Nod2-Dependent Th2 Polarization of Antigen-Specific Immunity

被引:153
作者
Magalhaes, Joao Gamelas [1 ]
Fritz, Joerg H. [1 ]
Le Bourhis, Lionel [1 ]
Sellge, Gernot [3 ]
Travassos, Leonardo H. [1 ]
Selvanantham, Thirumahal [1 ]
Girardin, Stephen E. [2 ]
Gommerman, Jennifer L. [1 ]
Philpott, Dana J. [1 ]
机构
[1] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada
[2] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON M5S 1A8, Canada
[3] Inst Pasteur, Unite Pathogenie Microbienne Mol, Paris, France
基金
加拿大健康研究院;
关键词
D O I
10.4049/jimmunol.181.11.7925
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:7925 / 7935
页数:11
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