title: The chemokine receptor CCR9 is required for the T-cell-mediated regulation of chronic ileitis in mice.
abstract: OBJECTIVE
  A balance between effector and regulatory T-cell (Treg) responses is required to maintain intestinal homeostasis. To regulate immunity, T cells migrate to the intestine using a combination of adhesion molecules and chemokine receptors. However, it is not known whether the migration pathways of effector cells and Tregs are distinct or shared. We sought to determine whether interaction between the chemokine receptor 9 (CCR9) and its ligand, chemokine ligand 25 (CCL25), allows effectors or Tregs to localize to chronically inflamed small intestine.
  
  
  METHODS
  By using a mouse model that develops Crohn's-like ileitis (tumor necrosis factor Δadenosine uracyl-rich element [TNFΔARE] mice) we examined the role of CCL25-CCR9 interactions for effector and Treg traffic using flow cytometry, quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, immunoneutralization, and proliferation analyses.
  
  
  RESULTS
  In TNFΔARE mice, expression of CCL25 and the frequency of CCR9-expressing lymphocytes increased during late-stage disease. In the absence of CCR9, TNFΔARE mice developed exacerbated disease, compared with their CCR9-sufficient counterparts, which coincided with a deficiency of CD4(+)/CD25(+)/forkhead box P3(+) and CD8(+)/CD103(+) Tregs within the intestinal lamina propria and mesenteric lymph nodes. Furthermore, the CD8(+)/CCR9(+) subset decreased the proliferation of CD4(+) T cells in vitro. Administration of a monoclonal antibody against CCR9 to TNFΔARE mice exacerbated ileitis in vivo, confirming the regulatory role of CD8(+)/CCR9(+) cells.
  
  
  CONCLUSIONS
  Signaling of the chemokine CCL25 through its receptor CCR9 induces Tregs to migrate to the intestine. These findings raise concerns about the development of reagents to disrupt this pathway for the treatment of patients with Crohn's disease.
authors.affiliation: Mucosal Inflammation Program, Department of Internal Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Wermers
authors.forename: Eoin N
authors.initials: EN
authors.lastname: McNamee
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Wurbel
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Jesús
authors.initials: J
authors.lastname: Rivera-Nieves
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D002908:Chronic Disease; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007079:Ileitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007082:Ileum / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054388:Receptors, CCR / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: C119309:CC chemokine receptor 9; D054388:Receptors, CCR; D004247:DNA