Innate signals from Nod2 block respiratory tolerance and program T(H)2-driven allergic inflammation.
BACKGROUND
Airway tolerance is critical for protecting the lung from inflammatory disease driven by allergens. However, factors that disrupt tolerance processes and then lead to susceptibility to developing allergic asthma remain elusive.


OBJECTIVE
To investigate whether recognition of bacterial microbial-associated molecular patterns in the lung may result in susceptibility to developing allergic reactions, and to understand the molecular mechanisms by which such triggers block natural tolerance.


METHODS
Ligands of intracellular microbial-associated molecular pattern recognition receptors-the nucleotide-binding oligomerization domain (Nod)-like receptors, Nod1 and Nod2-were given intranasally with antigen, and their ability to modulate airway tolerance was analyzed.


RESULTS
Intranasal Nod2 ligand rapidly induced lung expression of the innate cytokines thymic stromal lymphopoietin and IL-25, and thymic stromal lymphopoietin promoted expression of OX40 ligand, a T-cell-costimulatory ligand, on lung CD11c(+)CD11b(+) cells and B220(+) cells. Together these 3 molecules blocked the generation of antigen-specific CD4(+)forkhead box protein 3(+) adaptive regulatory T cells and concomitantly drove IL-4-producing CD4 T cells. By altering the regulatory T/T(H)2-cell balance, tolerance was blocked, and sensing of Nod2 ligand resulted in subsequent susceptibility to developing eosinophil-dominated airway inflammation.


CONCLUSIONS
We show that a Nod-like receptor is a novel, previously unrecognized, pathway that adversely links innate and adaptive immunity and leads to allergic disease and asthmatic lung inflammation.
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Wei
W
Duan
Amit K
AK
Mehta
Joao G
JG
Magalhaes
Steven F
SF
Ziegler
Chen
C
Dong
Dana J
DJ
Philpott
Michael
M
Croft
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000494:pharmacology; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004802:Eosinophilia; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007108:Immune Tolerance / Q000187:drug effects; D007113:Immunity, Innate / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053473:Nod2 Signaling Adaptor Protein / Q000008:administration & dosage* / Q000819:agonists; D053278:OX40 Ligand / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000094632:Thymic Stromal Lymphopoietin
D000485:Allergens; D016207:Cytokines; C486701:IL25 protein, human; D020381:Interleukin-17; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D053278:OX40 Ligand; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse