The function of immunoproteasomes in cytokine production and autoimmune diseases

免疫蛋白酶体以其在MHC I类途径的抗原加工中的作用而闻名。最近，我们观察到免疫蛋白酶体亚基LMP2、MECL-1和LMP7是病毒感染小鼠T细胞正常扩增和存活所必需的。这使我们假设免疫蛋白酶体的抑制可能是抑制自身免疫性疾病中不想要的T细胞反应的一种手段。事实上，LMP7抑制剂可以预防胶原诱导关节炎和胶原抗体诱导关节炎的疾病症状。LMP7抑制会干扰促炎细胞因子TNFα、IL-6和IL-23的产生以及Th17细胞的体外分化。鉴于Th17细胞参与多种自身免疫性疾病的病因学，我们希望在炎症性肠病、多发性硬化症和糖尿病的小鼠模型中测试LMP7抑制或缺失是否可以在体内抑制这些疾病。为了研究免疫蛋白酶体如何在机制上参与细胞因子产生的控制，我们将研究LMP7和MECL-1缺陷如何影响增殖的小鼠T细胞的转录组和蛋白质组。我们将研究已知参与Th1和Thl7细胞T细胞分化的转录因子在LMP7抑制剂存在和不存在时的磷酸化状态和表达水平。特别是，我们将研究为什么PR-957存在时STAT3的lL-6依赖性磷酸化被抑制。通过这些实验，我们研究了免疫蛋白酶体可能选择性地加工或降解参与Th17分化的因子的中心假设。

The immunoproteasome is known for its role in antigen processing along the MHC class I pathway. Recently, we have observed that the immunoproteasome subunits LMP2, MECL-1 and LMP7 are required for normal expansion and survival of T cells in virus infected mice. This has led us to hypothesize that the inhibition of immunoproteasomes could be a means to dampen undesired T cell responses in autoimmune diseases. Indeed, an inhibitor of LMP7 could prevent disease symptoms in collagen induced arthritis and collagen antibody induced arthritis. LMP7 inhibition interfered with the production of proinflammatory cytokines TNFα, IL-6, and IL-23 and the differentiation of Th17 cells in vitro. Given that Th17 cells are involved in the etiology of several autoimmune diseases, we would like to test in mouse models of inflammatory bowel disease, multiple sclerosis, and diabetes whether LMP7 inhibilion or deletion can suppress these diseases in vivo. In order lo investigate how the immunoproteasome may be mechanistically involved in the control of cytokine production we will investigate how LMP7 and MECL-1 deficiency affects the transcriptome and proteome of proliferating mouse T cells. Transcription factors known to be involved in T cell differentiation of Th1 and Thl7 cells will be investigated with respect to their phosphorylation status and expression level in the presence and absence of LMP7 inhibitor. In particular we will investigate why the lL-6 dependent phosphorylation of STAT3 is suppressed in the presence of PR-957. With these experiments we investigate the central hypothesis that the immunoproteasome may selectively process or degrade a factor involved in Th17 differentiation.