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Th17 cell plasticity towards a T-bet-dependent Th1 phenotype is required for bacterial control in Staphylococcus aureus infection

Authors :
Patricia Bartsch
Christoph Kilian
Malte Hellmig
Hans-Joachim Paust
Alina Borchers
Amirrtavarshni Sivayoganathan
Leon Enk
Yu Zhao
Nikhat Shaikh
Henning Büttner
Milagros N. Wong
Victor G. Puelles
Thorsten Wiech
Richard Flavell
Tobias B. Huber
Jan-Eric Turner
Stefan Bonn
Samuel Huber
Nicola Gagliani
Hans-Willi Mittrücker
Holger Rohde
Ulf Panzer
Christian F. Krebs
Source :
PLOS Pathogens. 18:e1010430
Publication Year :
2022
Publisher :
Public Library of Science (PLoS), 2022.

Abstract

Staphylococcus aureus is frequently detected in patients with sepsis and thus represents a major health burden worldwide. CD4+ T helper cells are involved in the immune response to S. aureus by supporting antibody production and phagocytosis. In particular, Th1 and Th17 cells secreting IFN-γ and IL-17A, are involved in the control of systemic S. aureus infections in humans and mice. To investigate the role of T cells in severe S. aureus infections, we established a mouse sepsis model in which the kidney was identified to be the organ with the highest bacterial load and abundance of Th17 cells. In this model, IL-17A but not IFN-γ was required for bacterial control. Using Il17aCre × R26YFP mice we could show that Th17 fate cells produce Th17 and Th1 cytokines, indicating a high degree of Th17 cell plasticity. Single cell RNA-sequencing of renal Th17 fate cells uncovered their heterogeneity and identified a cluster with a Th1 expression profile within the Th17 cell population, which was absent in mice with T-bet/Tbx21-deficiency in Th17 cells (Il17aCre x R26eYFP x Tbx21-flox). Blocking Th17 to Th1 transdifferentiation in Th17 fate cells in these mice resulted in increased S. aureus tissue loads. In summary, we highlight the impact of Th17 cells in controlling systemic S. aureus infections and show that T-bet expression by Th17 cells is required for bacterial clearance. While targeting the Th17 cell immune response is an important therapeutic option in autoimmunity, silencing Th17 cells might have detrimental effects in bacterial infections.

Details

ISSN :
15537374
Volume :
18
Database :
OpenAIRE
Journal :
PLOS Pathogens
Accession number :
edsair.doi.dedup.....dec0013e225b3f5cf0a70d2afc075274
Full Text :
https://doi.org/10.1371/journal.ppat.1010430