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Expansion of T follicular helper-T helper 1 like cells through epigenetic regulation by signal transducer and activator of transcription factors
  1. Xiaoxue Ma1,2,
  2. Shingo Nakayamada1,
  3. Satoshi Kubo1,
  4. Kei Sakata1,3,
  5. Kaoru Yamagata1,
  6. Yusuke Miyazaki1,
  7. Maiko Yoshikawa1,
  8. Yukihiro Kitanaga1,4,
  9. Mingzeng Zhang1,5,
  10. Yoshiya Tanaka1
  1. 1 First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
  2. 2 Department of Pediatrics, The First Hospital of China Medical University, Shenyang, China
  3. 3 Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
  4. 4 Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan
  5. 5 Department of Hematology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
  1. Correspondence to Dr Yoshiya Tanaka, The First Department of Internal Medicine, School of Medicine, University of Occupational & Environmental Health, Kitakyushu 807-8555, Japan; tanaka{at}


Objectives T follicular helper (Tfh) cells are critical in the development and progression of systemic lupus erythematosus (SLE). To assess the characteristics and mechanisms of differentiation of Tfh cells, we investigated the phenotype of T helper cells in patients with SLE and underlying epigenetic modifications by cytokine-induced signal transducer and activators of transcription (STAT) family factors.

Methods Peripheral blood mononuclear cells from patients and healthy donors were analysed by flow cytometry. CD4+ T cells were isolated and cultured under various stimulations. Expression of characteristic markers and phosphorylation of STATs were analysed by flow cytometry and quantitative PCR. Histone modifications were analysed by chromatin immunoprecipitation (ChIP)-PCR.

Results Differentiation of CD4+CXCR5+CXCR3+Bcl-6+T-bet+IL-21+IFN-γ+Tfh-Th1-like cells was induced by interleukin (IL)-12-induced activation of STAT1 and STAT4 simultaneously. The loci of Bcl-6 and T-bet at STAT binding sites were marked by bivalent histone modifications. After IL-12 stimulation, both STAT1 and STAT4 directly bound on BCL6 and TBX21 gene loci accompanied by suppression of repressive histone mark trimethylated histone 3 lysine 27. Levels of serum IL-12 and interferon (IFN)-γ, expression of IL-12 receptors and proportion of CXCR5+CXCR3+ activated Tfh-Th1-like cells were increased in patients with SLE. Furthermore, the level of pSTAT1, pSTAT4 and T-bet were higher in activated Tfh-Th1-like cells than non-Tfh-Th1 cells.

Conclusion Our findings suggest that IL-12-mediated co-activation of STAT1 and STAT4 alters histone modification, resulting in differentiation of Tfh-Th1-like cells that are characteristically expanded in patients with SLE. This could be one of the underlying mechanisms responsible for expansion of Tfh-Th1-like cells and potentially helpful towards development of cell-specific treatment for SLE.

  • systemic lupus erythematosus
  • t cells
  • cytokines

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  • Handling editor Josef S Smolen

  • Contributors XM and SN designed the study. XM conducted the experiments, analysed the data and wrote the manuscript. SK, KS, KY, YM, MY, YK and MZ helped to conduct the experiments and YT created the research concept and supervised the research and writing of the manuscript.

  • Funding This work was supported in part by Research on Rare and Intractable Diseases and Research Grant-In-Aid for Scientific Research by the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan and the University of Occupational and Environmental Health, Japan and UOEH Grant for Advanced Research (H23-Q-916).

  • Competing interests YT has received consulting fees, speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Pfizer, Mitsubishi-Tanabe, Bristol-Myers, Chugai, YL Biologics, Eli Lilly, Sanofi, Janssen, UCB and has received research grants from Mitsubishi-Tanabe, Takeda, Bristol-Myers, Chugai, Astellas, Abbvie, MSD, Daiichi-Sankyo, Pfizer, Kyowa-Kirin, Eisai, Ono. SN has received speaking fees from Bristol-Myers, UCB, Astellas, Abbvie, Eisai, Pfizer, Takeda and has received research grants from Mitsubishi-Tanabe, Novartis and MSD. All other authors declare no conflict of interest. None of the material presented in our manuscript has been previously submitted or published.

  • Patient consent Not required.

  • Ethics approval The study was approved by Institutional Review Board of the University of Occupational and Environmental Health. Informed consent was obtained from each subject.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.