ZIKV infection induces robust Th1-like Tfh cell and long-term protective antibody responses in immunocompetent mice
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PROVIDER: PRJNA496481 | ENA |
REPOSITORIES: ENA
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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.
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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:Generating durable humoral immunity through vaccination depends upon effective interaction of follicular helper T cells (Tfh) with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing co-stimulatory and cytokine-dependent Tfh help to B cells. However, the question remains whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced anti-Envelope (Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein (IP)-10-adjuvanted HIV-1 DNA prime, followed by an MPLA+QS-21-adjuvanted Env protein boost in macaques (DIP-10 PALFQ), we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity to V1V2, and effector functions when compared to macaques primed with DNA lacking IP-10 and boosted with MPLA+alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibodies in serum, showing for the first time that adjuvants can dramatically impact the IgG subclass profile in macaques. The DIP-10 PALFQ regimen also increased vaginal and rectal IgA antibodies to a greater extent. Within lymph nodes, we observed augmented GC B cell responses and promotion of Th1 gene expression profiles in GC Tfh cells. The frequency of GC Tfh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of Th1-Tfh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody response.
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2018-12-31 | GSE120532 | GEO
Project description:Microarray experiments were performed to demonstrate the transcriptome changes due to Rictor deficiency in memory follicular T helper (Tfh) and Type 1 T helper (Th1) cells. These data revealed that the immunological memory formation and persistance associated genes are changed in Rictor-null memory Tfh and Th1 cells, indicating that Rictor is essential for memory CD4 T cell pool.
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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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Project description:CD4+ memory T cells play a pivatol role in mediating long-term immunity and therefore are an important target in vaccine development. Multiple functionally distinct helper CD4+ T cell subsets can arise in response to a single invading pathogen, complicating the identification of rare memory CD4+ T cells. Here we found that expression of Id3, an inhibitor of E protein transcription factors, identified a population of cells within both the CD4+ Tfh and Th1 helper lineages that exhibited memory potential in response to secondary infection. Notably, a subset of Th1 memory cells expressing Id3 exhibited enhanced expansion upon response to pathogen, generating both Th1 and Tfh secondary effector cell populations, and displayed enrichment of key molecules associated with memory potential when compared to Id3lo Th1 cells. Thus, Id3 expression serves as an important marker of multipotent memory CD4+ T cells.
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