Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

Joao G. Magalhaes, Stephen J. Rubino, Leonardo H. Travassos, Lionel Le Bourhis, Wei Duan, Gernot Sellge, Karou Geddes, Colin Reardon, Matthias Lechmann, Leticia A. Carneiro, Thirumahal Selvanantham, Jorg H. Fritz, Betsy C. Taylor, David Artis, Tak Wah Mak, Michael R. Comeau, Michael Croft, Stephen E. Girardin, Dana J. Philpott

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Abstract

Although a number of studies have examined the development of T-helper cell type 2 (Th2) immunity in different settings, the mechanisms underlying the initiation of this arm of adaptive immunity are not well understood. We exploited the fact that immunization with antigen plus either nucleotide-binding oligomerization domain-containing proteins 1 (Nod1) or 2 (Nod2) agonists drives Th2 induction to understand how these patternrecognition receptors mediate the development of systemic Th2 immune responses. Here, we show in bone-marrow chimeric mice that Nod1 and Nod2 expression within the stromal compartment is necessary for priming of effector CD4 + Th2 responses and specific IgG1 antibodies. In contrast, sensing of these ligands by dendritic cells was not sufficient to induce Th2 immunity, although these cells contribute to the response. Moreover, we determined that CD11c +cells were the critical antigen-presenting cells, whereas basophils and B cells did not affect the capacity of Nod ligands to induce CD4 +Th2 effector function. Finally,wefound that full Th2 induction upon Nod1 and Nod2 activation was dependent on both thymic stromal lymphopoietin production by the stromal cells and the up-regulation of the costimulatory molecule, OX40 ligand, on dendritic cells. This study provides in vivo evidence of how systemic Th2 immunity is induced in the context of Nod stimulation. Such understanding will influence the rational design of therapeutics that could reprogram the immune system during an active Th1-mediated disease, such as Crohn's disease.

Original languageEnglish (US)
Pages (from-to)14896-14901
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number36
DOIs
StatePublished - Sep 6 2011
Externally publishedYes

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    Magalhaes, J. G., Rubino, S. J., Travassos, L. H., Bourhis, L. L., Duan, W., Sellge, G., Geddes, K., Reardon, C., Lechmann, M., Carneiro, L. A., Selvanantham, T., Fritz, J. H., Taylor, B. C., Artis, D., Mak, T. W., Comeau, M. R., Croft, M., Girardin, S. E., & Philpott, D. J. (2011). Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation. Proceedings of the National Academy of Sciences of the United States of America, 108(36), 14896-14901. https://doi.org/10.1073/pnas.1015063108