The regulation of Dendritic Cell function by Cytokine signal

细胞因子信号受“细胞因子信号转导抑制因子（Suppressor of Cytokine Signaling，SOCS）”家族蛋白的严格调控。研究的目的是阐明SOCS调节的细胞因子信号如何控制调节性树突状细胞（DC）和Treg细胞的发育和功能，Treg细胞在体内发挥免疫耐受^（1）和预防肠道慢性炎症以维持肠道稳态^（2）的作用。(1)在T细胞中缺失SOCS 3（一种STAT 3相关细胞因子信号的抑制因子）导致TGFβ产生增加，从而导致优先分化为调节性Th 3细胞。此外，缺乏SOCS 3的DC表现出不成熟的表型和升高的TGFβ水平，其选择性地从幼稚T细胞扩增Th 3细胞。此外，组成性激活STAT 3，SOCS 3的靶信号分子，在DC中抑制DC成熟。重要的是，在EAE模型小鼠中注射抗原脉冲的SOCS 3缺陷型DC可以改善自身免疫性疾病的发展。(2)TCR α KO小鼠中Th 2介导的慢性结肠炎的自发发展在缺乏SOCS 1（STAT 1/6相关细胞因子信号的抑制剂）的情况下恶化。结肠炎的恶化不仅是由于Th 2型细胞因子IL-4的信号增强，而且还由于Th 1型细胞因子IFNγ和LPS的信号增强，这表明SOCS 1通过阻断Th 1和Th 2细胞因子信号来抑制IBD。此外，除T和B细胞外，缺乏SOCS 1的小鼠表现出IFN γ依赖性、严重的结肠炎和结肠直肠癌的自发发展，伴有炎性细胞浸润和致癌相关酶如iNOS和COX 2的上调。这些结果有力地表明，SOCS 1是一种独特的抗癌基因，通过调节IFNγ/STAT 1通路来防止慢性炎症介导的致癌作用。

The cytokine signals are regulated strictly by "Suppressor of Cytokine Signaling (SOCS)" family proteins. The aim of study is to clarify how cytokine signals modulated by SOCS control the development and function of regulatory dendritic cells (DC) as well as Treg cells, which serves immune tolerance^ (1) and prevent chronic inflammation in the gut to maintain the gut homeostasis in vivd^ (2).(1) Deletion of SOCS3, a suppressor of STAT3-related cytokine signal, in T cells resulted in augmented TGFβ production leading to preferential differentiation into regulatory Th3 cells. Moreover, DC lacking SOCS3 showed immature phenotype and elevated levels of TGFβ, that selectively expanded Th3 cells from naive T cells. In addition, constitutive activation of STAT3, a target signal molecule of SOCS3, in DC inhibited DC maturation. Importantly, injection of antigen-pulsed SOCS3-deficient DC in EAE model mice could ameliorate the development of autoimmune disease.(2) Spontaneous development of Th2-mediated chronic colitis in TCRa KO mice was deteriorated in the absence of SOCS1, a suppressor of STAT1/6-related cytokine signal. The deterioration of colitis was due to enhanced signal of not only Th2-type cytokine, IL-4 but also Th1-type cytokine, IFNγ, and LPS, suggesting that SOCS1 suppresses IBD by blocking both Thl and Th2 cytokine signals. Furthermore, mice lacking SOCS1 except for T and B cells showed IFN γ-dependent, severe colitis and spontaneous development of colorectal carcinomas accompanied with infiltration of inflammatory cells and upregulation of carcinogenesis-related enzymes such as iNOS and COX2. These results strongly suggest that SOCS1 is a unique antioncogene that prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNγ/STAT1 pathway.