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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Resumé

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.

OriginalsprogEngelsk
TidsskriftNature Immunology
Vol/bind19
Udgave nummer4
Sider (fra-til)386-396
ISSN1529-2908
DOI
StatusUdgivet - apr. 2018

Fingeraftryk

Microbial Viability
Cell Differentiation
Bacterial RNA
Attenuated Vaccines
Ligands

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Ugolini, Matteo ; Gerhard, Jenny ; Burkert, Sanne ; Jensen, Kristoffer Jarlov ; Georg, Philipp ; Ebner, Friederike ; Volkers, Sarah M. ; Thada, Shruthi ; Dietert, Kristina ; Bauer, Laura ; Schäfer, Alexander ; Helbig, Elisa T. ; Opitz, Bastian ; Kurth, Florian ; Sur, Saubashya ; Dittrich, Nickel ; Gaddam, Sumanlatha ; Conrad, Melanie L. ; Benn, Christine S. ; Blohm, Ulrike ; Gruber, Achim D. ; Hutloff, Andreas ; Hartmann, Susanne ; Boekschoten, Mark V. ; Müller, Michael ; Jungersen, Gregers ; Schumann, Ralf R. ; Suttorp, Norbert ; Sander, Leif E. / Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses. I: Nature Immunology. 2018 ; Bind 19, Nr. 4. s. 386-396.
@article{8bdc4d311ae240c7b04da150b2c36b7b,
title = "Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses",
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-Gu{\'e}rin (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.",
keywords = "Adult, Animals, Antibody Formation/immunology, Cell Differentiation/immunology, Female, Humans, Lymphocyte Activation/immunology, Male, Microbial Viability/immunology, Swine, T-Lymphocytes, Helper-Inducer/immunology, Toll-Like Receptor 8/immunology, Vaccines, Attenuated/immunology",
author = "Matteo Ugolini and Jenny Gerhard and Sanne Burkert and Jensen, {Kristoffer Jarlov} and Philipp Georg and Friederike Ebner and Volkers, {Sarah M.} and Shruthi Thada and Kristina Dietert and Laura Bauer and Alexander Sch{\"a}fer and Helbig, {Elisa T.} and Bastian Opitz and Florian Kurth and Saubashya Sur and Nickel Dittrich and Sumanlatha Gaddam and Conrad, {Melanie L.} and Benn, {Christine S.} and Ulrike Blohm and Gruber, {Achim D.} and Andreas Hutloff and Susanne Hartmann and Boekschoten, {Mark V.} and Michael M{\"u}ller and Gregers Jungersen and Schumann, {Ralf R.} and Norbert Suttorp and Sander, {Leif E.}",
year = "2018",
month = "4",
doi = "10.1038/s41590-018-0068-4",
language = "English",
volume = "19",
pages = "386--396",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "4",

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Ugolini, M, Gerhard, J, Burkert, S, Jensen, KJ, Georg, P, Ebner, F, Volkers, SM, Thada, S, Dietert, K, Bauer, L, Schäfer, A, Helbig, ET, Opitz, B, Kurth, F, Sur, S, Dittrich, N, Gaddam, S, Conrad, ML, Benn, CS, Blohm, U, Gruber, AD, Hutloff, A, Hartmann, S, Boekschoten, MV, Müller, M, Jungersen, G, Schumann, RR, Suttorp, N & Sander, LE 2018, 'Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses', Nature Immunology, bind 19, nr. 4, s. 386-396. https://doi.org/10.1038/s41590-018-0068-4

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses. / Ugolini, Matteo; Gerhard, Jenny; Burkert, Sanne; Jensen, Kristoffer Jarlov; Georg, Philipp; Ebner, Friederike; Volkers, Sarah M.; Thada, Shruthi; Dietert, Kristina; Bauer, Laura; Schäfer, Alexander; Helbig, Elisa T.; Opitz, Bastian; Kurth, Florian; Sur, Saubashya; Dittrich, Nickel; Gaddam, Sumanlatha; Conrad, Melanie L.; Benn, Christine S.; Blohm, Ulrike; Gruber, Achim D.; Hutloff, Andreas; Hartmann, Susanne; Boekschoten, Mark V.; Müller, Michael; Jungersen, Gregers; Schumann, Ralf R.; Suttorp, Norbert; Sander, Leif E.

I: Nature Immunology, Bind 19, Nr. 4, 04.2018, s. 386-396.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

AU - Ugolini, Matteo

AU - Gerhard, Jenny

AU - Burkert, Sanne

AU - Jensen, Kristoffer Jarlov

AU - Georg, Philipp

AU - Ebner, Friederike

AU - Volkers, Sarah M.

AU - Thada, Shruthi

AU - Dietert, Kristina

AU - Bauer, Laura

AU - Schäfer, Alexander

AU - Helbig, Elisa T.

AU - Opitz, Bastian

AU - Kurth, Florian

AU - Sur, Saubashya

AU - Dittrich, Nickel

AU - Gaddam, Sumanlatha

AU - Conrad, Melanie L.

AU - Benn, Christine S.

AU - Blohm, Ulrike

AU - Gruber, Achim D.

AU - Hutloff, Andreas

AU - Hartmann, Susanne

AU - Boekschoten, Mark V.

AU - Müller, Michael

AU - Jungersen, Gregers

AU - Schumann, Ralf R.

AU - Suttorp, Norbert

AU - Sander, Leif E.

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

KW - Adult

KW - Animals

KW - Antibody Formation/immunology

KW - Cell Differentiation/immunology

KW - Female

KW - Humans

KW - Lymphocyte Activation/immunology

KW - Male

KW - Microbial Viability/immunology

KW - Swine

KW - T-Lymphocytes, Helper-Inducer/immunology

KW - Toll-Like Receptor 8/immunology

KW - Vaccines, Attenuated/immunology

U2 - 10.1038/s41590-018-0068-4

DO - 10.1038/s41590-018-0068-4

M3 - Journal article

C2 - 29556002

AN - SCOPUS:85044220410

VL - 19

SP - 386

EP - 396

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 4

ER -