IFNγ induces epigenetic programming of human T-bethi B cells and promotesTLR7/8 and IL-21 induced differentiation
- The University of Alabama at Birmingham, United States
- Emory University, United States
- University of Rochester, United States
Abstract
Although B cells expressing the IFNgR or the IFNg-inducible transcription factor T-bet drive autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNg signaling in human antibody responses is unknown. We show that elevated levels of IFNg in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFNg, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNg or IFNg-producing T cells. IFNg promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNg signals poise B cells to differentiate by increasing their responsiveness to IL-21.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE95282 and GSE118984. All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files for sequencing analysis are included as Supplementary Files 1 and 2 (excel files).
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Chromatin accessibility of ex vivo derived Be-g2 cellsNCBI Gene Expression Omnibus, GSE119726.
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Be1 and Be2 B cells are transcriptionally distinctNCBI Gene Expression Omnibus, GSE95282.
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Gene expression studies of lupus and healthy B cell subsets through RNA sequencingNCBI Gene Expression Omnibus, GSE92387.
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Molecular Signatures Database (MSigDB)Molecular Signatures Database.
Article and author information
Author details
Christopher D Scharer
Funding
NIH Office of the Director (UL1 TR001417)
- Travis Ptacek
NIH Office of the Director (1P30 DK079337)
- Trenton R Schoeb
NIH Office of the Director (P01 AI078907)
- Frances E Lund
NIH Office of the Director (R01 AI110508)
- Frances E Lund
NIH Office of the Director (R01 AI123733)
- Jeremy Boss
NIH Office of the Director (P01 AI125180)
- Jeremy M Boss
NIH Office of the Director (R37 AI049660)
- Sanz Inaki
NIH Office of the Director (U19 AI110483)
- Sanz Inaki
NIH Office of the Director (T32 GM008361)
- Sara L Stone
NIH Office of the Director (K23 AR062100)
- Maria I Danila
Lupus Research Alliance (#550070)
- Frances E Lund
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures involving animals were approved by the UAB Institutional Animal Care and Use Committee and were conducted in accordance with the principles outlined by the National Research Council. UAB IACUC approval IACUC-09648 and IACUC-21203.
Human subjects: All subjects gave written informed consent for participation and provided peripheral blood for analysis. The UAB and Emory Human Subjects Institutional Review Board approved all study protocols for healthy donors and SLE patients. IRB protocols 160301002, X020805006, X140213002, and N140102003 for UAB and 58515 for Emory.
Reviewing Editor
- Facundo D Batista, Ragon Institute of MGH, MIT and Harvard, United States
Publication history
- Received: September 1, 2018
- Accepted: May 10, 2019
- Accepted Manuscript published: May 15, 2019 (version 1)
- Version of Record published: May 31, 2019 (version 2)
Copyright
© 2019, Zumaquero et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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IFNγ induces epigenetic programming of human T-bethi B cells and promotesTLR7/8 and IL-21 induced differentiation
eLife 8:e41641.
https://doi.org/10.7554/eLife.41641
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