Cdx2 regulates immune cell infiltration in the intestine

The intestinal epithelium is a unique tissue, serving both as a barrier against pathogens and to conduct the end digestion and adsorption of nutrients. As regards the former, the intestinal epithelium contains a diverse repertoire of immune cells, including a variety of resident lymphocytes, macroph...

Descripción completa

Detalles Bibliográficos
Autores principales: Chewchuk, Simon, Jahan, Sanzida, Lohnes, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339112/
https://www.ncbi.nlm.nih.gov/pubmed/34349205
http://dx.doi.org/10.1038/s41598-021-95412-w
_version_ 1783733528005967872
author Chewchuk, Simon
Jahan, Sanzida
Lohnes, David
author_facet Chewchuk, Simon
Jahan, Sanzida
Lohnes, David
author_sort Chewchuk, Simon
collection PubMed
description The intestinal epithelium is a unique tissue, serving both as a barrier against pathogens and to conduct the end digestion and adsorption of nutrients. As regards the former, the intestinal epithelium contains a diverse repertoire of immune cells, including a variety of resident lymphocytes, macrophages and dendritic cells. These cells serve a number of roles including mitigation of infection and to stimulate regeneration in response to damage. The transcription factor Cdx2, and to a lesser extent Cdx1, plays essential roles in intestinal homeostasis, and acts as a context-dependent tumour suppressor in colorectal cancer. Deletion of Cdx2 from the murine intestinal epithelium leads to macrophage infiltration resulting in a chronic inflammatory response. However the mechanisms by which Cdx2 loss evokes this response are poorly understood. To better understand this relationship, we used a conditional mouse model lacking all intestinal Cdx function to identify potential target genes which may contribute to this inflammatory phenotype. One such candidate encodes the histocompatability complex protein H2-T3, which functions to regulate intestinal iCD8α lymphocyte activity. We found that Cdx2 occupies the H3-T3 promoter in vivo and directly regulates its expression via a Cdx response element. Loss of Cdx function leads to a rapid and pronounced attenuation of H2-T3, followed by a decrease in iCD8α cell number, an increase in macrophage infiltration and activation of pro-inflammatory cascades. These findings suggest a previously unrecognized role for Cdx in intestinal homeostasis through H2-T3-dependent regulation of iCD8α cells.
format Online
Article
Text
id pubmed-8339112
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-83391122021-08-06 Cdx2 regulates immune cell infiltration in the intestine Chewchuk, Simon Jahan, Sanzida Lohnes, David Sci Rep Article The intestinal epithelium is a unique tissue, serving both as a barrier against pathogens and to conduct the end digestion and adsorption of nutrients. As regards the former, the intestinal epithelium contains a diverse repertoire of immune cells, including a variety of resident lymphocytes, macrophages and dendritic cells. These cells serve a number of roles including mitigation of infection and to stimulate regeneration in response to damage. The transcription factor Cdx2, and to a lesser extent Cdx1, plays essential roles in intestinal homeostasis, and acts as a context-dependent tumour suppressor in colorectal cancer. Deletion of Cdx2 from the murine intestinal epithelium leads to macrophage infiltration resulting in a chronic inflammatory response. However the mechanisms by which Cdx2 loss evokes this response are poorly understood. To better understand this relationship, we used a conditional mouse model lacking all intestinal Cdx function to identify potential target genes which may contribute to this inflammatory phenotype. One such candidate encodes the histocompatability complex protein H2-T3, which functions to regulate intestinal iCD8α lymphocyte activity. We found that Cdx2 occupies the H3-T3 promoter in vivo and directly regulates its expression via a Cdx response element. Loss of Cdx function leads to a rapid and pronounced attenuation of H2-T3, followed by a decrease in iCD8α cell number, an increase in macrophage infiltration and activation of pro-inflammatory cascades. These findings suggest a previously unrecognized role for Cdx in intestinal homeostasis through H2-T3-dependent regulation of iCD8α cells. Nature Publishing Group UK 2021-08-04 /pmc/articles/PMC8339112/ /pubmed/34349205 http://dx.doi.org/10.1038/s41598-021-95412-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Chewchuk, Simon
Jahan, Sanzida
Lohnes, David
Cdx2 regulates immune cell infiltration in the intestine
title Cdx2 regulates immune cell infiltration in the intestine
title_full Cdx2 regulates immune cell infiltration in the intestine
title_fullStr Cdx2 regulates immune cell infiltration in the intestine
title_full_unstemmed Cdx2 regulates immune cell infiltration in the intestine
title_short Cdx2 regulates immune cell infiltration in the intestine
title_sort cdx2 regulates immune cell infiltration in the intestine
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339112/
https://www.ncbi.nlm.nih.gov/pubmed/34349205
http://dx.doi.org/10.1038/s41598-021-95412-w
work_keys_str_mv AT chewchuksimon cdx2regulatesimmunecellinfiltrationintheintestine
AT jahansanzida cdx2regulatesimmunecellinfiltrationintheintestine
AT lohnesdavid cdx2regulatesimmunecellinfiltrationintheintestine