Skip to main content

Main menu

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons

User menu

  • Subscribe
  • Log in

Search

  • Advanced search
The Journal of Immunology
  • Other Publications
    • American Association of Immunologists
    • ImmunoHorizons
  • Subscribe
  • Log in
The Journal of Immunology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Next in The JI
    • Archive
    • Brief Reviews
    • Pillars of Immunology
    • Translating Immunology
    • Most Read
    • Top Downloads
    • Annual Meeting Abstracts
  • COVID-19/SARS/MERS Articles
  • Info
    • About the Journal
    • For Authors
    • Journal Policies
    • Influence Statement
    • For Advertisers
  • Editors
  • Submit
    • Submit a Manuscript
    • Instructions for Authors
    • Journal Policies
  • Subscribe
    • Journal Subscriptions
    • Email Alerts
    • RSS Feeds
    • ImmunoCasts
  • More
    • Most Read
    • Most Cited
    • ImmunoCasts
    • AAI Disclaimer
    • Feedback
    • Help
    • Accessibility Statement
  • Follow The Journal of Immunology on Twitter
  • Follow The Journal of Immunology on RSS

Restoration of Follicular T Regulatory/Helper Cell Balance by OX40L–JAG1 Cotreatment Suppresses Lupus Nephritis in NZBWF1/j Mice

Prabhakaran Kumar, Sivasangari Balakrishnan, Swarali Surendra Lele, Suman Setty, Shaurya Dhingra, Alan L. Epstein and Bellur S. Prabhakar
J Immunol June 1, 2022, 208 (11) 2467-2481; DOI: https://doi.org/10.4049/jimmunol.2200057
Prabhakaran Kumar
*Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Prabhakaran Kumar
Sivasangari Balakrishnan
*Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Swarali Surendra Lele
*Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Suman Setty
†Department of Pathology, University of Illinois College of Medicine, Chicago, IL; and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shaurya Dhingra
*Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alan L. Epstein
‡Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Alan L. Epstein
Bellur S. Prabhakar
*Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Bellur S. Prabhakar
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF + SI
  • PDF
Loading

Key Points

  • TFR/TFH cell ratio is impaired during the onset of lupus nephritis in NZBWF1/j mice.

  • OX40L–JAG1 cotreatment expands TFR cells and suppresses TFH cells.

  • Restoration of TFR/TFH balance ameliorates lupus nephritis in NZBWF1/j mice.

Abstract

Class-switched antinuclear autoantibodies produced by T follicular helper (TFH) cell–dependent germinal center (GC) B cell response play an essential pathogenic role in lupus nephritis (LN). The role of T follicular regulatory (TFR) cells, an effector subset of CD4+Foxp3+ T regulatory cells (Tregs), which are specialized in suppressing TFH-GC response and Ab production, remains elusive in LN. Contrasting reports have shown increased/reduced circulating TFR cells in human lupus that might not accurately reflect their presence in the GCs of relevant lymphoid organs. In this study, we report a progressive reduction in TFR cells and decreased TFR/TFH ratio despite increased Tregs in the renal lymph nodes of NZBWF1/j mice, which correlated with increased GC-B cells and proteinuria onset. Cotreatment with soluble OX40L and Jagged-1 (JAG1) proteins increased Tregs, TFR cells, and TFR/TFH ratio, with a concomitant reduction in TFH cells, GC B cells, and anti-dsDNA IgG Ab levels, and suppressed LN onset. Mechanistic studies showed attenuated TFH functions and diminished GC events such as somatic hypermutation and isotype class-switching in OX40L-JAG1–treated mice. RNA sequencing studies revealed inhibition of hypoxia-inducible factor 1-α (HIF-1a) and STAT3 signaling in T conventional cells from OX40L-JAG1–treated mice, which are critical for the glycolytic flux and differentiation into TFH cell lineage. Therefore, the increased TFR/TFH ratio seen in OX40L-JAG1–treated mice could involve both impaired differentiation of TFH cells from T conventional cells and expansion of TFR cells. We show a key role for GC-TFR/TFH imbalance in LN pathogenesis and how restoring homeostatic balance can suppress LN.

This article is featured in Top Reads, p.

