Journal
HEPATOLOGY
Volume 55, Issue 6, Pages 1976-1984Publisher
WILEY-BLACKWELL
DOI: 10.1002/hep.24816
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Funding
- German Research Foundation [SFB 633]
- [KL 1183/2-1]
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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 a4 beta 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 a4 beta 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 a4 beta 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. (HEPATOLOGY 2012;55:19761984)
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