MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation

• Published in: Science advances Vol. 5; no. 12; p. eaaw1715
• Main Authors: Wu, Cheng-Jang, Cho, Sunglim, Huang, Hsi-Yuan, Lu, Chun-Hao, Russ, Jasmin, Cruz, Leilani O, da Cunha, Flavia Franco, Chen, Mei-Chi, Lin, Ling-Li, Warner, Lindsey M, Liao, Hsin-Kai, Utzschneider, Daniel T, Quon, Sara, Berner, Jacqueline, Camara, Niels Olsen Saraiva, Zehn, Dietmar, Belmonte, Juan Carlos Izpisua, Chen, Li-Chen, Huang, Shiang-Fu, Kuo, Ming-Ling, Lu, Li-Fan
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 11.12.2019
• Subjects: Animals; Cell Differentiation - genetics; Gene Expression Regulation, Developmental - immunology; High Mobility Group Proteins - genetics; Humans; Immunity, Humoral - genetics; Immunity, Humoral - immunology; Immunology; Lymphocyte Activation - immunology; Mice; MicroRNAs - genetics; Proto-Oncogene Proteins c-bcl-6 - genetics; SciAdv r-articles; Signal Transduction; T-Lymphocytes - immunology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aaw1715

Follicular helper T (T ) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating T cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated T cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced T cell responses. Mechanistically, miR-23~27~24 clusters coordinately control T cells through targeting a network of genes that are crucial for T cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in T cell development. TOX is highly up-regulated in both mouse and human T cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in T cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal T cell responses for resultant humoral immunity.