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Differential homing mechanisms regulate regionalized effector CD8 alpha beta(+) T cell accumulation within the small intestine

Stenstad, Hanna LU ; Svensson Frej, Marcus LU ; Cucak, Helena LU ; Kotarsky, Knut LU and Agace, William LU (2007) In Proceedings of the National Academy of Sciences 104(24). p.10122-10127
Abstract
The CC chemokine receptor (CCR)9 is expressed on the majority of small intestinal, but few colonic, T cells, whereas its ligand CCL25 is constitutively expressed by small intestinal epithelial cells. As such, CCR9/CCL25 have been proposed to play a central role in regulating small intestinal but not colonic immune responses and thus to organize regionalized immunity within the intestinal mucosa. Here, we demonstrate that CCL25 is expressed at reduced levels by epithelial cells in the distal compared with proximal small intestine, which correlated with less efficient CCR9-dependent effector CD8 alpha ss(+) T cell entry into the ileal epithelium. In vitro-generated alpha(4)ss(+)(7) effector CD8 alpha ss(+) T cell entry into the lamina... (More)
The CC chemokine receptor (CCR)9 is expressed on the majority of small intestinal, but few colonic, T cells, whereas its ligand CCL25 is constitutively expressed by small intestinal epithelial cells. As such, CCR9/CCL25 have been proposed to play a central role in regulating small intestinal but not colonic immune responses and thus to organize regionalized immunity within the intestinal mucosa. Here, we demonstrate that CCL25 is expressed at reduced levels by epithelial cells in the distal compared with proximal small intestine, which correlated with less efficient CCR9-dependent effector CD8 alpha ss(+) T cell entry into the ileal epithelium. In vitro-generated alpha(4)ss(+)(7) effector CD8 alpha ss(+) T cell entry into the lamina propria was less dependent on CCR9 than entry into the epithelium along the entire length of the small intestine and in particular in the ileum. CCR9-independent alpha(4)ss(+)(7) effector CD8 alpha ss(+) T cell entry was pertussis toxin-sensitive, suggesting a role for additional Gal-linked G protein-coupled receptors. Finally, in vivo-primed effector CD8 alpha ss(+) T cells displayed regionalized differences in their entry to the small intestinal epithelium with enhanced CCR9-independent entry to the ileum. These results highlight a hitherto underappreciated compartmentalization of immune responses within the small intestine and have direct implications for targeting strategies aimed at regulating T cell localization to the small intestinal mucosa. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
chemokine receptor, intestinal mucosa
in
Proceedings of the National Academy of Sciences
volume
104
issue
24
pages
10122 - 10127
publisher
National Acad Sciences
external identifiers
  • wos:000247363000038
  • scopus:34547219103
ISSN
1091-6490
DOI
10.1073/pnas.0700269104
language
English
LU publication?
yes
id
ff72a2a2-cf1d-4b66-ba03-242be1b6c0e7 (old id 657673)
date added to LUP
2007-12-20 12:06:52
date last changed
2017-05-28 03:40:15
@article{ff72a2a2-cf1d-4b66-ba03-242be1b6c0e7,
  abstract     = {The CC chemokine receptor (CCR)9 is expressed on the majority of small intestinal, but few colonic, T cells, whereas its ligand CCL25 is constitutively expressed by small intestinal epithelial cells. As such, CCR9/CCL25 have been proposed to play a central role in regulating small intestinal but not colonic immune responses and thus to organize regionalized immunity within the intestinal mucosa. Here, we demonstrate that CCL25 is expressed at reduced levels by epithelial cells in the distal compared with proximal small intestine, which correlated with less efficient CCR9-dependent effector CD8 alpha ss(+) T cell entry into the ileal epithelium. In vitro-generated alpha(4)ss(+)(7) effector CD8 alpha ss(+) T cell entry into the lamina propria was less dependent on CCR9 than entry into the epithelium along the entire length of the small intestine and in particular in the ileum. CCR9-independent alpha(4)ss(+)(7) effector CD8 alpha ss(+) T cell entry was pertussis toxin-sensitive, suggesting a role for additional Gal-linked G protein-coupled receptors. Finally, in vivo-primed effector CD8 alpha ss(+) T cells displayed regionalized differences in their entry to the small intestinal epithelium with enhanced CCR9-independent entry to the ileum. These results highlight a hitherto underappreciated compartmentalization of immune responses within the small intestine and have direct implications for targeting strategies aimed at regulating T cell localization to the small intestinal mucosa.},
  author       = {Stenstad, Hanna and Svensson Frej, Marcus and Cucak, Helena and Kotarsky, Knut and Agace, William},
  issn         = {1091-6490},
  keyword      = {chemokine receptor,intestinal mucosa},
  language     = {eng},
  number       = {24},
  pages        = {10122--10127},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Differential homing mechanisms regulate regionalized effector CD8 alpha beta(+) T cell accumulation within the small intestine},
  url          = {http://dx.doi.org/10.1073/pnas.0700269104},
  volume       = {104},
  year         = {2007},
}