1. MiR-23~27~24–mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation
- Author
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Jasmin Russ, Niels Olsen Saraiva Camara, Shiang-Fu Huang, Mei-Chi Chen, Juan Carlos Izpisua Belmonte, Li-Fan Lu, Lindsey M. Warner, Flavia Franco da Cunha, Sunglim Cho, Sara Quon, Cheng-Jang Wu, Daniel T. Utzschneider, Ming-Ling Kuo, Chun-Hao Lu, Li-Chen Chen, Jacqueline Berner, Dietmar Zehn, Hsin-Kai Liao, Hsi-Yuan Huang, Ling-Li Lin, and Leilani O. Cruz
- Subjects
T-Lymphocytes ,Cellular differentiation ,Immunology ,Cell ,Biology ,Lymphocyte Activation ,Mice ,03 medical and health sciences ,fluids and secretions ,0302 clinical medicine ,Immune system ,medicine ,Animals ,Humans ,Research Articles ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,Cell growth ,High Mobility Group Proteins ,Gene Expression Regulation, Developmental ,SciAdv r-articles ,Cell Differentiation ,T-Lymphocytes, Helper-Inducer ,BCL6 ,ddc ,Immunity, Humoral ,3. Good health ,Cell biology ,MicroRNAs ,Thymocyte ,medicine.anatomical_structure ,ÁCIDOS NUCLEICOS ,Humoral immunity ,Proto-Oncogene Proteins c-bcl-6 ,bacteria ,Signal Transduction ,Research Article ,030215 immunology - Abstract
miR-23~27~24 regulates TFH cells through targeting multiple genes including TOX, a key transcription factor for TFH cell biology., Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control TFH cells through targeting a network of genes that are crucial for TFH cell biology. Among them, thymocyte selection–associated HMG-box protein (TOX) was identified as a central transcription regulator in TFH cell development. TOX is highly up-regulated in both mouse and human TFH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in TFH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal TFH cell responses for resultant humoral immunity.
- Published
- 2019
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