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 6

miR-21 promotes Tfh cell–mediated GC response.

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miR-21 promotes Tfh cell–mediated GC response. 8-week-old WT (n = 5) or ...
8-week-old WT (n = 5) or miR-21 cKO mice (n = 5) were immunized with sheep red blood cells (SRBCs) for 7 days. After 7 days of SRBCs stimulation, mice were sacrificed for analysis. (A) Representative flow cytometry and quantification of CD4+ T cells. (B) Representative flow cytometry and quantification of CD4+CXCR5+PD-1+ Tfh cells. (C) Representative flow cytometry and quantification of B220+GL-7+FAS+ GC B cells. (D) Serum levels of anti-SRBC IgG isotypes after 7 days of SRBC immunization. (E) Representative histology of spleens at day 7 after SRBC immunization and quantification of GC number and GC area (dashed line). Blue, CD3; red, B220; green, PNA. Scale bar: 100 μM. For A–C, cells were isolated from the spleens of 8-week-old WT or miR-21 cKO mice after 7 days of SRBC immunization. Data are shown as mean ± SEM. Data are representative of 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (unpaired 2-tailed Student’s t test for A–E).