title: Connecting liver and gut: murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid.
abstract: Gut-activated T cells migrating into the liver can cause extraintestinal manifestations of inflammatory bowel disease. T cells acquire a gut-homing phenotype dependent on retinoic acid (RA) provided by intestinal dendritic cells (DC). We investigated whether liver antigen-presenting cells can induce gut tropism supporting an enterohepatic lymphocyte circulation. Priming of CD4(+) T cells by liver sinusoidal endothelial cells (LSEC) supported migration into gut and gut-associated lymphoid tissue. As observed for T cells primed by intestinal DCs, this gut tropism depended on α(4) β(7) integrin and CC chemokine receptor 9 (CCR9) expression by LSEC-primed CD4(+) T cells. The induction of gut-homing molecules was mediated by RA, a derivate of vitamin A that is stored in large amounts within the liver. LSECs expressed functional retinal dehydrogenases and could convert vitamin A to RA. Conversely, the lack of signaling via the RA receptor prevented the expression of α(4) β(7) integrin and CCR9 on LSEC-primed CD4(+) T cells, consequently reducing their in vivo migration to the intestine. Other liver antigen-presenting cells failed to support high expression of α(4) β(7) integrin on CD4(+) T cells, thus, the potential to induce gut homing is restricted to LSECs.
  
  
  CONCLUSIONS
  The capacity to promote gut tropism via vitamin A use is not unique for intestinal DCs but is also a feature of LSECs. Our data support the assumption that CD4(+) T cells can migrate from the liver to the gut as one branch of a postulated enterohepatic lymphocyte circulation.
authors: Medical Clinic I,Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: Katrin
authors: K
authors: Neumann
authors: Nils
authors: N
authors: Kruse
authors: Balint
authors: B
authors: Szilagyi
authors: Ulrike
authors: U
authors: Erben
authors: Christine
authors: C
authors: Rudolph
authors: Anne
authors: A
authors: Flach
authors: Martin
authors: M
authors: Zeitz
authors: Alf
authors: A
authors: Hamann
authors: Katja
authors: K
authors: Klugewitz
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000445:Aldehyde Oxidoreductases / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002465:Cell Movement; D042783:Endothelial Cells / Q000502:physiology*; D004764:Enterohepatic Circulation; D016023:Integrins / Q000032:analysis; D007422:Intestines / Q000276:immunology*; D007527:Isoenzymes / Q000235:genetics; D008099:Liver / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D054388:Receptors, CCR / Q000032:analysis; D050697:Retinal Dehydrogenase / Q000235:genetics; D014212:Tretinoin / Q000502:physiology*; D018523:Tropism
chemical_list: C119309:CC chemokine receptor 9; D016023:Integrins; D007527:Isoenzymes; D054388:Receptors, CCR; C071777:integrin alpha4beta7; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; D000080924:Aldehyde Dehydrogenase 1 Family; C515028:ALDH1A1 protein, mouse; C470579:RALDH2 protein, mouse; D050697:Retinal Dehydrogenase