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

• DOI: 10.1016/j.celrep.2017.09.020
• Publication Date: 2017-10-04T01:04:14Z
• Authors: Sonia Agüera-Gonz...; Oliver T. Burton; Elena Vázquez-Chávez; Céline Cuche; Floriane Herit; Jérôme Bouchet; Rémi Lasserre; Iratxe del Río-Iñ...; Vincenzo Di Bartolo; Andrés Alcover
• Keywords: NFAT; intestinal tumors; QH301-705.5; Adenomatous Polyposis Coli Protein; colorectal cancer; Mice, Transgenic; Lymphocyte Activation; Microtubules; T-Lymphocytes, Regulatory; microtubules; Jurkat Cells; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Biology (General); RNA, Small Interfering; 0303 health sciences; NFATC Transcription Factors; T cell activation; adenomatous polyposis coli; immunological synapse; Cell Differentiation; HCT116 Cells; Interleukin-10; 3. Good health; Treg; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; cell polarity; [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology; Adenomatous Polyposis Coli; [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology; IL-10; Lymph Nodes; Signal Transduction

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.