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

Sonia Agüera-Gonzalez (1, 2, 3) , Oliver T. Burton (4, 5) , Elena Vázquez-Chávez (1, 2) , Céline Cuche (1, 2) , Floriane Herit (1, 2, 6) , Jérôme Bouchet (1, 2) , Rémi Lasserre (1, 2, 7) , Iratxe del Río-Iñiguez (1, 2) , Vincenzo Di Bartolo (1, 2) , Andres Alcover (1, 2)

1 Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology
2 Biologie des Populations Lymphocytaires
3 CDC - Compartimentation et dynamique cellulaires
4 HMS - Harvard Medical School [Boston]
5 Boston Children's Hospital
6 IC UM3 (UMR 8104 / U1016) - Institut Cochin
7 CIML - Centre d'Immunologie de Marseille - Luminy

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.

Domaines: Immunité adaptative

Sonia Agüera-Gonzalez, Oliver T. Burton, Elena Vázquez-Chávez, Céline Cuche, Floriane Herit, et al.. Adenomatous Polyposis Coli Defines Treg Differentiation and Anti-inflammatory Function through Microtubule-Mediated NFAT Localization. Cell Reports, 2017, 21 (1), pp.181-194. ⟨10.1016/j.celrep.2017.09.020⟩. ⟨hal-01614654⟩