TY - JOUR
T1 - NOD2 regulates CXCR3-dependent CD8+ T cell accumulation in intestinal tissues with acute injury
AU - Wu, Xingxin
AU - Lahiri, Amit
AU - Haines, G. Kenneth
AU - Flavell, Richard A.
AU - Abraham, Clara
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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. The Journal of Immunology, 2014, 192: 3409-3418.
AB - 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. The Journal of Immunology, 2014, 192: 3409-3418.
UR - http://www.scopus.com/inward/record.url?scp=84897508343&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1302436
DO - 10.4049/jimmunol.1302436
M3 - Article
C2 - 24591373
AN - SCOPUS:84897508343
SN - 0022-1767
VL - 192
SP - 3409
EP - 3418
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -