title: Chemokine receptor CCR7 regulates the intestinal TH1/TH17/Treg balance during Crohn's-like murine ileitis.
abstract: The regulation of T cell and DC retention and lymphatic egress within and from the intestine is critical for intestinal immunosurveillance; however, the cellular processes that orchestrate this balance during IBD remain poorly defined. With the use of a mouse model of TNF-driven Crohn's-like ileitis (TNF(Δ) (ARE)), we examined the role of CCR7 in the control of intestinal T cell and DC retention/egress during experimental CD. We observed that the frequency of CCR7-expressing TH1/TH17 effector lymphocytes increased during active disease in TNF(Δ) (ARE) mice and that ΔARE/CCR7(-/-) mice developed exacerbated ileitis and multiorgan inflammation, with a marked polarization and ileal retention of TH1 effector CD4(+) T cells. Furthermore, adoptive transfer of ΔARE/CCR7(-/-) effector CD4(+) into lymphopenic hosts resulted in ileo-colitis, whereas those transferred with ΔARE/CCR7(+/+) CD4(+) T cells developed ileitis. ΔARE/CCR7(-/-) mice had an acellular draining MLN, decreased CD103(+) DC, and decreased expression of RALDH enzymes and of CD4(+)CD25(+)FoxP3(+) Tregs. Lastly, a mAb against CCR7 exacerbated ileitis in TNF(Δ) (ARE) mice, phenocopying the effects of congenital CCR7 deficiency. Our data underscore a critical role for the lymphoid chemokine receptor CCR7 in orchestrating immune cell traffic and TH1 versus TH17 bias during chronic murine ileitis.
authors: *Mucosal Inflammation Program, School of Medicine, Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, and Department of Pathology, University of Colorado Denver, Colorado, USA; Department of Inflammation Research, Amgen, Thousand Oaks, California, USA; and Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego and San Diego VA Medical Center, San Diego, California, USA eoin.mcnamee@ucdenver.edu.
authors: Eóin N
authors: EN
authors: McNamee
authors: *Mucosal Inflammation Program, School of Medicine, Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, and Department of Pathology, University of Colorado Denver, Colorado, USA; Department of Inflammation Research, Amgen, Thousand Oaks, California, USA; and Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego and San Diego VA Medical Center, San Diego, California, USA.
authors: Joanne C
authors: JC
authors: Masterson
authors: *Mucosal Inflammation Program, School of Medicine, Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, and Department of Pathology, University of Colorado Denver, Colorado, USA; Department of Inflammation Research, Amgen, Thousand Oaks, California, USA; and Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego and San Diego VA Medical Center, San Diego, California, USA.
authors: Marisol
authors: M
authors: Veny
authors: *Mucosal Inflammation Program, School of Medicine, Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, and Department of Pathology, University of Colorado Denver, Colorado, USA; Department of Inflammation Research, Amgen, Thousand Oaks, California, USA; and Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego and San Diego VA Medical Center, San Diego, California, USA.
authors: Colm B
authors: CB
authors: Collins
authors: *Mucosal Inflammation Program, School of Medicine, Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, and Department of Pathology, University of Colorado Denver, Colorado, USA; Department of Inflammation Research, Amgen, Thousand Oaks, California, USA; and Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego and San Diego VA Medical Center, San Diego, California, USA.
authors: Paul
authors: P
authors: Jedlicka
authors: *Mucosal Inflammation Program, School of Medicine, Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, and Department of Pathology, University of Colorado Denver, Colorado, USA; Department of Inflammation Research, Amgen, Thousand Oaks, California, USA; and Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego and San Diego VA Medical Center, San Diego, California, USA.
authors: Fergus R
authors: FR
authors: Byrne
authors: *Mucosal Inflammation Program, School of Medicine, Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, and Department of Pathology, University of Colorado Denver, Colorado, USA; Department of Inflammation Research, Amgen, Thousand Oaks, California, USA; and Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego and San Diego VA Medical Center, San Diego, California, USA.
authors: Gordon Y
authors: GY
authors: Ng
authors: *Mucosal Inflammation Program, School of Medicine, Gastrointestinal Eosinophilic Disease Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, and Department of Pathology, University of Colorado Denver, Colorado, USA; Department of Inflammation Research, Amgen, Thousand Oaks, California, USA; and Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego and San Diego VA Medical Center, San Diego, California, USA.