Footnotes

  • This work was supported by grants from the National Institutes of Health (R01 AI107516-01A1) and Sirazi Foundation (to B.S.P.).

  • Conceptualization: B.S.P. and P.K.; methodology: B.S.P. and P.K.; investigation: P.K., S.B., and S.S.L.; visualization: S.S. and S.D.; funding acquisition: B.S.P.; writing – original draft: P.K.; and writing – review & editing: B.S.P., A.L.E., and S.S.

  • RNA sequencing data have been submitted to National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) under accession number GSE181433 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE181433).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    Cat.
    catalog
    DC
    dendritic cell
    FC
    fold change
    gc
    glomerular cross-section
    GC
    germinal center
    ILK
    integrin linked kinase
    IPA
    Ingenuity Pathway Analysis
    iTreg
    induced Treg
    JAG1
    Jagged-1
    LN
    lupus nephritis
    MFI
    median fluorescence intensity
    mTOR
    mammalian target of rapamycin
    RLN
    renal lymph node
    RNA-seq
    RNA sequencing
    SHM
    somatic hypermutation
    SLE
    systemic lupus erythematosus
    Tconv
    T conventional
    Teff
    T effector
    TFH
    T follicular helper
    TFR
    T follicular regulatory
    Treg
    T regulatory cell

  • Received January 14, 2022.
  • Accepted March 17, 2022.
  • Copyright © 2022 by The American Association of Immunologists, Inc.
View Full Text

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$37.50

Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.

Log in using your username and password

Forgot your user name or password?
PreviousNext
Back to top

In this issue

The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about The Journal of Immunology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Restoration of Follicular T Regulatory/Helper Cell Balance by OX40L–JAG1 Cotreatment Suppresses Lupus Nephritis in NZBWF1/j Mice
(Your Name) has forwarded a page to you from The Journal of Immunology
(Your Name) thought you would like to see this page from the The Journal of Immunology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Restoration of Follicular T Regulatory/Helper Cell Balance by OX40L–JAG1 Cotreatment Suppresses Lupus Nephritis in NZBWF1/j Mice
Prabhakaran Kumar, Sivasangari Balakrishnan, Swarali Surendra Lele, Suman Setty, Shaurya Dhingra, Alan L. Epstein, Bellur S. Prabhakar
The Journal of Immunology June 1, 2022, 208 (11) 2467-2481; DOI: 10.4049/jimmunol.2200057

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Restoration of Follicular T Regulatory/Helper Cell Balance by OX40L–JAG1 Cotreatment Suppresses Lupus Nephritis in NZBWF1/j Mice
Prabhakaran Kumar, Sivasangari Balakrishnan, Swarali Surendra Lele, Suman Setty, Shaurya Dhingra, Alan L. Epstein, Bellur S. Prabhakar
The Journal of Immunology June 1, 2022, 208 (11) 2467-2481; DOI: 10.4049/jimmunol.2200057
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Disclosures
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • CD47 Promotes Autoimmune Valvular Carditis by Impairing Macrophage Efferocytosis and Enhancing Cytokine Production
  • The IL-33/ST2 Axis Promotes Primary Sjögren’s Syndrome by Enhancing Salivary Epithelial Cell Activation and Type 1 Immune Response
  • Analysis of Gene Expression and TCR/B Cell Receptor Profiling of Immune Cells in Primary Sjögren’s Syndrome by Single-Cell Sequencing
Show more AUTOIMMUNITY

Similar Articles

Navigate

  • Home
  • Current Issue
  • Next in The JI
  • Archive
  • Brief Reviews
  • Pillars of Immunology
  • Translating Immunology

For Authors

  • Submit a Manuscript
  • Instructions for Authors
  • About the Journal
  • Journal Policies
  • Editors

General Information

  • Advertisers
  • Subscribers
  • Rights and Permissions
  • Accessibility Statement
  • FAR 889
  • Privacy Policy
  • Disclaimer

Journal Services

  • Email Alerts
  • RSS Feeds
  • ImmunoCasts
  • Twitter

Copyright © 2022 by The American Association of Immunologists, Inc.

Print ISSN 0022-1767        Online ISSN 1550-6606