NOD2 regulates CXCR3-dependent CD8+ T cell accumulation in intestinal tissues with acute injury

Xingxin Wu, Amit Lahiri, G. Kenneth Haines, Richard A. Flavell, Clara Abraham

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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. The Journal of Immunology, 2014, 192: 3409-3418.

Original languageEnglish
Pages (from-to)3409-3418
Number of pages10
JournalJournal of Immunology
Volume192
Issue number7
DOIs
StatePublished - 1 Apr 2014
Externally publishedYes

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