Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses
Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses
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DOI：
10.1038/s41590-018-0068-4
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发表时间：
2018-04-01
影响因子：
30.5
通讯作者：
Sander, Leif E.
中科院分区：
文献类型：
--
作者：
Ugolini, Matteo;Gerhard, Jenny;Sander, Leif E.
减毒活疫苗通常是高效的，而且往往优于灭活疫苗，但其潜在机制仍很不清楚。在这里，我们确认微生物活性是卵泡辅助性T细胞(T-FH细胞)分化和疫苗反应的有力刺激。抗原提呈细胞(APC)通过Toll样受体8(TLR8)依赖的细菌RNA检测来区分活细菌和死亡细菌。与死亡细菌和其他TLR配体不同，活细菌、细菌RNA和合成的TLR8激动剂在人和猪的APC中诱导特定的细胞因子谱，从而促进T-FH细胞的分化。在家猪中，用活细菌疫苗免疫会产生强大的T-FH细胞和抗体反应，而用热灭活的活疫苗免疫则不能。最后，TLR8基因多态与卡介苗(BCG)免疫人群的保护性免疫有关。因此，我们确定TLR8是T-FH细胞分化的重要驱动因素，也是T-FH细胞偏斜疫苗佐剂的一个有前途的靶点。
Live attenuated vaccines are generally highly efficacious and often superior to inactivated vaccines, yet the underlying mechanisms of this remain largely unclear. Here we identify recognition of microbial viability as a potent stimulus for follicular helper T cell (T-FH cell) differentiation and vaccine responses. Antigen-presenting cells (APCs) distinguished viable bacteria from dead bacteria through Toll-like receptor 8 (TLR8)-dependent detection of bacterial RNA. In contrast to dead bacteria and other TLR ligands, live bacteria, bacterial RNA and synthetic TLR8 agonists induced a specific cytokine profile in human and porcine APCs, thereby promoting T-FH cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust T-FH cell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8 polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Gudrin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of T-FH cell differentiation and a promising target for T-FH cell-skewing vaccine adjuvants.