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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.
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Research Article Autoimmunity Article has an altmetric score of 2

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

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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

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Figure 9

The miR-21/BDH2 axis promotes DNA hydroxymethylation of the BCL6 gene by regulating intracellular iron.

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The miR-21/BDH2 axis promotes DNA hydroxymethylation of the BCL6 gene by...
Healthy naive CD4+ T cells were isolated from peripheral blood from healthy donors and cultured under Tfh cell–polarized conditions for 3 days. After 3 days of stimulation, cells were collected for analysis. (A) Activity of TET enzymes, and (B) relative hydroxymethylation and (C) methylation levels in the promoter of Tfh cell–related genes BCL6, CXCR5, PDCD1, and IL21 in induced Tfh cells transfected with Agomir-NC or Agomir-21 (n = 3). (D) Activity of TET enzymes, and (E) relative hydroxymethylation and (F) methylation levels in the promoter of BCL6, CXCR5, PDCD1, and IL21 in induced human Tfh cells transfected with siRNA-NC or siRNA-BDH2 (n = 3). (G) Activity of TET enzymes, and (H) relative hydroxymethylation and (I) methylation levels in the promoter of BCL6, CXCR5, PDCD1, and IL21 in induced human Tfh cells transfected with Antagomir-NC or Antagomir-21 (n = 3). (J) Activity of TET enzymes, and (K) relative hydroxymethylation and (L) methylation levels in the promoter of BCL6, CXCR5, PDCD1, and IL21 in induced human Tfh cells transfected with pCMV6-NC or pCMV6-BDH2 (n = 3). Data are shown as mean ± SEM. Data are representative of 3 independent experiments with 3 donors. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (2-tailed Student’s t test for A–L).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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