title: Gut homing receptors on CD8 T cells are retinoic acid dependent and not maintained by liver dendritic or stellate cells.
abstract: OBJECTIVE
  Lymphocytes primed by intestinal dendritic cells (DC) express the gut-homing receptors CCR9 and alpha4beta7, which recognize CCL25 and mucosal addressin cell-adhesion molecule-1 in the intestine promoting the development of regional immunity. In mice, imprinting of CCR9 and alpha4beta7 is dependent on retinoic acid during T-cell activation. Tissue specificity is lost in primary sclerosing cholangitis (PSC), an extraintestinal manifestation of inflammatory bowel disease, when ectopic expression of mucosal addressin cell-adhesion molecule-1 and CCL25 in the liver promotes recruitment of CCR9+alpha4beta7+ T cells to the liver. We investigated the processes that control enterohepatic T-cell migration and whether the ability to imprint CCR9 and alpha4beta7 is restricted to intestinal DCs or can under some circumstances be acquired by hepatic DCs in diseases such as PSC.
  
  
  METHODS
  Human and murine DCs from gut, liver, or portal lymph nodes and hepatic stellate cells were used to activate CD8 T cells. Imprinting of CCR9 and alpha4beta7 and functional migration responses were determined. Crossover activation protocols assessed plasticity of gut homing.
  
  
  RESULTS
  Activation by gut DCs imprinted high levels of functional CCR9 and alpha4beta7 on naïve CD8 T cells, whereas hepatic DCs and stellate cells proved inferior. Imprinting was RA dependent and demonstrated plasticity.
  
  
  CONCLUSIONS
  Imprinting and plasticity of gut-homing human CD8 T cells requires primary activation or reactivation by gut DCs and is retinoic acid dependent. The inability of liver DCs to imprint gut tropism implies that alpha4beta7+CCR9+ T cell that infiltrate the liver in PSC are primed in the gut.
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Bertus
authors.initials: B
authors.lastname: Eksteen
authors.forename: J Rodrigo
authors.initials: JR
authors.lastname: Mora
authors.forename: Emma L
authors.initials: EL
authors.lastname: Haughton
authors.forename: Neil C
authors.initials: NC
authors.lastname: Henderson
authors.forename: Laura
authors.initials: L
authors.lastname: Lee-Turner
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Villablanca
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Curbishley
authors.forename: Alex I
authors.initials: AI
authors.lastname: Aspinall
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D002478:Cells, Cultured; D015209:Cholangitis, Sclerosing / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D041981:Gastrointestinal Tract / Q000276:immunology*; D055166:Hepatic Stellate Cells / Q000276:immunology*; D006801:Humans; D016023:Integrins / Q000276:immunology; D008099:Liver / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D054388:Receptors, CCR / Q000276:immunology; D016201:Receptors, Lymphocyte Homing / Q000276:immunology*; D013997:Time Factors; D014212:Tretinoin / Q000276:immunology*; D015854:Up-Regulation
chemical_list: C119309:CC chemokine receptor 9; D016023:Integrins; D054388:Receptors, CCR; D016201:Receptors, Lymphocyte Homing; C071777:integrin alpha4beta7; D014212:Tretinoin