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Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis

Abstract

Appropriate regulation of B cell differentiation into plasma cells is essential for humoral immunity while preventing antibody-mediated autoimmunity; however, the underlying mechanisms, especially those with pathological consequences, remain unclear. Here, we found that the expression of Jmjd1c, a member of JmjC domain histone demethylase, in B cells but not in other immune cells, protected mice from rheumatoid arthritis (RA). In humans with RA, JMJD1C expression levels in B cells were negatively associated with plasma cell frequency and disease severity. Mechanistically, Jmjd1c demethylated STAT3, rather than histone substrate, to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused by Jmjd1c deletion inhibited the interaction with phosphatase Ptpn6 and resulted in abnormally sustained STAT3 phosphorylation and activity, which in turn promoted plasma cell generation. Germinal center B cells devoid of Jmjd1c also acquired strikingly increased propensity to differentiate into plasma cells. STAT3 Lys140Arg point mutation completely abrogated the effect caused by Jmjd1c loss. Mice with Jmjd1c overexpression in B cells exhibited opposite phenotypes to Jmjd1c-deficient mice. Overall, our study revealed Jmjd1c as a critical regulator of plasma cell differentiation and RA and also highlighted the importance of demethylation modification for STAT3 in B cells.

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Fig. 1: B cell-expressed Jmjd1c suppresses autoimmune arthritis.
Fig. 2: Jmjd1c restrains STAT3 activation in B cells.
Fig. 3: Jmjd1c deficiency enhances B cell differentiation into plasma cells.
Fig. 4: STAT3 hyperactivation accounts for the enhanced plasma cell differentiation in Jmjd1c-KO B cells.
Fig. 5: Jmjd1c demethylates STAT3 to facilitate its dephosphorylation by Ptpn6.
Fig. 6: Jmjd1c demethylates STAT3 at Lys140.
Fig. 7: Jmjd1c overexpression represses plasma cell differentiation and rheumatoid arthritis progression.

Data availability

RNA-seq data and CUT&Tag data reported in this paper are accessible at the Gene Expression Omnibus under accessions GSE193752 and GSE195462 respectively. MS data are available at iProX (PXD031855). There are no restrictions for data availability. Source data are provided with this paper.

Code availability

The codes for RNA-seq and CUT&Tag data analyses reported in this study have been deposited in GitHub at https://github.com/MikeYuliang/NGSdataanalysis/.

Any additional information required to reanalyze the data is available from the corresponding author upon request.

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Acknowledgements

The authors thank all the members of the Wang laboratory for feedback. We thank W. Zhang, W. Zeng and J. Li for genetic mouse generation and technical support. This study was supported by grants from the National Natural Science Foundation of China (82101827 to J.C., 31970828 to X.W. and 82171793 to N.C.), National Key R&D Program of China (2018YFC1003900 to X.W.), China Postdoctoral Science Foundation (2020M681665 to J.C.) and Jiangsu Outstanding Young Investigator Program (BK20200030 to X.W.).

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Authors and Affiliations

Authors

Contributions

X.W. and J.C. conceived and directed the study. Y.Y., X.Y., S.W. and Y.C. designed and performed most of the experiments. N.C. designed and directed the experiments with human samples. Y.W. performed the bioinformatic analysis. H.Z., X.L., X.D. and S.Z. helped with mouse caring and some in vitro experiments. X.W. and J.C. wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Nan Che, Jingjing Chen or Xiaoming Wang.

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Nature Immunology thanks Stephen Nutt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: L. A. Dempsey, in collaboration with the Nature Immunology team. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Normal B cell development in the absence of Jmjd1c.

a, The Jmjd1c gene conditional targeting strategy. Exon 9 and 10 was floxed and deleted by crossing to Cre+ mouse strain. Enzymatic JmjC domain was encoded by Exon 21-26. b, Left, flow cytometric analysis showing expression of CD11b, B220, CD43, BP-1, CD24, IgM and IgD in bone marrow cells from Jmjd1c+/+ Mb1Cre+ (n=4) and Jmjd1cfl/fl Mb1Cre+ mice (n=4). Right, absolute numbers of B220+CD43+ and B220+CD43 bone marrow cells per femur in each developmental stage. c,Left, expression of B220, IgD, IgM, AA4.1, CD23, and CD21 in splenocytes from Jmjd1c+/+ Mb1Cre+ (n=5) and Jmjd1cfl/fl Mb1Cre+ (n=5) mice. Right, absolute number of B220+ splenocytes in each developmental stage. Data are means ± SEM. Student’s t tests were used (NS, not significant).

Source data

Extended Data Fig. 2 Expression of Jmjd1c during B cell differentiation.

a, mRNA of Jmjd1c were examined by RT-qPCR in cells as indicated. b, Jmjd1c protein expression was examined by immunoblot with cells as indicated. Naïve B cells (NB) were sorted as CD19+IgDhi and stimulated with anti-IgM plus anti-CD40 for 24hr to obtain activated B cells (ABC). Germinal center B cells (GCB, CD19+IgDlowFas+GL7+) and plasma cells (PC, B220lowCD138+) were sorted from day 8 SRBC immunized mice.

