ZIKV infection induces robust Th1-like Tfh cell and long-term protective antibody responses in immunocompetent mice
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ABSTRACT:
PROVIDER: PRJNA496481 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8056572_1.fastq.gz | Fastqsanger.gz | |||
| SRR8056572_2.fastq.gz | Fastqsanger.gz | |||
| SRR8056573_1.fastq.gz | Fastqsanger.gz | |||
| SRR8056573_2.fastq.gz | Fastqsanger.gz | |||
| SRR8056574_1.fastq.gz | Fastqsanger.gz |
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Project description:Induction of long-lived antibody responses during infection or vaccination is often essential for subsequent protection, but the relative contributions of T follicular helper (Tfh) cells and T helper 1 (Th1) cells for induction of antigen specific antibody responses to viruses are unclear. Here, we establish an acute Zika virus (ZIKV) infection model in immunocompetent mice, and show that ZIKV infection elicits robust Th1-like Tfh cell and protective antibody responses. While these Th1-like Tfh cells share phenotypic and transcriptomic profiles with both Tfh and Th1 cells, they also have unique surface markers and gene expression characteristics, and are dependent on T-bet for their development. Th1-like Tfh cells, but not Th1 cells, are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. Our study suggests that specific modulation of the Th1-like Tfh cell response during infection or vaccination may augment the induction of antiviral antibody response to ZIKV and other viruses.
2019-05-01 | GSE121250 | GEO
Project description:Induction of long-lived antibody responses during infection or vaccination is often essential for subsequent protection, but the relative contributions of T follicular helper (Tfh) cells and T helper 1 (Th1) cells for induction of antigen specific antibody responses to viruses are unclear. Here, we establish an acute Zika virus (ZIKV) infection model in immunocompetent mice, and show that ZIKV infection elicits robust Th1-like Tfh cell and protective antibody responses. While these Th1-like Tfh cells share phenotypic and transcriptomic profiles with both Tfh and Th1 cells, they also have unique surface markers and gene expression characteristics, and are dependent on T-bet for their development. Th1-like Tfh cells, but not Th1 cells, are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. Our study suggests that specific modulation of the Th1-like Tfh cell response during infection or vaccination may augment the induction of antiviral antibody response to ZIKV and other viruses.
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Project description:Comparison of transcriptome between early Tfh vs. early Th1 cells Blimp-1-YFP LCMV gp specific TCRtg Smarta cells were transferred into B6 mice, which were then infected with LCMV Armstrong. On day 3 after infection, splenocytes were stained to sort Blimp-1-YFP+IL-2Ra+ Th1 cells or Blimp-1-YFP-IL-2Ra- Tfh cells for RNAseq analysis. Contributor: LIAI RNAi center (LIAI)
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Project description:Differentiation of naive CD4+ T cells into T-helper (Th) effector subsets is critical for protection against pathogens. Together, E-protein transcription factors and the inhibitor-of-DNA binding (Id) proteins are important arbiters of T cell development, but their role in the differentiation of Th1 and Tfh cells is not well understood. Th1 cells show robust Id2 expression compared to Tfh cells, and RNAi depletion of Id2 increased Tfh cell frequencies and germinal center responses, while impairing Th1 cell accumulation during viral infection. Further, Th1 cell differentiation was blocked by genetic ablation of Id2, leading to E-protein dependent accumulation of effector cells with 78% of Th1-associated genes showing diminished expression and a concurrent enrichment of the Tfh gene-expression program. The Tfh-defining transcriptional repressor Bcl6 bound to the Id2 locus inhibiting expression, providing a mechanism by which bimodal expression of Id2 in Tfh and Th1 cells can be established. Thus, Id2 is critical in enforcing the reciprocal development of Th1 and Tfh cell fates. We used microarray to assess the changes in gene expression between Id2-sufficient and -deficient Th1 and Tfh cells.
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Project description:Comparison of transcriptome between early Tfh vs. early Th1 cells
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Project description:ATAC-Seq experiments were performed to elucidate the chromatin state changes among naïve CD4+ T cells, WT follicular helper T (TFH) cells and WT type 1 helper T (TH1) cells Day2 (D2), Day5 (D5), Day8 (D8) post-LCMV-Armstrong infection, as well as EZH2-null (KO) TFH and TH1 at Day8 post-LCMV-infection. The analysis suggested stringent lineage-specific mode of chromatin accessibility in each group, indicating chromatin remodeling is tightly associated with TFH versus TH1 lineage differentiation in response to acute viral infection. Furthermore, the comparison between wild-type and EZH2-null TFH cells showed that less-opening state of certain chromatin accessible region in TFH-differentiation associated genes in the formers, suggesting EZH2 led to permissive chromatin accessibility primarily at specific regions of TFH-associated genes. H3K27me3-ChIP-seq was performed in WT TFH and TH1 cells to confirm the deposition of the histone marks at those loci.
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Project description:Follicular helper T cells (TFH), known as the primary helpers of the germinal center (GC) reaction, promote the humoral immune response to defend against various pathogens. Under conditions of infection by different types of pathogens, many shared transcription factors (TFs), such as Bcl-6, TCF-1 and Maf, are broadly expressed in TFH cells, orchesting TFH cell differentiation and function. In addtion, TFH cells also coexpress environmentally specific TFs as their conventional T cell counterparts (such as T-bet, GATA-3 or ROR-γt, which are expressed in Th1, Th2 or Th17 cells, respectively). This phenomenon indicates the complexity and environmental adaptivity of the TFH cell response. However, the extent to which the TFH cell response relies on these environmentally specific TFs is not completely understood. Here, we found that transcription factor T-bet was specifically expressed in type I but not type II TFH cells and that the T-bet-IFN-γ axis was essential for the maintenance of TFH cells, promoting their proliferation and inhibiting their apoptosis during acute viral infection. Microarray analysis showed both similarities and differences in transcriptome dependency on T-bet in TFH and Th1 cells, suggesting the distinctive role of T-bet in TFH cells. Collectively, our findings reveal an important and specific supporting role for T-bet in type I TFH cell response, which can help us gain a depper understanding of TFH cell subsets.
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