Connecting liver and gut: murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid

Hepatology. 2012 Jun;55(6):1976-84. doi: 10.1002/hep.24816. Epub 2012 Mar 18.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Oxidoreductases / genetics
  • Amino Acid Sequence
  • Animals
  • CD4-Positive T-Lymphocytes / physiology*
  • Cell Movement
  • Endothelial Cells / physiology*
  • Enterohepatic Circulation
  • Integrins / analysis
  • Intestines / immunology*
  • Isoenzymes / genetics
  • Liver / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Receptors, CCR / analysis
  • Retinal Dehydrogenase / genetics
  • Tretinoin / physiology*
  • Tropism

Substances

  • CC chemokine receptor 9
  • Integrins
  • Isoenzymes
  • Receptors, CCR
  • integrin alpha4beta7
  • Tretinoin
  • Aldehyde Oxidoreductases
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, mouse
  • RALDH2 protein, mouse
  • Retinal Dehydrogenase