Role of Myeloid Derived Suppressor Cells in intestinal inflammation

描述(申请人提供)：效应T细胞及其细胞因子是炎症性肠病(IBD)的关键因素。目前针对T细胞的治疗方法可以缓解IBD，但不能治愈，而且有显著的副作用。髓系抑制细胞(MDSCs)是一群异质性的未成熟髓系细胞，可抑制T细胞的激活。在IBD患者和葡聚糖硫酸盐(DSS)诱导的结肠炎恢复期，以及通过注射WT CD4+CD45RBhi T细胞诱导结肠炎的SCID小鼠中，MDSCs被扩增。我们的初步数据显示，在三种不同的结肠炎小鼠模型(WASP/WIP DKO小鼠、DSS治疗小鼠和Rag1/-初始T细胞受体)中，CD11b+Gr1+MDSCs在脾和固有层(LP)中的扩张与驻留在脾和LP中的T细胞中STAT5的降解有关。活动期结肠炎患者外周血T细胞中的Stat5也被降解。DSS处理的小鼠T细胞的增殖能力下降，但T细胞受体(TCR)结扎后IL-17A的产生增加。与来自结肠炎小鼠的CD11b+Gr1+细胞共培养，但不引起WT对照的CD11b+Gr1+细胞的STAT5裂解，但不引起CD4+Foxp3+Treg细胞的STAT5裂解。它还导致T细胞增殖下降，这一作用可被STAT5信号转导部分逆转，并增加IL-17A的产生。DSS结肠炎小鼠T细胞中Stat5的裂解依赖于caspase-1。初步数据显示，来自caspase1-/-小鼠的T细胞比WT细胞的结肠率低。我们将测试这一假设，即结肠炎中MDSCs的扩张和激活导致Tef细胞中caspase-1依赖的STAT5裂解，改变它们对TCR结扎的反应，从而调节疾病的严重程度。我们还将检验这一假设 结肠炎中的MDSCs触发NLRP3炎症小体激活caspase-1，然后caspase-1裂解T细胞中的STAT5，从而介导MDSCs驱动的T细胞功能改变。最后，我们将验证来自IBD患者的MDSCs导致人类T细胞中STAT5裂解并改变其功能的假设。拟议的研究可能会提出旨在控制IBD中T细胞激活的新策略。

DESCRIPTION (provided by applicant): Effector T cells and their cytokines are key players in Inflammatory Bowel Disease (IBD). Current therapies targeting T cells can result in remission of IBD, but are not curative, and have significant side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which suppress T cell activation. MDSCs are expanded in patients with IBD and during the recovery phase of dextran sulfate (DSS)-induced colitis and in scid mice in which colitis is induced by administration of WT CD4+CD45RBhi T cells. Our preliminary data show that expansion of CD11b+Gr1+ MDSCs in the spleen, and lamina propria (LP) in three distinct mouse models of colitis (WASP/WIP DKO mice, DSS-treated mice and Rag1-/- recipients of naive T cells) was associated with STAT5 degradation in T cells residing in the spleen and LP. STAT5 was also degraded in peripheral blood T cells from patients with active colitis. T cells from DSS treated mice had decreased proliferation, but increased production of IL-17A in response to T cell receptor (TCR) ligation. Co-culture with CD11b+Gr1+ cells from mice with colitis, but not from WT controls, caused STAT5 cleavage in WT CD4+Foxp3- Teff cells, but not CD4+Foxp3+ Treg cells. It also caused decreased T cell proliferation that was partially reversed by STAT5 transduction, and increased the production of IL-17A. STAT5 cleavage in T cells from mice with DSS colitis was dependent on caspase-1. Preliminary data shows that T cells from caspase1-/- mice are less colitogenic than WT cells. We will test the hypothesis that expansion and activation of MDSCs in colitis causes caspase-1 dependent STAT5 cleavage in Teff cells, altering their response to TCR ligation, and thereby modulating the severity of the disease. We will also test the hypothesis that MDSCs in colitis trigger the NLRP3 inflammasome to activate caspase-1, which then cleaves STAT5 in T cells, thereby mediating MDSCs driven alteration of T cell function. Finally, we will test the hypothesis that MDSCs from patients with IBD cause STAT5 cleavage in human T cells and alter their function. The proposed studies may suggest novel strategies that aim to control T cell activation in IBD.