Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection.
Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection.
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DOI：
10.4049/jimmunol.1500653
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发表时间：
2015-08-15
期刊：
影响因子：
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通讯作者：
Egwuagu CE
中科院分区：
文献类型：
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作者：
Kim SH;Burton J;Yu CR;Sun L;He C;Wang H;Morse HC 3rd;Egwuagu CE
干扰素调节因子8 （IRF8）在单核细胞和B细胞中组成性表达，在小胶质细胞的功能成熟中起关键作用。它是在抗原刺激后在t细胞中诱导的，但其功能尚不清楚。然而，最近在Lck启动子（Lck - irf8ko）指导下T细胞特异性Irf8中断的小鼠中进行的研究表明，Irf8指导了Th17分化的沉默程序，并且在Irf8缺陷的T细胞中IL-17的产生显着增加。矛盾的是，在小鼠结肠炎模型中，t细胞中IRF8的缺失对实验性自身免疫性脑脊髓炎（EAE）的发展或严重程度没有影响，而加重了结肠炎。另一方面，巨噬细胞/小胶质细胞特异性Irf8破坏的小鼠对EAE具有抗性，这进一步混淆了我们对Irf8在宿主免疫和自身免疫中的作用的理解。为了阐明IRF8在自身免疫性疾病中的作用，我们在视网膜细胞（包括小胶质细胞）中产生了两个靶向缺失IRF8的小鼠品系，在非混杂的CD4启动子（CD4- irf8ko）的指导下，在t细胞中产生了第三个靶向缺失IRF8的小鼠品系。与t细胞中IRF8缺失对EAE没有影响的报道相反，实验性自身免疫性葡萄膜炎在CD4-IRF8KO小鼠中加剧，疾病增强与Th17细胞的显著扩增和Tregs的减少相关。与CD4-IRF8KO小鼠相比，Irf8在视网膜细胞中的缺失可以保护其免受葡萄膜炎，这强调了Irf8在宿主免疫中的发散性和组织特异性作用。这些结果对IRF8的靶向治疗提出了警示。
Interferon regulatory factor 8 (IRF8) is constitutively expressed in monocytes and B cells and plays critical role in the functional maturation of microglia cells. It is induced in T-cells following antigen stimulation but its functions are less well understood. However, recent studies in mice with T cell-specific Irf8 disruption under direction of the Lck promoter (LCK-IRF8KO) suggest that IRF8 directs a silencing program for Th17 differentiation and IL-17 production is markedly increased in IRF8 deficient T-cells. Paradoxically, loss of IRF8 in T-cells has no effect on the development or severity of experimental autoimmune encephalomyelitis (EAE) while exacerbating colitis in a mouse colitis model. On the other hand, mice with a macrophage/microglia-specific Irf8 disruption are resistant to EAE, further confounding our understanding of the roles of IRF8 in host immunity and autoimmunity. To clarify the role of IRF8 in autoimmune diseases, we have generated two mouse strains with targeted deletion of Irf8 in retinal cells including microglial cells and a third mouse strain with targeted Irf8 deletion in T-cells under direction of the non-promiscuous, CD4 promoter (CD4-IRF8KO). In contrast to the report that IRF8 deletion in T-cells has no effect on EAE, experimental autoimmune uveitis is exacerbated in CD4-IRF8KO mice and disease enhancement correlates with significant expansion of Th17 cells and a reduction in Tregs. In contrast to CD4-IRF8KO mice, Irf8 deletion in retinal cells confers protection from uveitis, underscoring divergent and tissue-specific roles of IRF8 in host immunity. These results raise cautionary note in context of therapeutic targeting of IRF8.