College of Veterinary Medicine, Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China.
J Immunol. 2024 Oct 1;213(7):1008-1022. doi: 10.4049/jimmunol.2300867.
The functions of the natural dsRNA sensors TLR3 (TRIF) and RIG-I (MAVS) are crucial during viral challenge and have not been accurately clarified in adaptive immune responses to rotavirus (RV) infection. In this study, we found that RV infection caused severe pathological damage to the small intestine of TLR3-/- and TRIF-/- mice. Our data found that dendritic cells from TLR3-/- and TRIF-/- mice had impaired Ag presentation to the RV and attenuated initiation of T cells upon viral infection. These attenuated functions resulted in impaired CD4+ T and CD8+ T function in mice lacking TLR3-TRIF signaling postinfection. Additionally, attenuated proliferative capacity of T cells from TLR3-/- and TRIF-/- mice was observed. Subsequently, we observed a significant reduction in the absolute number of memory T cells in the spleen and mesenteric lymph node (MLN) of TRIF-/- recipient mice following RV infection in a bone marrow chimeric model. Furthermore, there was reduced migration of type 2 classical dendritic cells from the intestine to MLNs after RV infection in TLR3-/- and TRIF-/- mice. Notably, RV infection resulted in attenuated killing of spleen and MLN tissues in TRIF-/- and MAVS-/- mice. Finally, we demonstrated that RV infection promoted apoptosis of CD8+ T cells in TRIF-/- and TLR3-/-MAVS-/- mice. Taken together, our findings highlight an important mechanism of TLR3 signaling through TRIF in mucosal T cell responses to RV and lay the foundation for the development of a novel vaccine.
天然 dsRNA 传感器 TLR3（TRIF）和 RIG-I（MAVS）的功能在病毒攻击期间至关重要，但在轮状病毒（RV）感染的适应性免疫反应中尚未得到准确阐明。在这项研究中，我们发现 RV 感染导致 TLR3-/-和 TRIF-/-小鼠的小肠严重病理损伤。我们的数据发现，TLR3-/-和 TRIF-/-小鼠的树突状细胞对 RV 的抗原呈递受损，并且在病毒感染时对 T 细胞的起始作用减弱。这些减弱的功能导致 TLR3-TRIF 信号缺失的感染后小鼠 CD4+T 和 CD8+T 功能受损。此外，还观察到 TLR3-/-和 TRIF-/-小鼠 T 细胞的增殖能力减弱。随后，我们在骨髓嵌合模型中观察到，RV 感染后 TRIF-/-受者小鼠的脾脏和肠系膜淋巴结（MLN）中记忆 T 细胞的绝对数量显著减少。此外，在 TLR3-/-和 TRIF-/-小鼠中，RV 感染后肠道向 MLN 的 2 型经典树突状细胞迁移减少。值得注意的是，RV 感染导致 TRIF-/-和 MAVS-/-小鼠的脾脏和 MLN 组织杀伤能力减弱。最后，我们证明 RV 感染促进了 TRIF-/-和 TLR3-/-MAVS-/-小鼠中 CD8+T 细胞的凋亡。总之，我们的研究结果强调了 TLR3 通过 TRIF 在 RV 黏膜 T 细胞反应中的信号传导的重要机制，并为新型疫苗的开发奠定了基础。
