Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
J Immunol. 2013 Nov 1;191(9):4818-27. doi: 10.4049/jimmunol.1301301. Epub 2013 Sep 27.
TLRs play a central role in the innate recognition of pathogens and the activation of dendritic cells (DCs). In this study, we establish that, in addition to TLR11, TLR12 recognizes the profilin protein of the protozoan parasite Toxoplasma gondii and regulates IL-12 production by DCs in response to the parasite. Similar to TLR11, TLR12 is an endolysosomal innate immune receptor that colocalizes and interacts with UNC93B1. Biochemical experiments revealed that TLR11 and TLR12 directly bind to T. gondii profilin and are capable of forming a heterodimer complex. We also establish that the transcription factor IFN regulatory factor 8, not NF-κB, plays a central role in the regulation of the TLR11- and TLR12-dependent IL-12 response of DCs. These results suggest a central role for IFN regulatory factor 8-expressing CD8(+) DCs in governing the TLR11- and TLR12-mediated host defense against T. gondii.
TLRs 在病原体的先天识别和树突状细胞 (DC) 的激活中发挥核心作用。在这项研究中，我们发现 TLR12 除了识别 TLR11 外，还能识别原生动物寄生虫弓形虫的原肌球蛋白蛋白，并调节 DC 对寄生虫的 IL-12 产生。与 TLR11 类似，TLR12 是一种内体溶酶体先天免疫受体，与 UNC93B1 共定位并相互作用。生化实验表明，TLR11 和 TLR12 直接结合弓形虫原肌球蛋白，并且能够形成异二聚体复合物。我们还确定转录因子 IFN 调节因子 8（而非 NF-κB）在调节 TLR11 和 TLR12 依赖的 DC 的 IL-12 反应中发挥核心作用。这些结果表明表达 IFN 调节因子 8 的 CD8(+) DC 在调节 TLR11 和 TLR12 介导的宿主对弓形虫的防御中起核心作用。
