Metabolic control of Tfh and humoral immunity by phosphatidylethanolamine
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ABSTRACT:
PROVIDER: PRJNA613290 | ENA |
REPOSITORIES: ENA
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Project description:Cytidine diphosphate (CDP)-ethanolamine pathway of phospholipid metabolism coordinates metabolic programming of Tfh cell responses and humoral immunity.
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Project description:During chronic viral infection, the inflammatory function of CD4 T cells becomes gradually attenuated. Concurrently, Th1 cells progressively acquire the capacity to secrete the cytokine IL-10, a potent suppressor of antiviral T cell responses. To determine the transcriptional changes that underlie this T cell adaption process, we applied a single-cell RNA-sequencing approach and assessed the heterogeneity of IL-10-expressing CD4 T cells during chronic infection. Unexpectedly, our analyses revealed an IL-10-producing population with a robust Tfh-signature. Using IL-10 and IL-21 double-reporter mice, we further demonstrate that IL-10+IL-21+co-producing Tfh cells arise predominantly during chronic but not acute LCMV infection. Importantly, depletion of IL-10+IL-21+co-producing CD4 T cells or deletion of Il10 specifically in Tfh cells resulted in impaired humoral immunity and viral control. Mechanistically, B cell-intrinsic IL-10 signaling was required for sustaining germinal center reactions. Lastly, we demonstrate that IL-27 and type I IFNs differentially regulate the formation of this protective IL-10-producing Tfh subset. Thus, our findings elucidate a critical role for Tfh-derived IL-10 in promoting humoral immunity during persistent viral infection.
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Project description:An alluring strategy for improving protective humoral immunity against infectious diseases would be to directly target the germinal center (GC). There remains a critical need for next generation vaccine approaches to elicit more potent GC responses and durable humoral immunity. Here, we investigated whether cytokines could be scaffolded on nanoparticles to further enhance antigen-specific GC responses. We designed a chimeric nanoparticle using the GT8-60mer, a germline-targeting HIV immunogen, as a model to scaffold IL-21. Nanoparticle immunoadjuvant complexes (NICs) scaffolding GT8 and IL-21 (GT8-IL-21-NIC) drove improved serum antibody titers, antigen-specific GC B cells, and functional Tfh cell responses relative to antigen-only nanoparticles and to co-delivery of IL-21 monomer. Single-cell RNA sequencing of antigen-specific GC B cells from GT8-IL-21-NIC immunized mice demonstrated upregulation of LZ and selection-associated gene signatures. The NIC platform was versatile and could support changes to both the antigen and cytokine domains utilizing numerous GC-associated cytokines. Thus, NICs may provide value as a tool to improve antigen-specific vaccine-induced immunity.
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Project description:After activation, CD4+ helper T (Th) cells differentiate; into distinct effector subsets. Although chemokine; (C-X-C motif) receptor 5-expressing T follicular; helper (Tfh) cells are important in humoral immunity,; their developmental regulation is unclear. Here we; show that Tfh cells had a distinct gene expression; profile and developed in vivo independently of the; Th1 or Th2 cell lineages. Tfh cell generation was regulated; by ICOS ligand (ICOSL) expressed on B cells; and was dependent on interleukin-21 (IL-21), IL-6,; and signal transducer and activator of transcription; 3. However, unlike Th17 cells, differentiation of Tfh; cells did not require transforming growth factor; b (TGF-b) or Th17-specific orphan nuclear receptors; RORa and RORg in vivo. Finally, naive T cells activated; in vitro in the presence of IL-21 but not; TGF-b signaling preferentially acquired Tfh gene; expression and promoted germinal-center reactions; in vivo. This study thus demonstrates that Tfh is a; distinct Th cell lineage. Experiment Overall Design: Splenic CD4+CXCR5+ T cells were isolated from KLH-immunized mice and restimulated with anti-CD3 for 4 hours before total RNA preparation. Affymetrix gene chips were used to analyze their gene expression.
2008-10-21 | E-GEOD-11924 | biostudies-arrayexpress
Project description:Follicular regulatory T (Tfr) cells suppress Tfh-mediated B cell responses to regulate humoral immunity, yet the signaling pathway governing their differentiation remain largely undefined. In this study, we reveal that IL-6-induced C/EBPa is essential for Tfr cell differentiation and function in mice. To investigate whether C/EBPa directly regulates Tfr-related genes and identify endogenous C/EBPa binding targets in Tfr cells, we performed Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing in Tfr and CXCR5- Treg cells. Collectively, we identify the IL-6-C/EBPa-Bcl6/Cxcr5 axis as a central mechanism to promote Treg-to-Tfr differentiation to control pathogenic humoral immune responses.
2026-06-01 | GSE328688 | GEO
Project description:The transcription factor Mef2d regulates B:T synapse-dependent GC-Tfh differentiation and IL-21-mediated humoral immunity
| PRJNA909580 | ENA
Project description:After activation, CD4+ helper T (Th) cells differentiate into distinct effector subsets. Although chemokine (C-X-C motif) receptor 5-expressing T follicular helper (Tfh) cells are important in humoral immunity, their developmental regulation is unclear. Here we show that Tfh cells had a distinct gene expression profile and developed in vivo independently of the Th1 or Th2 cell lineages. Tfh cell generation was regulated by ICOS ligand (ICOSL) expressed on B cells and was dependent on interleukin-21 (IL-21), IL-6, and signal transducer and activator of transcription 3. However, unlike Th17 cells, differentiation of Tfh cells did not require transforming growth factor b (TGF-b) or Th17-specific orphan nuclear receptors RORa and RORg in vivo. Finally, naive T cells activated in vitro in the presence of IL-21 but not TGF-b signaling preferentially acquired Tfh gene expression and promoted germinal-center reactions in vivo. This study thus demonstrates that Tfh is a distinct Th cell lineage.
2008-07-03 | GSE11924 | GEO
Project description: Not available
| S-EPMC8448202 | biostudies-literature