Role of Blimp-1 in preventing chronic intestinal mucosal inflammation.

描述(申请人提供)：肠粘膜动态平衡的维持是通过复杂的机制实现的，包括主动下调免疫反应1，2.破坏这些机制导致对共生菌的慢性免疫反应，这可能导致炎症性肠病(IBD)的发展，3，4，也可能导致肠外的自身免疫性疾病5，6.CD4T辅助细胞效应(TEF)和调节性(Treg)淋巴细胞是维持肠粘膜动态平衡的重要角色2，但其在肠粘膜的动态平衡和炎症条件下发挥作用的分子机制尚不完全清楚。B淋巴细胞诱导成熟蛋白-1(Blimp-1)是一种对正常发育和免疫必不可少的转录因子。Blimp-1在T细胞11-15和Treg细胞11-15中表达，小鼠T细胞特异性Blimp-1缺失(Blimp-1CKO)导致严重的肠道炎症11，与结肠中CD4T细胞的聚集和炎性细胞因子11、16、17的异常产生有关。PRDM1(编码Blimp-1)的多态与人类严重的炎症情况有关，包括IBD18、19。因此，Blimp-1似乎是Tef细胞终末分化的关键调节因子，尽管Blimp-1在T细胞中控制的特异性转录程序在很大程度上仍不清楚。本文提出的研究将验证Blimp-1需要抑制粘膜T细胞获得炎性表型的假设，因此在维持肠粘膜动态平衡方面发挥着非多余的作用。为了验证这一假设，我们将a)鉴定肠粘膜中表达Blimp-1的T细胞，并确定调节Blimp-1表达的机制；b)确定T细胞特异性缺乏Blimp-1导致慢性肠道炎症的机制；以及c)确定Blimp-1阻止炎症表型获得的分子机制。我们预计，这些研究的完成将为炎症效应T细胞分化的遗传程序提供新的见解，并暗示Blimp-1是导致IBD等慢性疾病过程的关键抑制因子。

DESCRIPTION (provided by applicant): Maintenance of the intestinal mucosa homeostasis is achieved by complex mechanisms, including active downregulation of immune responses1, 2. Disruption of these mechanisms results in chronic immune responses towards the commensal flora which can lead to the development of Inflammatory Bowel Diseases (IBD), 3, 4 and may also contribute to autoimmune diseases at extra-intestinal sites5, 6. CD4+T helper effector (Teff) and regulatory (Treg) lymphocytes are important players in the maintenance of intestinal mucosa homeostasis2, but the molecular mechanisms underlying their function under homeostatic and inflammatory conditions at the intestinal mucosa are not fully understood. B-lymphocyte-induced maturation protein -1 (Blimp-1) is a transcription factor essential for normal development and immunity7. Blimp-1 is expressed in Teff and Treg cells11-15 and T-cell specific deletion of Blimp-1 in mice (Blimp-1CKO) results in development of severe intestinal inflammation11, associated with the accumulation of CD4+ T cells in the colon and aberrant production of inflammatory cytokines11, 16, 17. Polymorphisms in PRDM1 (encoding Blimp-1) are associated with severe inflammatory conditions in humans, including IBD18, 19. Thus, Blimp-1 appears to be a critical regulator of Teff cell terminal differentiation although the speciic transcriptional programs controlled by Blimp-1 in T cells remain largely unknown. The studies proposed here will test the hypothesis that Blimp-1 is required to repress the acquisition of an inflammatory phenotype by mucosal T cells and therefore plays a non redundant role in the maintenance of intestinal mucosa homeostasis. To test this hypothesis we will a) characterize Blimp-1-expressing T cells in the intestinal mucosa and determine the mechanisms regulating Blimp-1 expression; b) identify the mechanisms by which T cell-specific lack of Blimp-1 leads to chronic intestinal inflammation; and c) Determine the molecular mechanisms by which Blimp-1 prevents the acquisition of inflammatory phenotype. We anticipate that the completion of these studies will provide new insights into the genetic programs underlying the differentiation of inflammatory effector T cells, and implicate Blimp-1 as a key repressor of the processes leading to chronic conditions such as IBD.