bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.03.04.583401

Inducible deletion of Ezh2 in CD4+ T cells inhibits kidney T cell infiltration and prevents interstitial nephritis in MRL/lpr lupus-prone mice

Zheng, X.·Dozmorov, M. G.·Espinoza, L.·Bowes, M. M.·Bastacky, S.·Sawalha, A. H.
View original source ↗Export metadata ↓

Abstract

Systemic lupus erythematosus is a remitting relapsing autoimmune disease characterized by autoantibody production and multi-organ involvement. T cell epigenetic dysregulation plays an important role in the pathogenesis of lupus. We have previously demonstrated upregulation of the key epigenetic regulator EZH2 in CD4+ T cells isolated from lupus patients. To further investigate the role of EZH2 in the pathogenesis of lupus, we generated a tamoxifen-inducible CD4+ T cell Ezh2 conditional knockout mouse on the MRL/lpr lupus-prone background. We demonstrate that Ezh2 deletion abrogates lupus-like disease and prevents T cell differentiation. Single-cell analysis suggests impaired T cell function and activation of programed cell death pathways in EZH2-deficient mice. Ezh2 deletion in CD4+ T cells restricts TCR clonal repertoire and prevents kidney-infiltrating effector CD4+ T cell expansion and tubulointerstitial nephritis, which has been linked to end-stage renal disease in patients with lupus nephritis.

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Zheng, X., Dozmorov, M. G., Espinoza, L., Bowes, M. M., Bastacky, S., Sawalha, A. H.. 2024-03-07. Inducible deletion of Ezh2 in CD4+ T cells inhibits kidney T cell infiltration and prevents interstitial nephritis in MRL/lpr lupus-prone mice. https://doi.org/10.1101/2024.03.04.583401

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

CTR1-mediated copper uptake orchestrates metabolic-epigenetic regulation of pathogenic TH17 cells in autoimmune disease

Pathogenic T helper 17 (pTH17) cells are a subset of CD4+ T cells driving autoimmune diseases including multiple sclerosis (MS). Compared to homeostatic TH17 cells and other TH subsets, pTH17 have enhanced mitochondrial function and oxidative phosphorylation (OXPHOS) that supports their differentiation and pathogenic function. Here we identify Copper Transporter 1 (CTR1), encoded by Slc31a1, as essential for copper uptake in CD4+ T cells, OXPHOS and pTH17 cell differentiation and function. While copper levels are known to be higher in the cerebrospinal fluid of patients with MS compared to healthy individuals, and excess copper contributes to oligodendrocyte loss in murine models of MS, the effect of copper on T cell function and pathogenicity in MS are unclear. We demonstrate that deletion of Slc31a1 in CD4+ T cells decreased intracellular copper levels, disrupting mitochondrial respiration and rewiring metabolism. These changes altered the epigenetic landscape of pTH17 cells by impairing DNA demethylation capacity, leading to hypermethylated DNA and altered chromatin accessibility at key binding sites for AP-1 transcription factors essential for pTH17 differentiation. As a result, CTR1-deficient T cells showed defective differentiation into pTH17 cells, with decreased production of IL-17A and expression of TH17 signature genes, while the differentiation of other CD4+ T cell subsets remained largely unaffected. Moreover, T cell-specific deletion of Slc31a1 protected mice from central nervous system (CNS) inflammation in the experimental autoimmune encephalomyelitis (EAE) model of MS by suppressing clonal expansion of autoreactive CD4+ T cells. These findings establish copper as a critical regulator of pTH17 differentiation and function, revealing a previously unknown molecular link between copper homeostasis, metabolism and epigenetic regulation governing pTH17-mediated autoimmunity.

immunology↗
bioRxiv2026

Fetal-intrinsic antiviral mechanisms emerge over the course of gestation

Congenital viral infections have variable effects on pregnancy outcomes with implications for maternal and fetal health. However, the maternal and fetal immune mechanisms that emerge over the course of gestation to determine protective or pathological outcomes remain poorly understood. Here, we use the emerging congenital pathogen Oropouche virus (OROV) to examine gestational stage-dependent differences in maternal and fetal outcomes in a mouse model of congenital infection. Pregnant mice (dams) infected during early gestation resist severe OROV disease, whereas mid-gestation-infected dams succumb to infection. In contrast, fetal pathology is substantial following early gestation infection but limited following infection during mid-gestation, revealing discordant maternal and fetal susceptibility across gestation. Mid-gestation fetal tissues effectively restricted vertical transmission compared to early gestation fetal tissues, corresponding with reduced fetal pathology. Moreover, both placental and fetal tissue cleared OROV RNA over the course of infection, independent of gestational stage, and failure to clear viral RNA was associated with severe fetal pathology. Spatial analysis of early gestation implantation sites further revealed distinct regional susceptibility to OROV infection across the maternal-fetal interface. We identified potential instances of placental-independent vertical transmission via direct fetal contact with highly infected regions of the contralateral maternal uterus. Finally, we uncovered an unexpected mechanism by which type I interferon signaling contributes to inter-fetal immune crosstalk to restrict both OROV vertical transmission and pathology. Together, these findings establish the fetus as an active participant in antiviral defense and reveal previously unrecognized mechanisms by which fetal-intrinsic antiviral immune responses limit congenital viral infection and disease.

immunology↗
bioRxiv2026

Interferon lambda drives immunological maturation in the infant lung and protects against lethal Bordetella pertussis infection

Serious pertussis infections disproportionately affect infants but the biological basis for this age-dependent susceptibility remains unclear. Infant mouse models recapitulate features of severe human infant pertussis. We investigated the role of interferon lambda (IFN-{lambda}), a key regulator of mucosal immunity, in Bordetella pertussis infection of infant mice. While infected adult mice upregulate lung IFN-{lambda}, infant mice inoculated at P7 fail to upregulate IFN-{lambda} and succumb to infection. We hypothesized that failure to produce IFN-{lambda} during infection represents a critical immunological deficit in infant mice, and that restoring IFN-{lambda} signaling would improve survival outcomes. Whereas wild-type mice gained complete protection from lethal B. pertussis infection by P10, mice lacking the IFN-{lambda} receptor component IFNLR1 did not achieve full protection until P21. Loss of IFNLR1 was associated with enhanced bacterial dissemination to systemic organs. Infant mice possessed a functional IFN-{lambda} receptor in the lungs but failed to upregulate IFN-{lambda} during infection, and supplementing IFN-{lambda} exogenously extended survival. RNA sequencing of lung tissue from infected and uninfected wild-type and IFNLR1-deficient mice inoculated at different ages identified an immune transcriptional framework distinguishing susceptible from resistant animals at a systems level and revealed IFN-{lambda} signaling as a critical driver of immunological maturation in the infant lung. Infected infant IFNLR1-deficient mice had dysregulated immune cell recruitment to the lungs, indicating a quantitatively expanded but qualitatively impaired response. These findings demonstrate that IFN-{lambda} affects immune maturation accounting for a critical window of age-dependent resistance to lethal pertussis with novel therapeutic possibilities for human infants with this disease.

immunology↗