title: Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation.
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 pattern-recognition 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, we found 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.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada M5A 2N4.
authors.forename: Joao G
authors.initials: JG
authors.lastname: Magalhaes
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rubino
authors.forename: Leonardo H
authors.initials: LH
authors.lastname: Travassos
authors.forename: Lionel
authors.initials: L
authors.lastname: Le Bourhis
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.forename: Gernot
authors.initials: G
authors.lastname: Sellge
authors.forename: Kaoru
authors.initials: K
authors.lastname: Geddes
authors.forename: Karou
authors.initials: K
authors.lastname: Geddes
authors.forename: Colin
authors.initials: C
authors.lastname: Reardon
authors.forename: Matthias
authors.initials: M
authors.lastname: Lechmann
authors.forename: Leticia A
authors.initials: LA
authors.lastname: Carneiro
authors.forename: Thirumahal
authors.initials: T
authors.lastname: Selvanantham
authors.forename: Jorg H
authors.initials: JH
authors.lastname: Fritz
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Taylor
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.forename: Tak Wah
authors.initials: TW
authors.lastname: Mak
authors.forename: Michael R
authors.initials: MR
authors.lastname: Comeau
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001491:Basophils / Q000276:immunology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000628:therapy; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D007111:Immunity, Cellular / Q000502:physiology; D007114:Immunization; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*; D053278:OX40 Ligand; D017434:Protein Structure, Tertiary; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse