Gut Homing Receptors on CD8 T Cells Are Retinoic Acid Dependent and Not Maintained by Liver Dendritic or Stellate Cells

Bertus Eksteen, J. Rodrigo Mora, Emma L. Haughton, Neil C. Henderson, Laura Lee-Turner, Eduardo J. Villablanca, Stuart M. Curbishley, Alex I. Aspinall, Ulrich H. von Andrian, David H. Adams

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND & AIMS
Lymphocytes primed by intestinal dendritic cells (DC) express the gut-homing receptors CCR9 and alpha 4 beta 7, 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 alpha 4 beta 7 is dependent on retinoic acid during T-cell activation. Tissue specificity is lost in primary sclerosing cholangitis (PSC), an extra-intestinal manifestation of inflammatory bowel disease, when ectopic expression of mucosal addressin cell-adhesion molecule-1 and CCL25 in the liver promotes recruitment of CCR9+alpha 4 beta 7+ T cells to the liver. We investigated the processes that control enterohepatic T-cell migration and whether the ability to imprint CCR9 and alpha 4 beta 7 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 alpha 4 beta 7 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 alpha 4 beta 7 on naive 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 alpha 4 beta 7+CCR9+ T cell that infiltrate the liver in PSC are primed in the gut.

Original languageEnglish
Pages (from-to)320-329
Number of pages10
JournalGastroenterology
Volume137
Issue number1
DOIs
Publication statusPublished - Jul 2009

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