Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): 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
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.

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Teaser

Agüera-González et al. investigate the role of the polarity regulator and tumor suppressor Adenomatous polyposis coli (APC) in CD4 T cell activation and effector function. APC controls microtubule reorganization, NFAT transcription factor localization, and cytokine gene expression. In Apc^Min/+ mutant mice, regulatory T cell (Treg) differentiation and anti-inflammatory function were intrinsically affected.


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