Control of Th2 and Th17 differentiation by BCL6

描述(申请人提供)：过敏性疾病，如哮喘，是由辅助性T细胞2型(Th2)细胞的异常分化引起的。最近发现的一种T细胞亚群(称为“Th17”细胞)可以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。治疗T细胞介导的疾病的一个重要目标是全面了解控制Th2和Th17细胞类型分化的调控机制。BCL-6基因最初被确定为B细胞淋巴瘤的癌基因，编码一种转录抑制蛋白。我们以前已经证明bcl6是一种有效的Th2细胞分化抑制因子，bcl6基因缺陷的小鼠表现出严重夸大的Th2反应和Th2型炎症。我们最近发现bcl6基因缺陷的T细胞的Th17分化能力严重受损，表明bcl6功能是正常Th17分化所必需的。细胞因子IL-6可促进Th17细胞分化，而Th2细胞因子IL-4强烈抑制Th17细胞分化。我们发现，在Th17分化过程中，bcl6对于抑制IL-6诱导的IL-4的表达是必要的。此外，我们还发现在Th17条件下刺激的T细胞中bcl6表达上调，这表明在Th17分化过程中对bcl6有独特的要求。我们的假设是，bcl6对于Th17的反应是至关重要的，因为bcl6抑制了IL-6诱导的IL-4和/或IL-4信号，从而阻断了Th17的分化。我们将用下面概述的四个具体目标来检验这一假设。Bcl6基因缺陷小鼠的致死性Th2型炎症性疾病强调了bcl6在T细胞分化中的关键作用。阐明bcl6在Th2和Th17通路中作用的分子细节将增加我们对T辅助细胞分化调控的理解，并将促进治疗人类变态反应性和自身免疫性疾病的新药靶点的开发。此外，由于bcl6是人类B细胞淋巴瘤的主要致癌基因，对bcl6功能的了解将加深我们对B细胞淋巴瘤的总体认识和治疗。公共卫生相关性：变态反应性疾病、炎症性疾病和自身免疫性疾病是通过T辅助细胞的异常分化而促进的。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。这项工作将促进治疗人类过敏性和自身免疫性疾病的新药靶点的开发。

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.