bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.11.25.625088

Glutaminolysis promotes the function of follicular helper T cells in lupus-prone mice

Choi, S. C.·Ge, Y.·Joshi, M. V.·Jimenez, D.·Padilla, L.·LaPlante, C.·Rathmell, J. C.·Mohamadzadeh, M.·Morel, L.
View original source ↗Export metadata ↓

Abstract

Glutamine metabolism is essential for T cell activation and functions. The inhibition of glutaminolysis impairs Th17 cell differentiation and alters Th1 cell functions. There is evidence for an active glutaminolysis in the immune cells of lupus patients. Treatment of lupus-prone mice with glutaminolysis inhibitors ameliorated disease in association with a reduced frequency of Th17 cells. This study was performed to determine the role of glutaminolysis in murine Tfh cells, a critical subset of helper CD4+ T cells in lupus that provide help to autoreactive B cells to produce autoantibodies. We showed that lupus Tfh present a high level of glutamine metabolism. The pharmacological inhibition of glutaminolysis with DON had little effect on the Tfh cells of healthy mice, but it reduced the expression of the critical costimulatory molecule ICOS on lupus Tfh cells, in association with a reduction of autoantibody production, germinal center B cell dynamics, as well as a reduction of the frequency of atypical age-related B cells and plasma cells. Accordingly, profound transcriptomic and metabolic changes, including an inhibition of glycolysis, were induced in lupus Tfh cells by DON, while healthy Tfh cells showed little changes. The T cell-specific inhibition of glutaminolysis by deletion of the gene encoding for the glutaminase enzyme GLS1 largely phenocopied the effects of DON on Tfh cells and B cells in an autoimmune genetic background with little effect in a congenic control background. These results were confirmed in an induced model of lupus. Finally, we showed that T cell-specific Gls1 deletion impaired T- dependent humoral responses in autoimmune mice as well as their Tfh response to a viral infection. Overall, these results demonstrated a greater intrinsic requirement of lupus Tfh cells for their helper functions, and they suggest that targeting glutaminolysis may be beneficial to treat lupus.

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Choi, S. C., Ge, Y., Joshi, M. V., Jimenez, D., Padilla, L., LaPlante, C., Rathmell, J. C., Mohamadzadeh, M., Morel, L.. 2024-11-25. Glutaminolysis promotes the function of follicular helper T cells in lupus-prone mice. https://doi.org/10.1101/2024.11.25.625088

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↗