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

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

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 5

miR-21 contributes to Tfh cell differentiation in vitro.

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miR-21 contributes to Tfh cell differentiation in vitro. (A) Healthy nai...
(A) Healthy naive CD4+ T cells were cultured under Tfh cell–polarized conditions for 1, 3, and 5 days. Representative flow cytometry and quantification of CD4+CXCR5+PD-1+ Tfh cells are shown (n = 3). (B) qPCR of miR-21 during the differentiation process of Tfh cells in A. (C–E) Healthy naive CD4+ T cells were transfected with Agomir-NC or Agomir-21 and cultured under Tfh cell–polarized conditions for 3 days (n = 5). After 3 days of polarization, (C) the expression level of miR-21, (D) flow cytometry and quantification of CD4+CXCR5+PD-1+ Tfh cells, and (E) mRNA expression of CXCR5, PDCD1, IL21, and BCL6 were analyzed. (F–H) Healthy naive CD4+ T cells were transfected with Antagomir-NC or Antagomir-21 and cultured under Tfh cell–polarized conditions for 3 days (n = 5). After 3 days of polarization, (F) the expression of miR-21, (G) flow cytometry and quantification of CD4+CXCR5+PD-1+ Tfh cells, and (H) mRNA expression of CXCR5, PDCD1, IL21, and BCL6 were analyzed. (I) Representative flow cytometry and quantification of CD4+CXCR5+PD-1+ Tfh cells transfected with Agomir-NC, Agomir-21, and Agomir-21 plus 2,5-DHBA (n = 3). (J) Representative flow cytometry and quantification of CD4+CXCR5+PD-1+ Tfh cells transfected with Antagomir-NC, Antagomir-21, or Antagomir-21 plus iron dextran (n = 3). Data are shown as mean ± SEM. Data are representative of at least 2 independent experiments with 3–5 donors. *P < 0.05, **P < 0.01, ****P < 0.0001 (1-way ANOVA with Tukey’s multiple-comparisons test for A, B, I, and J and 2-tailed Student’s t test for C–H).