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

doi:10.1053/j.gastro.2009.02.046

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 journal › Article › peer-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 language	English
Pages (from-to)	320-329
Number of pages	10
Journal	Gastroenterology
Volume	137
Issue number	1
DOIs	https://doi.org/10.1053/j.gastro.2009.02.046
Publication status	Published - Jul 2009

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10.1053/j.gastro.2009.02.046

Gut Homing Receptors on CD8 T Cells Are Retinoic Acid Dependent and Not Maintained by Liver Dendritic or Stellate Cells
Published in final edited form as: Gastroenterology. 2009 July ; 137(1): 320–329. doi:10.1053/j.gastro.2009.02.046.
Accepted author manuscript, 2.57 MB

http://www.sciencedirect.com/science/article/pii/S0016508509002868

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Eksteen, B., Mora, J. R., Haughton, E. L., Henderson, N. C., Lee-Turner, L., Villablanca, E. J., Curbishley, S. M., Aspinall, A. I., von Andrian, U. H., & Adams, D. H. (2009). Gut Homing Receptors on CD8 T Cells Are Retinoic Acid Dependent and Not Maintained by Liver Dendritic or Stellate Cells. Gastroenterology, 137(1), 320-329. https://doi.org/10.1053/j.gastro.2009.02.046

@article{15863301f7d146a895fc9824f8c5d354,

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

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.",

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

year = "2009",

month = jul,

doi = "10.1053/j.gastro.2009.02.046",

language = "English",

volume = "137",

pages = "320--329",

journal = "Gastroenterology",

issn = "1528-0012",

publisher = "W.B. Saunders Ltd",

number = "1",

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TY - JOUR

T1 - Gut Homing Receptors on CD8 T Cells Are Retinoic Acid Dependent and Not Maintained by Liver Dendritic or Stellate Cells

AU - Eksteen, Bertus

AU - Mora, J. Rodrigo

AU - Haughton, Emma L.

AU - Henderson, Neil C.

AU - Lee-Turner, Laura

AU - Villablanca, Eduardo J.

AU - Curbishley, Stuart M.

AU - Aspinall, Alex I.

AU - von Andrian, Ulrich H.

AU - Adams, David H.

PY - 2009/7

Y1 - 2009/7

N2 - 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.

AB - 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.

U2 - 10.1053/j.gastro.2009.02.046

DO - 10.1053/j.gastro.2009.02.046

M3 - Article

VL - 137

SP - 320

EP - 329

JO - Gastroenterology

JF - Gastroenterology

SN - 1528-0012

IS - 1

ER -

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

Abstract

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