Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis

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Abstract

Intestinal homeostasis is critical for efficient energy extraction from food and protection from pathogens. Its disruption can lead to an array of severe illnesses with major impacts on public health, such as inflammatory bowel disease characterized by self-destructive intestinal immunity. However, the mechanisms regulating the equilibrium between the large bacterial flora and the immune system remain unclear. Intestinal lymphoid tissues generate flora-reactive IgA-producing B cells, and include Peyer's patches and mesenteric lymph nodes, as well as numerous isolated lymphoid follicles (ILFs)1,2. Here we show that peptidoglycan from Gram-negative bacteria is necessary and sufficient to induce the genesis of ILFs in mice through recognition by the NOD1 (nucleotide-binding oligomerization domain containing 1) innate receptor in epithelial cells, and β-defensin 3- and CCL20-mediated signalling through the chemokine receptor CCR6. Maturation of ILFs into large B-cell clusters requires subsequent detection of bacteria by toll-like receptors. In the absence of ILFs, the composition of the intestinal bacterial community is profoundly altered. Our results demonstrate that intestinal bacterial commensals and the immune system communicate through an innate detection system to generate adaptive lymphoid tissues and maintain intestinal homeostasis.

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Figure 1: Intestinal commensal Gram - bacteria induce an extensive network of isolated lymphoid follicles (ILFs).
Figure 2: Peptidoglycans recognized by NOD1 induce the formation of ILFs.
Figure 3: A critical role for CCR6 ligands in the formation of ILFs.
Figure 4: The impact of the CP-ILF system on the commensal flora.

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Acknowledgements

We thank G. Milon, N. Cerf-Bensussan, P. Sansonetti, P. Cossart, A. Phalipon, D. Philpott, G. Marchal and D. Guy-Grand for discussions and critical reading of the manuscript; N. Huntington for intrahepatic injections; M. Cherrier for biochemistry; J. Perez, E. Maranghi and M. Manich for technical assistance; S. Akira, M. Chignard and V. Balloy for Myd88-/- , Trif-/- , Tlr2-/- or Tlr4-/- mice, J.P. Hugot for card15-/- mice, Millennium Pharmaceuticals for card4-/- mice and D. Philpott for card4-/- mice backcrossed to C57BL/6; J. Browning for LTβR-Ig and Z. Ge for the 16S rDNA plasmids. This work was supported by Institut Pasteur, CNRS, INSERM, ANR, Fondation de la Recherche Médicale, Mairie de Paris, a Marie Curie Excellence grant, La Fondation de France (D.B.) and la Ligue Nationale contre le Cancer (D.B.).

Author Contributions All authors, except R.V., contributed to the design of experiments, analysis of the data and writing of the manuscript. G.E. supervised experiments and wrote the manuscript, D.B. performed most experiments, C.B. and M.B. reconstituted germ-free mice with bacterial cocktails or strains, C.B. developed strain-specific qPCR on 16S rDNA, R.V. provided CCR6-deficient mice, I.G.B. purified PGNs and prepared E. coli mutants, and C.W. tested the functionality of PGNs and E. coli mutants.

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Correspondence to Gérard Eberl.

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Bouskra, D., Brézillon, C., Bérard, M. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008) doi:10.1038/nature07450

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