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* Department of Immunology and
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; and
Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France
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 of 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 J.G.M. received funding from The Fundaçaõ pana a Ciência e a Tecnologia, the Fondation Recherche Médicale and the Fondation Bettencourt Schueller. J.H.F. is a recipient of an APART fellowship of the Austrian Academy of Sciences at the University of Toronto. L.H.T. received support from the Canadian Institutes of Health Research (CIHR 174658). T.S. received funding from the Allergy/Asthma Information Association. D.J.P. is a Howard Hughes International Scholar. This work was supported by the following grants: CIHR: MOP480142 (to D.J.P.), CIHR: MOP67157 (to J.L.G.), and CIHR: MOP81360 (to S.E.G.), Sandler Program for Asthma Research (to D.J.P.), and Crohn’s and Colitis Foundation of Canada (to S.E.G.).
2 J.G.M. and J.H.F. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Dana J. Philpott, University of Toronto, Department of Immunology, Medical Sciences Building, 1 King’s College Circle, M5S 1A8 Toronto, Ontario, Canada. E-mail address: dana.philpott{at}utoronto.ca
4 Abbreviations used in this paper: MAMP, microbe-associated molecular pattern; BMDC, bone marrow-derived dendritic cell; BMM, BM-derived macrophage; DC, dendritic cell; MDP, muramyl dipeptide; NLR, Nod-like receptor; PGN, peptidoglycan; PRM, pattern recognition molecule; WT, wild type.
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  C. L. Loving, M. Osorio, Y.-G. Kim, G. Nunez, M. A. Hughes, and T. J. Merkel Nod1/Nod2-Mediated Recognition Plays a Critical Role in Induction of Adaptive Immunity to Anthrax after Aerosol Exposure Infect. Immun., October 1, 2009; 77(10): 4529 - 4537. [Abstract] [Full Text] [PDF]
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