期刊
GASTROENTEROLOGY
卷 137, 期 1, 页码 320-329出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2009.02.046
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资金
- Medical Research Council [G0601816] Funding Source: Medline
- NIAID NIH HHS [R01 AI069259, R01 AI061663] Funding Source: Medline
- Medical Research Council [G0601816, G9818340B] Funding Source: researchfish
- MRC [G0601816] Funding Source: UKRI
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.
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