Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus
Xiaofei Gao, … , Qianjin Lu, Ming Zhao
Xiaofei Gao, … , Qianjin Lu, Ming Zhao
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e152345. https://doi.org/10.1172/JCI152345.
View: Text | PDF
Research Article Autoimmunity

Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus

  • Text
  • PDF
Abstract

The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.

Authors

Xiaofei Gao, Yang Song, Jiali Wu, Shuang Lu, Xiaoli Min, Limin Liu, Longyuan Hu, Meiling Zheng, Pei Du, Yaqin Yu, Hai Long, Haijing Wu, Sujie Jia, Di Yu, Qianjin Lu, Ming Zhao

×

Figure 3

HID promotes exogenous antigen-induced GC response.

Options: View larger image (or click on image) Download as PowerPoint
HID promotes exogenous antigen-induced GC response.
3-week-old female B6...
3-week-old female B6 mice were treated with a normal iron diet (ND, 50 mg/kg, n = 5) and a high-iron diet (HID, 500 mg/kg, n = 5) for 5 weeks and immunized with sheep red blood cells (SRBCs) by i.p. injection. Mice were sacrificed for analysis after 2 weeks of immunization. (A) Schematic diagram of the HID treatment and SRBC immunization. (B) Body weight change of mice treated with ND or HID. (C) The level of serum iron in mice treated with ND or HID. (D) mRNA expression of Fth and Tfrc in splenic CD4+ T cells of ND- or HID-treated mice. (E) Representative flow cytometry and quantification of CD4+CXCR5+PD-1+ Tfh cells and CD4+CXCR5+PD-1+Foxp3+ Tfr cells. (F) Representative flow cytometry and quantification of B220+GL-7+FAS+ GC B cells. (G) Representative flow cytometry and quantification of B220–CD138+ plasma cells. (H–K) Quantification of the percentage and numbers of (H) CD4+IL-21+ cells, (I) CD4+IFN-γ+ cells, (J) CD4+IL-4+ cells, and (K) CD4+IL-17A+ cells. (L) Serum levels of anti-SRBC IgM and anti-SRBC IgG2a in ND- and HID-treated mice at day 7 and day 14 of SRBC immunization. (M) Representative histology and quantification of GCs in the spleen after 2 weeks of SRBC immunization. Blue, CD3; red, B220; green, PNA. Scar bar: 100 μM. Cells were isolated from the spleens of ND- and HID-treated mice immunized with SRBCs. Data are shown as mean ± SEM. Data are representative of 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 (unpaired 2-tailed Student’s t test for B–M).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts