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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 4

Intracellular iron promotes Tfh cell differentiation in vitro.

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Intracellular iron promotes Tfh cell differentiation in vitro.
(A) Quant...
(A) Quantification of intracellular iron in healthy donor naive CD4+ T cells cultured under Tfh cell–polarized conditions for different amounts of time (n = 3). (B) Healthy donor naive T cells were cultured under Tfh cell–polarized conditions in the presence of PBS control or iron dextran (20 μM), and the percentage and quantification of CD4+CXCR5+PD-1+ Tfh cells were determined by flow cytometry 3 days later (n = 5). (C) Healthy donor naive CD4+ T cells were cultured under Tfh cell–polarized conditions in the presence of 2,5-DHBA (10 μM and 20 μM). After 3 days of differentiation, the percentage and quantification of the CD4+CXCR5+PD-1+ Tfh percentage were determined (n = 3). (D and E) Healthy donor naive CD4+ T cells were cultured under Tfh cell–polarized conditions for 3 days and treated with DMSO or CPX (20 μM) for the last 4 hours. Representative flow cytometry and quantification of (D) viable cells and (E) CD4+CXCR5+PD-1+ Tfh cells are shown (n = 5). Data are shown as mean ± SEM. Data are representative of 2 independent experiments with 3–5 donors. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (1-way ANOVA with Tukey’s multiple-comparisons test for A and C, and paired 2-tailed Student’s t test for B, D, and E).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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