title: Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis.
abstract: In this study, we determined conditions leading to the development of colitis in mice with nucleotide binding oligomerization domain 2 (NOD2) deficiency, a susceptibility factor in Crohn's disease. We found that NOD2-deficient antigen-presenting cells (APCs) produced increased amounts of interleukin (IL)-12 in the presence of ovalbumin (OVA) peptide and peptidoglycan or recombinant E. coli that express OVA peptide (ECOVA). Furthermore, these APCs elicited heightened interferon-gamma (IFN-gamma) responses from cocultured OVA-specific CD4+ T cells. We then demonstrated that NOD2-deficient mice adoptively transferred OVA-specific CD4+ T cells and that administered intrarectal ECOVA developed colitis associated with the expansion of OVA-specific CD4+ T cells producing IFN-gamma. Importantly, this colitis was highly dependent on Toll-like receptor 2 (TLR2) function since it was suppressed in NOD2 and TLR2 double-deficient mice. Thus, NOD2-deficient mice become susceptible to colitis as a result of increased TLR2 responses when they have the capacity to respond to an antigen expressed by mucosal bacteria.
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC, Room 5W3940, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitani
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Wakatsuki
authors.forename: Ivan J
authors.initials: IJ
authors.lastname: Fuss
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000942:Antigens, Bacterial / Q000276:immunology*; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053473:Nod2 Signaling Adaptor Protein; D017434:Protein Structure, Tertiary / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
chemical_list: D000942:Antigens, Bacterial; D000939:Epitopes; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2