While a number of microbial-associated molecular patterns have been known for decades to act as adjuvants, the mechanisms and the signaling pathways underlying their action have remained elusive. Here, we examined the unfolding of the adaptive immune response induced by Nod2 in vivo upon activation by its specific ligand, muramyl dipeptide, a component of peptidoglycan. Our findings demonstrate that this bacterial sensor triggers a potent Ag-specific immune response with a Th2-type polarization profile, characterized by the induction of IL-4 and IL-5 by T cells and IgG1 Ab responses. Nod2 was also found to be critical for the induction or both Th1- and Th2-type responses following costimulation with TLR agonists. Importantly, the synergistic responses to Nod2 and TLR agonists seen in vivo were recapitulated by dendritic cells in vitro, suggesting that these cells likely play a central role in the integration of Nod2- and TLR-dependent signals for driving the adaptive immune response. Taken together, our results identify Nod2 as a critical mediator of microbial-induced potentiation and polarization of Ag-dependent immunity. Moreover, these findings affect our understanding of Crohn's diseases pathogenesis, where lack of Nod2-dependent Th2 signaling in a subset of these patients might explain heightened Th1-mediated inflammation at the level of the intestinal mucosa. The Journal of Immunology, 2008, 181: 7925-7935.
机构:
INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, FranceINSERM, U843, Paris, France
Barreau, Frederick
Meinzer, Ulrich
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h-index: 0
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INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, France
Hop Robert Debre, AP HP, Serv Gastroenterol, F-75019 Paris, FranceINSERM, U843, Paris, France
Meinzer, Ulrich
Chareyre, Fabrice
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机构:
Univ Paris Diderot, Inst Univ Hematol, Paris, France
INSERM, U674, Paris, FranceINSERM, U843, Paris, France
Chareyre, Fabrice
Berrebi, Dominique
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h-index: 0
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Univ Paris Diderot, EA3102, Paris, France
Inst Pasteur, Serv Anat Pathol, F-59019 Lille, FranceINSERM, U843, Paris, France
Berrebi, Dominique
Niwa-Kawakita, Michiko
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Univ Paris Diderot, Inst Univ Hematol, Paris, France
INSERM, U674, Paris, FranceINSERM, U843, Paris, France
Niwa-Kawakita, Michiko
Dussaillant, Monique
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INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, FranceINSERM, U843, Paris, France
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Univ Paul Cezanne, Fac St Jerome, INRA, UMR 1111, Marseille, France
Univ Paul Cezanne, Fac St Jerome, IMRN, Marseille, FranceINSERM, U843, Paris, France
Ollendorff, Vincent
Heyman, Martine
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h-index: 0
机构:
INSERM, U793, Paris, France
Univ Paris 05, IFR94, Paris, FranceINSERM, U843, Paris, France
Heyman, Martine
Bonacorsi, Stephane
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h-index: 0
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Univ Paris Diderot, EA3105, Paris, France
Hop Robert Debre, AP HP, Microbiol Serv, F-75019 Paris, FranceINSERM, U843, Paris, France
Bonacorsi, Stephane
Lesuffleur, Thecla
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h-index: 0
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INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, FranceINSERM, U843, Paris, France
Lesuffleur, Thecla
Sterkers, Ghislaine
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h-index: 0
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Hop Robert Debre, AP HP, Serv Immunol, F-75019 Paris, FranceINSERM, U843, Paris, France
Sterkers, Ghislaine
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Giovannini, Marco
Hugot, Jean-Pierre
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h-index: 0
机构:
INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, France
Hop Robert Debre, AP HP, Serv Gastroenterol, F-75019 Paris, FranceINSERM, U843, Paris, France
机构:
INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, FranceINSERM, U843, Paris, France
Barreau, Frederick
Meinzer, Ulrich
论文数: 0引用数: 0
h-index: 0
机构:
INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, France
Hop Robert Debre, AP HP, Serv Gastroenterol, F-75019 Paris, FranceINSERM, U843, Paris, France
Meinzer, Ulrich
Chareyre, Fabrice
论文数: 0引用数: 0
h-index: 0
机构:
Univ Paris Diderot, Inst Univ Hematol, Paris, France
INSERM, U674, Paris, FranceINSERM, U843, Paris, France
Chareyre, Fabrice
Berrebi, Dominique
论文数: 0引用数: 0
h-index: 0
机构:
Univ Paris Diderot, EA3102, Paris, France
Inst Pasteur, Serv Anat Pathol, F-59019 Lille, FranceINSERM, U843, Paris, France
Berrebi, Dominique
Niwa-Kawakita, Michiko
论文数: 0引用数: 0
h-index: 0
机构:
Univ Paris Diderot, Inst Univ Hematol, Paris, France
INSERM, U674, Paris, FranceINSERM, U843, Paris, France
Niwa-Kawakita, Michiko
Dussaillant, Monique
论文数: 0引用数: 0
h-index: 0
机构:
INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, FranceINSERM, U843, Paris, France
机构:
Univ Paul Cezanne, Fac St Jerome, INRA, UMR 1111, Marseille, France
Univ Paul Cezanne, Fac St Jerome, IMRN, Marseille, FranceINSERM, U843, Paris, France
Ollendorff, Vincent
Heyman, Martine
论文数: 0引用数: 0
h-index: 0
机构:
INSERM, U793, Paris, France
Univ Paris 05, IFR94, Paris, FranceINSERM, U843, Paris, France
Heyman, Martine
Bonacorsi, Stephane
论文数: 0引用数: 0
h-index: 0
机构:
Univ Paris Diderot, EA3105, Paris, France
Hop Robert Debre, AP HP, Microbiol Serv, F-75019 Paris, FranceINSERM, U843, Paris, France
Bonacorsi, Stephane
Lesuffleur, Thecla
论文数: 0引用数: 0
h-index: 0
机构:
INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, FranceINSERM, U843, Paris, France
Lesuffleur, Thecla
Sterkers, Ghislaine
论文数: 0引用数: 0
h-index: 0
机构:
Hop Robert Debre, AP HP, Serv Immunol, F-75019 Paris, FranceINSERM, U843, Paris, France
Sterkers, Ghislaine
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h-index:
机构:
Giovannini, Marco
Hugot, Jean-Pierre
论文数: 0引用数: 0
h-index: 0
机构:
INSERM, U843, Paris, France
Univ Paris Diderot, UMR S843, Paris, France
Hop Robert Debre, AP HP, Serv Gastroenterol, F-75019 Paris, FranceINSERM, U843, Paris, France