NOD2在Treg细胞的肠部归巢及免疫调节中的作用及其机制的研究

A frameshift mutation in NOD2, a pattern recognition receptor, confers a significant susceptibility to developing Crohn’s disease (CD), underlying mechanism of which is uncertain. Treg cells play an important role in immunomodulation and the pathogenesis of inflammatory bowel disease. We use NOD2 knockout (KO) mice as a model for mimicking people with the frameshift mutation of NOD2, and focus on Treg cells to determine the mechanism of the susceptibility. We have found that Treg cell number and CCL5 expression are increased in gut-associated lymphoid tissues from NOD2KO mice. Since CCL5 is required for kin homing of Treg cells, we are plan to determine mechanism of regulation of Treg gut-homing in NOD2KO mice. Although the increased Treg cells exist in the intestine of NOD2KO mice, they are not able to suppress the intestinal inflammation. Next, we will determine effects of the intestinal environment factors on Treg cells, and mechanisms of regulation of Th17/Treg balance. Thus, this study will help to discover important molecular events in gut-homing of Treg cells, and key regulators of immunomodulation mediated by Treg cells. It will also provide theoretic foundation of mechanisms of the frameshift mutation of NOD2 conferring a significant susceptibility to developing CD.

模式识别受体NOD2移码突变的人群易患克罗恩病，其机制目前尚无定论。Treg细胞作为免疫调节的重要组成部分，与炎症性肠病的发生发展关系密切。本研究利用NOD2敲除小鼠，模拟NOD2移码突变的人群，并从Treg细胞出发，试图解释NOD2移码突变的易感机制。前期研究发现，NOD2敲除小鼠中Treg细胞的数目及趋化因子5（CCL5）的表达在肠部淋巴组织中增加。CCL5信号是Treg细胞皮肤归巢的信号。为此，我们探索NOD2敲除小鼠中，调控Treg细胞向肠部归巢的机制。尽管Treg细胞在NOD2敲除小鼠肠部增加，却不能阻止肠炎发生。我们进一步研究NOD2敲除小鼠中，肠部微环境对Treg功能的影响，及Th17/Treg平衡的调控机制。因此，本研究有助于发现Treg细胞肠部归巢的重要分子事件，揭示影响肠部Treg细胞发挥免疫调节功能的环节，为阐明NOD2移码突变人群易患克罗恩病的机制提供理论支持。

模式识别受体NOD2移码突变的人群易患克罗恩病，其机制目前尚无定论。本研究利用NOD2敲除小鼠模拟NOD2移码突变的人群，探讨NOD2基因突变人群易患克罗恩病的机制，首次发现调节性T细胞（Treg）在NOD2敲除小鼠的肠系膜淋巴结及派氏结中显著增加，而该增加的Treg细胞并不能控制小肠炎症。针对NOD2敲除小鼠Treg细胞肠部增加的机制研究发现趋化因子5（CCL5）的表达在NOD2敲除小鼠的肠部淋巴组织中增加，胞壁酰二肽（MDP）激活的NOD2信号可抑制Treg细胞中趋化因子受体5（CCR5）的表达，进一步发现CCR5的拮抗剂马拉罗伟可抑制Treg细胞在NOD2敲除小鼠的肠系膜淋巴结中的增多，这些结果证明CCR5信号介导NOD2敲除小鼠中Treg细胞的肠部归巢。有意思的是NOD2敲除小鼠肠部CCL5表达上调，而MDP也可诱导CCL5的表达，抗生素处理可抑制NOD2敲除小鼠肠部CCL5的表达，这表明MDP-NOD2信号可能是促进CCL5表达的部分激活信号，进而揭示了微生物分子模式MAMP对CCL5表达调控的新模式。围绕NOD2敲除小鼠肠部增加的Treg细胞不能控制小肠炎症开展的研究发现，虽然体外实验证明NOD2缺失的Treg仍具有免疫抑制功能，但体内不能控制炎症可能与Th17/Treg细胞平衡有关，我们认为在正常状态下，NOD2敲除小鼠中促炎信号增强，抗炎信号也增强，此时肠部免疫平衡，在损伤状态下，NOD2敲除小鼠中促炎信号继续增强，抗炎信号得不到对应增强，此时肠部免疫失衡。本研究发现NOD2基因突变个体易患克罗恩氏病可能与NOD2调节肠部Th17/Treg平衡有关，为阐明NOD2移码突变人群易患克罗恩病的机制提供理论依据，并且提出促进Treg的肠部招募可能是治疗炎症性肠病的新策略。