authors: Jesús
authors: J
authors: Rivera-Nieves
mesh_terms: D019264:Adoptive Transfer; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007079:Ileitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007082:Ileum / Q000276:immunology* / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D054400:Receptors, CCR7 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C515371:Ccr7 protein, mouse; D007527:Isoenzymes; D054400:Receptors, CCR7; D014409:Tumor Necrosis Factor-alpha; D000444:Aldehyde Dehydrogenase
keywords: CD103+ dendritic cells; Crohn’s disease; effector memory T cells; inflammatory bowel disease; lymphatics
references: J Exp Med. 2007 Apr 16;204(4):723-34
references: 17371929
references: Cell. 1999 Oct 1;99(1):23-33
references: 10520991
references: J Exp Med. 2007 Aug 6;204(8):1775-85
references: 17620362
references: Nat Rev Immunol. 2008 May;8(5):362-71
references: 18379575
references: J Immunol. 2008 Oct 1;181(7):4723-32
references: 18802075
references: J Immunol. 2008 Dec 1;181(11):7681-8
references: 19017956
references: Gastroenterology. 2008 Dec;135(6):1993-2002
references: 18854186
references: J Immunol. 2009 Sep 1;183(5):3073-80
references: 19675158
references: Immunity. 2009 Sep 18;31(3):389-400
references: 19766082
references: Gastroenterology. 2009 Nov;137(5):1736-45
references: 19632232
references: Cell. 2009 Oct 30;139(3):485-98
references: 19836068
references: Aliment Pharmacol Ther. 2010 Mar;31(5):561-72
references: 19958311
references: Inflamm Bowel Dis. 2010 May;16(5):743-52
references: 19856411
references: Curr Opin Gastroenterol. 2010 Jul;26(4):310-7
references: 20473158
references: J Immunol. 2010 Oct 15;185(8):4873-82
references: 20833836
references: Inflamm Bowel Dis. 2011 Jan;17(1):268-78
references: 20812332
references: J Exp Med. 2007 Aug 6;204(8):1757-64
references: 17620361
references: Nature. 1999 Oct 14;401(6754):708-12
references: 10537110
references: J Exp Med. 2001 Jan 15;193(2):207-18
references: 11148224
references: J Immunol. 2001 Dec 15;167(12):6724-30
references: 11739486
references: Cancer Res. 2002 May 15;62(10):2937-41
references: 12019175
references: J Immunol. 2002 Jun 1;168(11):5441-7
references: 12023337
references: J Exp Med. 2002 Dec 16;196(12):1563-74
references: 12486099
references: J Immunol. 2004 Mar 15;172(6):3580-9
references: 15004159
references: Clin Exp Immunol. 1990 Aug;81(2):301-5
references: 2117510
references: J Exp Med. 1999 Feb 1;189(3):451-60
references: 9927507
references: J Immunol. 1999 Mar 1;162(5):2472-5
references: 10072485
references: Immunity. 1999 Mar;10(3):387-98
references: 10204494
references: Gastroenterology. 2005 Mar;128(3):654-66
references: 15765401
references: Immunity. 2005 Apr;22(4):493-505
references: 15845453
references: Cell Immunol. 2004 Sep-Oct;231(1-2):75-84
references: 15919372
references: Nat Immunol. 2005 Sep;6(9):866-8
references: 16116464
references: Nat Immunol. 2005 Sep;6(9):889-94
references: 16116468
references: Nat Immunol. 2005 Sep;6(9):895-901
references: 16116469
references: J Exp Med. 2005 Oct 17;202(8):1063-73
references: 16216890
references: Gut. 2006 Feb;55(2):220-7
references: 16118351
references: Scand J Immunol. 2006 Oct;64(4):361-9
references: 16970675
references: J Allergy Clin Immunol. 2006 Dec;118(6):1234-41
references: 17157652
references: Blood. 2007 Feb 1;109(3):886-95
references: 17018859
references: Eur J Immunol. 2007 Mar;37(3):613-22
references: 17304629
references: J Exp Med. 2007 Apr 16;204(4):735-45
references: 17371928
references: Gut. 2011 Mar;60(3):325-33
references: 21076126
references: Gastroenterology. 2011 May;140(5):1526-35.e3
references: 21300065
references: Nature. 2011 Jul 28;475(7357):514-8
references: 21765430
references: Gastroenterology. 2011 Nov;141(5):1821-31
references: 22027263
references: Gut. 2012 Aug;61(8):1154-62
references: 22068168
references: Gut. 2013 Jan;62(1):53-62
references: 22267601
references: Nature. 2013 Feb 7;494(7435):116-20
references: 23334413
references: J Immunol. 2013 Jun 1;190(11):5788-98
references: 23610141
references: N Engl J Med. 2013 Aug 22;369(8):699-710
references: 23964932
references: N Engl J Med. 2013 Aug 22;369(8):711-21
references: 23964933
references: J Immunol. 2013 Sep 15;191(6):3119-27
references: 23935190
references: Immunity. 2014 Apr 17;40(4):594-607
references: 24684957
references: J Immunol. 2014 Jul 1;193(1):431-8
references: 24899505