ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens

Michele Proietti,Marco Raffaelli,Lisa Perruzza,Fabio Grassi,Mauro Nicoletti,Santiago F Gonzalez,Marcus Thelen,Giovanni Pellegrini,Francesco Strati,Rocco D’Antuono,Wolf-Dietrich Hardt,Emma Slack,Daniela Scribano

doi:10.1038/s41467-018-08156-z

Abstract

T cell dependent secretory IgA (SIgA) generated in the Peyer’s patches (PPs) of the small intestine shapes a broadly diverse microbiota that is crucial for host physiology. The mutualistic co-evolution of host and microbes led to the relative tolerance of host’s immune system towards commensal microorganisms. The ATP-gated ionotropic P2X7 receptor limits T follicular helper (Tfh) cells expansion and germinal center (GC) reaction in the PPs. Here we show that transient depletion of intestinal ATP can dramatically improve high-affinity IgA response against both live and inactivated oral vaccines. Ectopic expression of Shigella flexneri periplasmic ATP-diphosphohydrolase (apyrase) abolishes ATP release by bacteria and improves the specific IgA response against live oral vaccines. Antibody responses primed in the absence of intestinal extracellular ATP (eATP) also provide superior protection from enteropathogenic infection. Thus, modulation of eATP in the small intestine can affect high-affinity IgA response against gut colonizing bacteria.

Highlights

T cell dependent secretory IgA (SIgA) generated in the Peyer’s patches (PPs) of the small intestine shapes a broadly diverse microbiota that is crucial for host physiology
T follicular helper (Tfh) cells express high levels of the ATPgated P2X7 receptor, a non-selective cationic channel that opens to form a cytolytic pore when exposed to micromolar concentrations of extracellular ATP
As extracellular ATP (eATP) is produced in large quantities by the intestinal microbiota, this directly suppresses commensal-specific IgA responses primed in the gutdraining lymphoid tissues and affects microbiota composition[6]

Summary

Introduction

T cell dependent secretory IgA (SIgA) generated in the Peyer’s patches (PPs) of the small intestine shapes a broadly diverse microbiota that is crucial for host physiology. The ATP-gated ionotropic P2X7 receptor limits T follicular helper (Tfh) cells expansion and germinal center (GC) reaction in the PPs. Here we show that transient depletion of intestinal ATP can dramatically improve high-affinity IgA response against both live and inactivated oral vaccines. We show that ATP released by intestinal bacteria permeates the intestinal epithelium and can be found at high concentrations in hepatic portal blood Eliminating this eATP, via administration of apyrase, dramatically improves the induction of specific IgA in response to either Salmonella infection or an inactivated oral vaccine. We could not measure any adverse effects of altered antimicrobiota immunity secondary to oral apyrase administration, suggesting that apyrase application is safe These enhanced immune responses provide superior protection from secondary infection

Methods

Results

Conclusion