The Kinase mTORC1 Promotes the Generation and Suppressive Function of Follicular Regulatory T Cells

• Published in: Immunity (Cambridge, Mass.) Vol. 47; no. 3; pp. 538 - 551.e5
• Main Authors: Xu, Lifan, Huang, Qizhao, Wang, Haoqiang, Hao, Yaxing, Bai, Qiang, Hu, Jianjun, Li, Yiding, Wang, Pengcheng, Chen, Xiangyu, He, Ran, Li, Bingshou, Yang, Xia, Zhao, Tingting, Zhang, Yanyan, Wang, Yifei, Ou, Juanjuan, Liang, Houjie, Wu, Yuzhang, Zhou, Xinyuan, Ye, Lilin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.09.2017; Elsevier Limited
• Subjects: acute viral infection; Animals; Bcl protein; Bcl-6 protein; Biomarkers; Cell differentiation; Cell Differentiation - immunology; Cell division; Cluster Analysis; Cues; Differentiation (biology); follicular helper T cells; follicular regulatory T cells; Gene Expression Profiling; Hepatocyte nuclear factor 1; Hepatocyte Nuclear Factor 1-alpha - metabolism; Homeostasis; Immunization; Immunomodulation; Immunophenotyping; Immunoregulation; Infections; Kinases; Lymphocytes; Lymphocytes B; Lymphocytes T; Mechanistic Target of Rapamycin Complex 1; Metabolism; Mice; Mice, Transgenic; mTORC1; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Phosphorylation; protein immunization; Protein kinase; Protein-serine/threonine kinase; Proto-Oncogene Proteins c-bcl-6 - metabolism; regulatory T cells; Rodents; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - metabolism; T cell receptors; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription factors; follicular helper T cells; acute viral infection; protein immunization; regulatory T cells; mTORC1; follicular regulatory T cells
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2017.08.011

Follicular regulatory T (Tfr) cells differentiate from conventional regulatory T (Treg) cells and suppress excessive germinal center (GC) responses by acting on both GC B cells and T follicular helper (Tfh) cells. Here, we examined the impact of mTOR, a serine/threonine protein kinase that senses and integrates diverse environmental cues, on the differentiation and functional competency of Tfr cells in response to protein immunization or viral infection. By genetically deleting Rptor or Rictor, essential components for mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), respectively, we found that mTORC1 but not mTORC2 is essential for Tfr differentiation. Mechanistically, mTORC1-mediated phosphorylation of the transcription factor STAT3 induced the expression of the transcription factor TCF-1 by promoting STAT3 binding to the Tcf7 5′-regulatory region. Subsequently, TCF-1 bound to the Bcl6 promoter to induce Bcl6 expression, which launched the Tfr cell differentiation program. Thus, mTORC1 initiates Tfr cell differentiation by activating the TCF-1-Bcl-6 axis during immunization or infection. [Display omitted] •Tfr cells exhibit elevated mTORC1 signaling compared to Treg cells after stimulation•mTORC1 signaling initiates Treg to Tfr cell differentiation•Differentiated Tfr cells require mTORC1 signaling to perform suppressive effects•mTORC1 regulates Tfr cell differentiation through p-STAT3-TCF-1-Bcl-6 pathway To differentiate from Treg cells, follicular regulatory T (Tfr) cells must integrate diverse signals within the germinal center. Xu et al. show that mTORC1 is essential for both the differentiation and functional competency of Tfr cells by activating a transcriptional axis consisting of Stat3-TCF-1-Bcl-6 and thus dictating Tfr cell fate.