The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Immunity. 2018 Mar 20;48(3):584-598.e5. doi: 10.1016/j.immuni.2018.02.015. Epub 2018 Mar 13.
Live vaccines historically afford superior protection, yet the cellular and molecular mechanisms mediating protective immunity remain unclear. Here we found that vaccination of mice with live, but not dead, Gram-negative bacteria heightened follicular T helper cell (Tfh) differentiation, germinal center formation, and protective antibody production through the signaling adaptor TRIF. Complementing the dead vaccine with an innate signature of bacterial viability, bacterial RNA, recapitulated these responses. The interferon (IFN) and inflammasome pathways downstream of TRIF orchestrated Tfh responses extrinsically to B cells and classical dendritic cells. Instead, CX3CR1CCR2 monocytes instructed Tfh differentiation through interleukin-1β (IL-1β), a tightly regulated cytokine secreted upon TRIF-dependent IFN licensing of the inflammasome. Hierarchical production of IFN-β and IL-1β dictated Tfh differentiation and elicited the augmented humoral responses characteristic of live vaccines. These findings identify bacterial RNA, an innate signature of microbial viability, as a trigger for Tfh differentiation and suggest new approaches toward vaccine formulations for coordinating augmented Tfh and B cell responses.
活疫苗在历史上提供了更好的保护，但介导保护性免疫的细胞和分子机制仍不清楚。在这里，我们发现活疫苗（而非死疫苗）接种小鼠可以通过信号适配器 TRIF 增强滤泡辅助性 T 细胞（Tfh）分化、生发中心形成和保护性抗体产生。通过细菌 RNA 补充死疫苗的细菌存活固有特征，重现了这些反应。TRIF 下游的干扰素 (IFN) 和炎性小体途径在外周组织协调 Tfh 对 B 细胞和经典树突状细胞的反应。相反，CX3CR1CCR2 单核细胞通过白细胞介素 1β (IL-1β) 指导 Tfh 分化，TRIF 依赖性 IFN 赋予炎性小体许可后，IL-1β 作为一种严格调控的细胞因子被分泌。IFN-β 和 IL-1β 的分级产生决定了 Tfh 分化，并引发了活疫苗的增强的体液反应。这些发现确定了细菌 RNA，一种微生物存活的固有特征，作为 Tfh 分化的触发因素，并为协调增强的 Tfh 和 B 细胞反应的疫苗制剂提供了新的方法。
