β干扰素TIR结构域衔接蛋白（TRIF）通过调节肠道菌群在1型糖尿病发病中的作用及机制

The pathogenesis of type 1 diabetes (T1D) is unclear till now. Both genetic predisposition and environment are involved. Gut microbiota has been identified as an important environmental factor that could modify T1D susceptibility. TIR-domain-containing adapter-inducing interferon-β (TRIF) is one of important TIR-domain-containing-adapters in the TLR3 and TLR4 downstream signal pathways, which exerts a role in initiating innate immunity, recognizing and eliminating gut microbiome and maintianing the homeostasis. But less is known about its role and mechanism in the development of T1D. In order to figure it out, we generated TRIF-/-NOD mice first in the world. Our previous study showed TRIF deficiency altered the composition of gut microbiota via anti-microbial peptides (AMP), thus delayed T1D. Based on this, we propose the hypothesis that TRIF deficiency decreases the gut permeability via modulating the composition of gut microbiota, thus attenuates the activation of antigen presenting cells, in turn T cells, which delays T1D onset. We try to investigate that TRIF deficiency could alter the composition of gut microbiota thus modulate adaptive immunity to influence T1D susceptibility in vitro and in vivo step by step, which could provide novel theoretical basis for the pathogenesis and the therapeutic intervention target in T1D.

1型糖尿病(T1D)病因未明，遗传和环境因素起主要作用。肠道菌群是T1D重要的易感因素。β干扰素TIR结构域衔接蛋白(TRIF)是TLR3和TLR4下游信号传导通路中重要的TIR衔接蛋白，在启动天然免疫、识别并清除肠道病原微生物及维持体内菌群平衡中起关键作用，但TRIF在T1D发病中的作用及机制不清。课题组首创了TRIF-/-NOD小鼠模型，前期研究提示TRIF缺陷导致抗微生物肽(AMP)水平降低，改变肠道菌群组成，延缓T1D的发生。据此，提出假设TRIF缺陷能通过改变肠道菌群组成降低肠道通透性，削弱抗原递呈细胞的抗原提呈能力，继而导致T细胞的活化增殖能力下降，从而延缓T1D的发生。本研究从天然免疫角度出发，体外体内多角度层层深入阐明TRIF缺陷通过改变肠道菌群构成，继而调节获得性免疫影响T1D的易感性这一免疫机制，为T1D的免疫发病提供新的理论依据，有希望为T1D预防治疗开辟新的靶点。

1型糖尿病(T1D)病因未明，遗传和环境因素起主要作用。肠道菌群是T1D重要的易感因素。β干扰素TIR结构域衔接蛋白(TRIF)是TLR3和TLR4下游信号传导通路中重要的TIR衔接蛋白，在启动天然免疫、识别并清除肠道病原微生物及维持体内菌群平衡中起关键作用，但TRIF在T1D发病中的作用及机制不清。课题组首创了TRIF-/-NOD小鼠模型，前期研究提示TRIF缺陷导致抗微生物肽(AMP)水平降低，改变肠道菌群组成，延缓T1D的发生。据此推测，TRIF缺陷能通过改变肠道菌群组成，削弱抗原递呈细胞的抗原提呈能力，继而导致T细胞的活化增殖能力下降，从而延缓T1D的发生。本研究从天然免疫角度出发，体外体内多角度层层深入阐明了TRIF缺陷通过改变肠道菌群构成，继而调节获得性免疫影响T1D的易感性这一免疫机制，为T1D的免疫发病提供新的理论依据，有希望为T1D预防治疗开辟新的靶点。