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Extended Data Fig. 3 Jmjd1c expressed in B cells was dispensable for T cell helper function, but was required for antibody production.

a, Left, representative flow cytometry plots of splenic CD4+ T cell subsets: CD4+ naïve T (CD44-CD62L+) and CD4+ T effector memory (CD44+CD62L) cells from Jmjd1c+/+ Mb1Cre+ (n=4) and Jmjd1cfl/fl Mb1Cre+ mice (n=5). Right, frequency of the T cell populations. b, Splenocytes from Jmjd1c+/+ Mb1Cre+ and Jmjd1cfl/fl Mb1Cre+ mice were cultured with or without 1 μg/ml synthetic Eα52–68 peptide for 1 h, and then the levels MHC-II-Ea complex on B cells were measured with Y-Ae antibody by FACS. c and d, Jmjd1c+/+ Mb1Cre+ and Jmjd1cfl/fl Mb1Cre+ mice were induced for the collagen arthritis. (C) Left, representative flow cytometry plots of Th1 (CD4+IFN-γ+) cells from inguinal lymph nodes. Right, number of the Th1 cells. (D) ELISA of anti- collagen IgG2b (left), IgG2c (middle) and IgG1 (right) from serial serum samples. Data are means ± SEM. Student’s t tests were used for analyses in (a) and (c) (NS, not significant). Two-way ANOVA were used for (d) (***p < 0.001). All data are representative of 3 individual experiments.

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Extended Data Fig. 4 Increased antibody production in Jmjd1cfl/fl Mb1Cre+ mice.

a, ELISA of NP-specific IgM and IgG antibody from serum of Jmjd1c+/+ Mb1Cre+ and Jmjd1cfl/fl Mb1Cre+ mice immunized with NP-Ficoll for 7 days. These data are representative of 2 individual experiments. b, ELISA of NP-specific IgG1 antibody from serum of Jmjd1c+/+ Mb1Cre+ and Jmjd1cfl/fl Mb1Cre+ mice immunized with NP-KLH at day 7, 14, 21. These data are representative of 3 individual experiments. Data are means ± SEM. Two-way ANOVA were used (***p < 0.001).

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Extended Data Fig. 5 Increased Stat3 phosphorylation and antibody production in Jmjd1cfl/fl CD19Cre+ mice.

a, B cells from Jmjd1c+/+ CD19Cre+ and Jmjd1cfl/fl CD19Cre+ mice were stimulated with anti-IgM (left) or IL-6 (right) for 16 h. Expression of p-Stat3 was subsequently analyzed by immunoblot. Blots were probed against total Stat3, phosphorylated Stat3 (Y705) and β-actin. b, ELISA of NP-specific IgM and IgG from serum of Jmjd1c+/+ CD19Cre+ and Jmjd1cfl/fl CD19Cre+ mice immunized with NP-Ficoll for 7 days. c, ELISA of NP-specific IgG1 from serum of Jmjd1c+/+ CD19Cre+ and Jmjd1cfl/fl CD19Cre+ mice immunized with NP-KLH at day 7, 14, 21. Data are means ± SEM. Two-way ANOVA were used (***p < 0.001). Data are representative of 2 individual experiments.

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Extended Data Fig. 6 The vector map of MSCV-U6-sgRNA-Thy1.1.

The U6 promoter and gRNA scaffold were synthesized and cloned into the MSCV-Thy1.1 retroviral plasmid to generate the MSCV-U6-sgRNA-Thy1.1 vector.

Extended Data Fig. 7 Jmjd1c did not regulate H3K9 methylation in B cells.

a, B cells were sorted from Jmjd1c+/+ Mb1Cre+ and Jmjd1cfl/fl Mb1Cre+ mice. The level of Jmjd1c and H3K9me was subsequently analyzed by western blot. Blots were probed against Jmjd1c, β-actin, H3K9me1, H3K9me2, H3K9me3 and total H3. Data are representative of 2 individual experiments. b, Anti-H3K9me2 CUT&Tag was performed with B cells from Jmjd1c+/+ Mb1Cre+ and Jmjd1cfl/fl Mb1Cre+ mice to analyze the genomic distribution of H3K9me2 modification. The overall H3K9me2 peak signal was shown in averaged profile plot (left) or heatmap (right).

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Extended Data Fig. 8 Stat3 interacted with Jmjd1c.

a, IB analysis of whole-cell lysates (WCLs) and immunoprecipitation (IP) of 293T cells transfected with the indicated plasmids. b, Schematic of Flag-tagged Jmjd1c deletions used to identify the Stat3-interacting domain. Immunoblot analysis of WCLs and IP of 293T cells transfected with the indicated expression vectors. Data are representative of 2 individual experiments.

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Extended Data Fig. 9 Jmjd1c expression in B cells suppressed lupus-like disease.

a and b, Jmjd1c+/+ Mb1Cre+, Jmjd1cfl/fl Mb1Cre+ and Jmjd1cOEMb1Cre+ mice were intraperitoneally injected with 7.5 million of CD4+ T cell from C57BL/6 mice (control) or from bm12 mice. a,ELISA of anti-dsDNA in serum from immunized mice at day 14. b, Representative immunofluorescent images showing IgG deposits in kidney by staining with Cy3-labeled anti-mouse IgG. Scale bar, 50 μm. Data are means ± SEM. Student’s t tests were used (NS, not significant, *p < 0.05, **p < 0.01, ***p < 0.001). Data are pooled from 2 experiments.

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Yin, Y., Yang, X., Wu, S. et al. Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis. Nat Immunol 23, 1342–1354 (2022). https://doi.org/10.1038/s41590-022-01287-y

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