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.
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.