Activation of the receptor NKG2D leads to production of Th17 cytokines in CD4+ T cells of patients with Crohn's disease.

BACKGROUND & AIMS The natural killer group 2 member D (NKG2D) is a stimulatory receptor expressed on a subset of mucosal and peripheral CD4+ T cells in patients with Crohn's disease (CD) and other inflammatory diseases. Ligand activation of NKG2D in patients induces CD4+ T cells to release T-helper (Th) 1 cytokines and become cytotoxic. We investigated the Th17 cytokines produced by T cells that express NKG2D in blood and intestinal mucosa samples from patients with CD. METHODS We isolated CD4+ T cells from peripheral blood and lamina propria samples of patients with CD or ulcerative colitis (UC) and healthy individuals (controls). We analyzed the phenotype and functions of the CD4+NKG2D+ T cells and the cytokines they produce in response to NKG2D stimulation. RESULTS In patients with CD, CD4+ T cells that express NKG2D produced high levels of interleukin (IL)-17 and IL-22 and expressed high levels of CCR6, the IL-23 receptor, CD161, and RORC (a transcription factor that regulates expression of Th17 cytokines). CD4+ T cells that produced IL-17 expressed high levels of NKG2D and CD161. Costimulation of NKG2D and the T-cell receptor (TCR) significantly increased production of IL-17 and tumor necrosis factor α by CD4+ T cells, compared with activation of only the TCR. CD4+NKG2D+ T cells also responded to Th17 polarization. CONCLUSIONS NKG2D is a functional marker of CD4+ T cells that produce IL-17 in patients with CD, via costimulation of the TCR and NKG2D. Reagents developed to block NKG2D might reduce gastrointestinal inflammation in patients with CD.

[1]  Atsushi Nakazawa,et al.  Defects in CD8+ Regulatory T Cells in the Lamina Propria of Patients with Inflammatory Bowel Disease 1 , 2005, The Journal of Immunology.

[2]  T. Mcclanahan,et al.  Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. , 2007, Gastroenterology.

[3]  L. Cosmi,et al.  Phenotypic and functional features of human Th 17 cells , 2007 .

[4]  T. Mcclanahan,et al.  #2202: Mucosal Autoimmunity Saturday, June 13 10:45 am–11:00 amCirculating and Gut-resident Human Th17 Cells Express CD161 and Promote Intestinal Inflammation , 2009 .

[5]  G. Bouma,et al.  The immunological and genetic basis of inflammatory bowel disease , 2003, Nature Reviews Immunology.

[6]  Stuart Adams,et al.  Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment , 2010, Proceedings of the National Academy of Sciences.

[7]  Richard A. Flavell,et al.  Nod2-Dependent Regulation of Innate and Adaptive Immunity in the Intestinal Tract , 2005, Science.

[8]  S. Bahram,et al.  Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[9]  A. Takayanagi,et al.  Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. , 2005, Gastroenterology.

[10]  A. Toubert,et al.  Binding of Escherichia coli adhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related molecule MICA , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

[12]  Yue Zhang,et al.  Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a T(h)17-independent manner. , 2007, International immunology.

[13]  Michael Karin,et al.  Nod2 Mutation in Crohn's Disease Potentiates NF-κB Activity and IL-1ß Processing , 2005, Science.

[14]  M. Neurath,et al.  Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. , 1996, Journal of immunology.

[15]  B. Ursø,et al.  Inhibition of NKG2D receptor function by antibody therapy attenuates transfer‐induced colitis in SCID mice , 2007, European journal of immunology.

[16]  T. Spies,et al.  Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  K. Hatakeyama,et al.  CD161+ T (NT) cells exist predominantly in human intestinal epithelium as well as in liver , 2002, Clinical and experimental immunology.

[18]  Clive M. Onnie,et al.  Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease , 2005, The Lancet.

[19]  L. Fouser,et al.  Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides , 2006, The Journal of experimental medicine.

[20]  J. Bluestone,et al.  NKG2D blockade prevents autoimmune diabetes in NOD mice. , 2004, Immunity.

[21]  A. Andoh,et al.  Increased expression of interleukin 17 in inflammatory bowel disease , 2003, Gut.

[22]  Judy H. Cho,et al.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene , 2006, Science.

[23]  L. Mayer,et al.  Regulatory T Cells: Peace Keepers in the Gut , 2004, Inflammatory bowel diseases.

[24]  A. Toubert,et al.  CD4+NKG2D+ T cells in Crohn's disease mediate inflammatory and cytotoxic responses through MICA interactions. , 2007, Gastroenterology.

[25]  Judy H Cho,et al.  Inflammatory bowel disease. , 2009, The New England journal of medicine.

[26]  D. Teitelbaum,et al.  Colostomy: formation and closure , 2006 .

[27]  R. Armitage,et al.  ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. , 2001, Immunity.

[28]  I. Dotan,et al.  Expansion of CD8+ T cells with regulatory function after interaction with intestinal epithelial cells. , 2002, Gastroenterology.

[29]  P. Barnes,et al.  NKG2D-Dependent IL-17 Production by Human T Cells in Response to an Intracellular Pathogen1 , 2009, The Journal of Immunology.