Tumour‐associated changes in intestinal epithelial cells cause local accumulation of KLRG1+ GATA3+ regulatory T cells in mice

• Published in: Immunology 2017-09, Vol.152 (1), p.74-88
• Main Authors: Meinicke, Holger, Bremser, Anna, Brack, Maria, Akeus, Paulina, Pearson, Claire, Bullers, Samuel, Hoffmeyer, Katrin, Stemmler, Marc P., Quiding‐Järbrink, Marianne, Izcue, Ana
• Format: Article
• Language: English
• Subjects: Ablation; Accumulation; Animal models; Animals; beta Catenin - genetics; beta Catenin - immunology; beta Catenin - metabolism; Cadherins - immunology; Cadherins - metabolism; cancer; Cancer and Oncology; Cancer och onkologi; CD4 antigen; Cdh1 Proteins - genetics; Cdh1 Proteins - immunology; Cdh1 Proteins - metabolism; cell surface molecules; Cells, Cultured; Chemotaxis, Leukocyte; Cytokines; E-cadherin; Effector cells; Epithelial cells; Epithelial Cells - immunology; Epithelial Cells - metabolism; Epithelial Cells - pathology; expression; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; foxp3; Foxp3 protein; GATA-3 protein; GATA3 Transcription Factor - immunology; GATA3 Transcription Factor - metabolism; gene; Genes, APC; Genetic modification; Genetic Predisposition to Disease; Immunology; Immunoregulation; inflammation; Interleukin-33 - immunology; Interleukin-33 - metabolism; Interleukins; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestinal Neoplasms - genetics; Intestinal Neoplasms - immunology; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Intestine; KLRG1 protein; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Mesenchyme; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microbiology in the medical area; Mikrobiologi inom det medicinska området; mucosa; mutation; Original; Phenotype; polyposis; Receptors, Immunologic - immunology; Receptors, Immunologic - metabolism; regulatory T cells; Rodents; Signal Transduction; Signaling; skin; stem-cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Transcription factors; Tumorigenesis; Tumors; tumour immunology; β-Catenin
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12750

Summary CD4+ 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 KLRG1+ GATA3+ 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 KLRG1+ GATA3+ 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 KLRG1+ GATA3+ 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 APCmin/+ mice was exclusively due to the increase in KLRG1+ GATA3+ Treg cells. Our data identify a novel axis through which epithelial cells control local Treg cell subsets, which may be activated during intestinal tumorigenesis. This article shows that two tumour‐associated changes in intestinal epithelial cells, namely replacement of E‐cadherin by N‐cadherin and increased β‐catenin signals, result in a strong increase in CD4+ Foxp3+ regulatory T (Treg) cells arising from the accumulation of a specific GATA3+ KLRG1+ Treg population. The epithelial changes were accompanied by an increase in interleukin‐33, which promotes KLRG1+ Treg cell survival and proliferation. The local accumulation of KLRG1+ Treg cell also took place in APC+/min intestinal tumours.