Role of BCL11B in CD4+ T Cells

描述（由申请人提供）：辅助性t细胞在中枢神经系统的迁移和浸润是多发性硬化症（MS）及其实验性自身免疫性脑脊髓炎（EAE）动物模型的关键事件。我们的初步结果表明，成熟T细胞中缺乏转录因子Bcl11b的小鼠，由于中枢神经系统中辅助性T细胞浸润减少，EAE严重程度降低，发病延迟。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。我们建议研究bcl11b缺陷CD4+ T细胞从引流淋巴结和中枢神经系统转移的分子机制，这将为多发性硬化症和其他自身免疫性疾病的治疗开辟新的途径。此外，这些研究具有重要意义，因为它们将进一步加深我们对控制效应CD4+ 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Bcl11b， Rorgt和Gata3在Th17谱系分化中的关系，以及Bcl11b， Gata3和Rorgt在Th2谱系分化中的关系，以及这两个交替谱系如何相互影响以维持专业化和可塑性之间的平衡。

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.