Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization
Sonia Agüera-González, Oliver T Burton, Elena Vázquez-Chávez, Céline Cuche, Floriane Herit, Jérôme Bouchet, Rémi Lasserre, Iratxe Del Río-Iñiguez, Vincenzo Di Bartolo, Andrés Alcover, Sonia Agüera-González, Oliver T Burton, Elena Vázquez-Chávez, Céline Cuche, Floriane Herit, Jérôme Bouchet, Rémi Lasserre, Iratxe Del Río-Iñiguez, Vincenzo Di Bartolo, Andrés Alcover
Abstract
Adenomatous polyposis coli (APC) is a polarity regulator and tumor suppressor associated with familial adenomatous polyposis and colorectal cancer development. Although extensively studied in epithelial transformation, the effect of APC on T lymphocyte activation remains poorly defined. We found that APC ensures T cell receptor-triggered activation through Nuclear Factor of Activated T cells (NFAT), since APC is necessary for NFAT's nuclear localization in a microtubule-dependent fashion and for NFAT-driven transcription leading to cytokine gene expression. Interestingly, NFAT forms clusters juxtaposed with microtubules. Ultimately, mouse Apc deficiency reduces the presence of NFAT in the nucleus of intestinal regulatory T cells (Tregs) and impairs Treg differentiation and the acquisition of a suppressive phenotype, which is characterized by the production of the anti-inflammatory cytokine IL-10. These findings suggest a dual role for APC mutations in colorectal cancer development, where mutations drive the initiation of epithelial neoplasms and also reduce Treg-mediated suppression of the detrimental inflammation that enhances cancer growth.
Keywords: IL-10; NFAT; T cell activation; Treg; adenomatous polyposis coli; cell polarity; colorectal cancer; immunological synapse; intestinal tumors; microtubules.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed