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。目前针对T细胞的治疗方法可以缓解IBD，但不能治愈，并且有明显的副作用。髓源性抑制细胞（myeloid -derived suppressor cells, MDSCs）是一种异质的未成熟髓细胞群，能够抑制T细胞的活化。MDSCs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WT CD4+CD45RBhi T细胞诱导结肠炎的scid小鼠中扩增。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处理小鼠和Rag1-/-初始T细胞受体）中，脾脏和固有层（LP）中CD11b+Gr1+ MDSCs的扩增与脾脏和LP中T细胞的STAT5降解有关。在活动性结肠炎患者的外周血T细胞中，STAT5也被降解。DSS处理小鼠的T细胞增殖减少，但在T细胞受体（TCR）连接的反应中增加了IL-17A的产生。与结肠炎小鼠的CD11b+Gr1+细胞共培养，而不是WT对照组的CD11b+Gr1+细胞，导致WT CD4+Foxp3- Teff细胞中STAT5分裂，而CD4+Foxp3+ Treg细胞中没有。它还导致T细胞增殖下降，这一现象被STAT5转导部分逆转，并增加了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细胞具有更少的结肠炎性。我们将验证结肠炎中MDSCs的扩增和激活导致Teff细胞中caspase-1依赖性STAT5裂解的假设，改变它们对TCR结扎的反应，从而调节疾病的严重程度。我们也会检验假设

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.