Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Matteo Ugolini, Jenny Gerhard, Sanne Burkert, Kristoffer Jarlov Jensen, Philipp Georg, Friederike Ebner, Sarah M. Volkers, Shruthi Thada, Kristina Dietert, Laura Bauer, Alexander Schäfer, Elisa T. Helbig, Bastian Opitz, Florian Kurth, Saubashya Sur, Nickel Dittrich, Sumanlatha Gaddam, Melanie L. Conrad, Christine S. Benn, Ulrike BlohmAchim D. Gruber, Andreas Hutloff, Susanne Hartmann, Mark V. Boekschoten, Michael Müller, Gregers Jungersen, Ralf R. Schumann, Norbert Suttorp, Leif E. Sander

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Abstract

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 (TFH 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 TFH cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust TFH 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-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of TFH cell differentiation and a promising target for TFH cell–skewing vaccine adjuvants.
Original languageEnglish
Pages (from-to)386–396
Number of pages11
JournalNature Immunology
Volume19
DOIs
Publication statusPublished - 19 Mar 2018

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