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

描述（由申请人提供）：肠黏膜稳态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。这些机制的破坏会导致对共生菌群的慢性免疫反应，从而导致炎症性肠病（IBD）的发展，3,4，也可能导致肠外部位的自身免疫性疾病5,6。CD4+T辅助效应淋巴细胞（Teff）和调节性淋巴细胞（Treg）在维持肠黏膜内稳态中起着重要作用2，但它们在肠黏膜内稳态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）是正常发育和免疫所必需的转录因子7。Blimp-1在Teff和Treg细胞中表达11-15，小鼠体内Blimp-1的T细胞特异性缺失（Blimp-1CKO）会导致严重的肠道炎症11，这与结肠中CD4+ T细胞的积累和炎症细胞因子的异常产生有关11,16,17。PRDM1（编码Blimp-1）的多态性与人类严重炎症有关，包括IBD18, 19。因此，尽管在T细胞中由Blimp-1控制的特异性转录程序仍然很大程度上未知，但Blimp-1似乎是Teff细胞末端分化的关键调节因子。本文提出的研究将验证一个假设，即Blimp-1是抑制粘膜T细胞获得炎症表型所必需的，因此在维持肠粘膜稳态中起着非冗余的作用。为了验证这一假设，我们将a)表征肠粘膜中表达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；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是导致慢性疾病（如IBD）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.