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Tumour‐associated changes in intestinal epithelial cells cause local accumulation of KLRG 1 + GATA 3 + regulatory T cells in mice
Author(s) -
Meinicke Holger,
Bremser Anna,
Brack Maria,
Akeus Paulina,
Pearson Claire,
Bullers Samuel,
Hoffmeyer Katrin,
Stemmler Marc P.,
QuidingJärbrink Marianne,
Izcue Ana
Publication year - 2017
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12750
Subject(s) - biology , foxp3 , microbiology and biotechnology , effector , cancer research , epithelial–mesenchymal transition , immunology , downregulation and upregulation , immune system , gene , biochemistry
Summary CD 4 + Foxp3 + regulatory T (Treg) cells include differentiated populations of effector Treg cells characterized by the expression of specific transcription factors. Tumours, including intestinal malignancies, often present with local accumulation of Treg cells that can prevent tumour clearance, but how tumour progression leads to Treg cell accumulation is incompletely understood. Here using genetically modified mouse models we show that ablation of E‐cadherin, a process associated with epithelial to mesenchymal transition and tumour progression, promotes the accumulation of intestinal Treg cells by the specific accumulation of the KLRG 1 + GATA 3 + Treg subset. Epithelial E‐cadherin ablation activates the β ‐catenin pathway, and we find that increasing β ‐catenin signals in intestinal epithelial cells also boosts Treg cell frequencies through local accumulation of KLRG 1 + GATA 3 + Treg cells. Both E‐cadherin ablation and increased β ‐catenin signals resulted in epithelial cells with higher levels of interleukin‐33, a cytokine that preferentially expands KLRG 1 + GATA 3 + Treg cells. Tumours often present reduced E‐cadherin expression and increased β ‐catenin signalling and interleukin‐33 production. Accordingly, Treg cell accumulation in intestinal tumours from APC min/+ mice was exclusively due to the increase in KLRG 1 + GATA 3 + Treg cells. Our data identify a novel axis through which epithelial cells control local Treg cell subsets, which may be activated during intestinal tumorigenesis.