Sensing Microbial Viability through Bacterial RNA Augments T Follicular Helper Cell and Antibody Responses

Gaetan Barbet, Leif E. Sander, Matthew Geswell, Irina Leonardi, Andrea Cerutti, Iliyan Iliev, J. Magarian Blander

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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, CX3CR1+CCR2 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. Live vaccines typically elicit augmented humoral responses, affording superior protection. Barbet et al. report that innate detection of bacterial RNA, a signature of microbial viability, directs a heightened Tfh cell response. This response is extrinsic to B cells and dendritic cells and involves CX3CR1+CCR2 monocyte instruction of Tfh differentiation via TRIF-dependent IFN-β licensing of bacterial RNA-driven inflammasome activation.

Original languageEnglish (US)
Pages (from-to)584-598.e5
JournalImmunity
Volume48
Issue number3
DOIs
StatePublished - Mar 20 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Infectious Diseases
  • Immunology and Allergy
  • Immunology

Keywords

  • Bacterial RNA
  • CX3CR1
  • Follicular T helper cell
  • inflammasome
  • microbial viability
  • monocytes
  • type-I interferon
  • vaccine

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