title: NOD2 regulates CXCR3-dependent CD8+ T cell accumulation in intestinal tissues with acute injury.
abstract: Polymorphisms in NOD2 confer risk for Crohn's disease, characterized by intestinal inflammation. How NOD2 regulates both inflammatory and regulatory intestinal T cells, which are critical to intestinal immune homeostasis, is not well understood. Anti-CD3 mAb administration is used as therapy in human autoimmune diseases, as well as a model of transient intestinal injury. The stages of T cell activation, intestinal injury, and subsequent T tolerance are dependent on migration of T cells into the small intestinal (SI) lamina propria. Upon anti-CD3 mAb treatment of mice, we found that NOD2 was required for optimal small intestinal IL-10 production, in particular from CD8(+) T cells. This requirement was associated with a critical role for NOD2 in SI CD8(+) T cell accumulation and induction of the CXCR3 ligands CXCL9 and CXCL10, which regulate T cell migration. NOD2 was required in both the hematopoietic and nonhematopoietic compartments for optimal expression of CXCR3 ligands in intestinal tissues. NOD2 synergized with IFN-γ to induce CXCL9 and CXCL10 secretion in dendritic cells, macrophages, and intestinal stromal cells in vitro. Consistent with the in vitro studies, during anti-CD3 mAb treatment in vivo, CXCR3 blockade, CD8(+) T cell depletion, or IFN-γ neutralization each inhibited SI CD8(+) T cell recruitment, and reduced chemokine expression and IL-10 expression. Thus, NOD2 synergizes with IFN-γ to promote CXCL9 and CXCL10 expression, thereby amplifying CXCR3-dependent SI CD8(+) T cell migration during T cell activation, which, in turn, contributes to induction of both inflammatory and regulatory T cell outcomes in the intestinal environment.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Xingxin
authors.initials: X
authors.lastname: Wu
authors.forename: Amit
authors.initials: A
authors.lastname: Lahiri
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Clara
authors.initials: C
authors.lastname: Abraham
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C515188:Cxcr3 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D054367:Receptors, CXCR3; D016753:Interleukin-10; D007371:Interferon-gamma