Role of BCL11B in CD4+ T Cells

描述（由申请人提供）：辅助T细胞在中枢神经系统中的迁移和浸润是多发性硬化（MS）及其实验性自身免疫性脑脊髓炎（EAE）动物模型中的关键事件。我们的初步研究结果表明，小鼠在成熟的T细胞转录因子Bcl 11b缺陷表现出降低EAE的严重性与延迟发病，减少辅助性T细胞浸润中枢神经系统造成的。相反，辅助性T细胞在肠道中积累，但不会引起明显的炎症性肠病。我们提出的研究，以破译的Bcl 11b缺陷的CD 4 + T细胞从引流淋巴结和中枢神经系统，这将开辟新的途径，多发性硬化症的治疗，和其他自身免疫性疾病的转移的分子机制。此外，这些研究是非常重要的，因为它们将进一步我们的控制效应CD 4 + T细胞分化和功能可塑性的转录因子网络的理解。具体而言，我们的研究将揭示转录因子Bcl 11b，Rogt和Gata 3在Th 17谱系分化中的关系，以及Bcl 11b，Gata 3和Rogt在Th 2谱系分化中的关系，以及这两种交替谱系如何相互影响以维持特化和可塑性之间的平衡。 公共卫生相关性：最佳的辅助T细胞免疫应答需要两个关键事件：（1）有效产生适当的细胞因子，这是通过调节其他免疫细胞来遏制入侵生物体所必需的;（2）效应CD 4 + T细胞有效迁移到炎症的特定部位，而不是其他部位。破译这两个过程背后的分子机制对于开发能够引发保护性免疫反应的疗法至关重要，同时阻断那些对宿主有害的免疫反应，例如多发性硬化症和其他自身免疫性疾病。

DESCRIPTION (provided by applicant): Helper T-cell migration and infiltration in central nervous system are critical events in multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE). Our preliminary results show that mice deficient in transcription factor Bcl11b in mature T cells showed reduced EAE severity with delayed onset, caused by diminished helper T-cell infiltration in the CNS. Instead helper T cells accumulated in the gut, however without causing overt inflammatory bowel disease. We propose studies to decipher the molecular mechanisms underlying the diversion of the Bcl11b-deficient CD4+ T cells from the draining lymph nodes and central nervous system, whichwill open new avenues for multiple sclerosis therapies, and other autoimmune disorders. Additionally, these studies are of major importance because they will further our understanding of the network of transcription factors that control effector CD4+ T cell differentiation and functional plasticity. Specifically, our studies will reveal the relationship between the transcription factors Bcl11b, Rorgt and Gata3 in Th17 lineage differentiation, Bcl11b, Gata3 and Rorgt in Th2 lineage differentiation, and how these two alternate lineages influence each other to maintain the balance between specialization and plasticity. PUBLIC HEALTH RELEVANCE: An optimal helper T cell immune response requires two critical events: (1) efficient production of the appropriate cytokines, necessary to contain an offending organism by regulating other immune cells; (2) efficient migration of effector CD4+ T cells to the specific site of inflammation, and not to other sites. Deciphering the molecular mechanisms underlying these two processes is essential for the development of therapies able to elicit protective immune responses, while blocking those detrimental to the host, such as those in multiple sclerosis and other autoimmune diseases.