节机制的完全理解。BCL-6基因最初被鉴定为B细胞淋巴瘤的癌基因，编码转录抑制蛋白。我们以前已经表明，BCL-6是一个有效的抑制剂的Th 2细胞分化，BCL-6缺陷小鼠发展大大夸大的Th 2反应和Th 2型炎症。我们最近发现，BCL-6缺陷型T细胞进行Th 17分化的能力严重受损，表明BCL-6功能是正常Th 17分化所必需的。细胞因子IL-6可促进Th 17分化，但Th 2细胞因子IL-4强烈阻断Th 17分化。我们发现BCL-6在抑制IL-6诱导的IL-4表达中是必需的。此外，我们发现BCL-6在Th 17条件下刺激的T细胞中上调，表明在Th 17分化中对BCL-6的独特需求。我们的假设是BCL-6是Th 17应答所必需的，因为BCL-6抑制IL-6诱导的IL-4和/或IL-4信号，这些信号可以阻断Th 17分化。我们将用下面列出的四个具体目标来检验这一假设。在BCL-6缺陷小鼠中发展的致死性Th 2型炎性疾病强调了BCL-6在T细胞分化中的关键作用。阐明BCL-6在Th 2和Th 17通路中的作用的分子细节将增加我们对T辅助细胞分化是如何调节的理解，并应促进用于治疗人类过敏性和自身免疫性疾病的新药靶点的开发。此外，由于BCL-6是人B细胞淋巴瘤中的主要癌基因，因此增加对BCL-6功能的了解将增强我们对B细胞淋巴瘤的总体理解和治疗。公共卫生相关性：过敏性疾病、炎症性疾病和自身免疫性疾病是由辅助性T细胞的异常分化促进的。在这项研究中，我们希望增加我们对T辅助细胞分化是如何调节的理解。这项工作将促进开发用于治疗人类过敏性和自身免疫性疾病的新药物靶点。

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.