Role of Myeloid Derived Suppressor Cells in intestinal inflammation

描述（由申请人提供）：效应T细胞及其细胞因子是炎症性肠病（IBD）的关键参与者。目前靶向T细胞的疗法可以导致IBD的缓解，但不是治愈性的，并且具有显著的副作用。骨髓源性抑制细胞（MDSC）是一种异质性的未成熟骨髓细胞群体，其抑制T细胞活化。MDSC在IBD患者中和硫酸葡聚糖（DSS）诱导的结肠炎的恢复期期间以及在scid小鼠中扩增，在scid小鼠中通过施用WT CD 4 + CD 45 RBhi T细胞诱导结肠炎。我们的初步数据显示，在三种不同的结肠炎小鼠模型（WASP/WARDKO小鼠、DSS处理的小鼠和Rag 1-/-幼稚T细胞受体）中，脾脏和固有层（LP）中CD 11b + Gr 1 + MDSC的扩增与脾脏和LP中T细胞的STAT 5降解相关。STAT 5在活动性结肠炎患者的外周血T细胞中也被降解。来自DSS处理的小鼠的T细胞具有降低的增殖，但响应于T细胞受体（TCR）连接而增加IL-17 A的产生。与来自结肠炎小鼠的CD 11b + Gr 1+细胞共培养，而不是与来自WT对照的细胞共培养，导致WT CD 4 + Foxp 3- Teff细胞中的STAT 5裂解，但不导致CD 4 + Foxp 3 + Treg细胞中的STAT 5裂解。它还导致T细胞增殖减少，这被STAT 5转导部分逆转，并增加IL-17 A的产生。来自患有DSS结肠炎的小鼠的T细胞中的STAT 5裂解依赖于半胱天冬酶-1。初步数据显示，来自半胱天冬酶1-/-小鼠的T细胞比WT细胞的大肠杆菌性更低。我们将检验结肠炎中MDSC的扩增和活化导致Teff细胞中半胱天冬酶-1依赖性STAT 5裂解的假设，改变它们对TCR连接的反应，从而调节疾病的严重程度。我们还将检验以下假设： 结肠炎中的MDSC触发NLRP 3炎性体激活半胱天冬酶-1，半胱天冬酶-1然后切割T细胞中的STAT 5，从而介导MDSC驱动的T细胞功能改变。最后，我们将检验来自IBD患者的MDSC引起人T细胞中STAT 5裂解并改变其功能的假设。拟议的研究可能提出旨在控制IBD中T细胞活化的新策略。

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.