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Interferon gamma suppresses T follicular helper cells and antibody responses upon viral infection

ABSTRACT: Humoral and cellular immunity upon viral infections usually co-exist; however, sometimes, one of the two responses emerges as dominant and is responsible for most of the antiviral activity. For example, infection with lymphocytic choriomeningitis virus (LCMV) induces very strong cellular responses, but weak and inefficient neutralizing Ab (nAb) responses. Lack of nAb responses is an important issue for complete clearance of LCMV and other similar viruses, which in some instances tend to establish chronic infections. Recent work from our group has shown that this unbalance is observed also at the level of CD4 T cells responses, with subcutaneous LCMV infection leading almost exclusively to TH1 but no TFH differentiation. Here, we report that LCMV-induced TH1 cells are heterogeneous and comprise a Tcf-1+ subset and a GzmB+ subset. We found that none of the subsets is dependent on the major TH1-polarizing cytokine IL-12. Instead, IFN-gamma (IFN-g) was found to promote the development of GzmB+ cells and to suppress the commitment of the Tcf-1+ population into fully differentiated TFH. As a result, blockade of IFN-g led to a rescue in the TFH population, germinal center B cells and antibody responses. Our results shed light on new mechanisms underlying the inefficient nAbs production in response to non-cytopathic viruses such as LCMV and are promising for the design of new vaccination strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE239968 | GEO | 2025/03/25

REPOSITORIES: GEO

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Interferon gamma suppresses T follicular helper cells and antibody responses upon viral infection

Project description:Humoral and cellular immunity upon viral infections usually co-exist; however, sometimes, one of the two responses emerges as dominant and is responsible for most of the antiviral activity. For example, infection with lymphocytic choriomeningitis virus (LCMV) induces very strong cellular responses, but weak and inefficient neutralizing Ab (nAb) responses. Lack of nAb responses is an important issue for complete clearance of LCMV and other similar viruses, which in some instances tend to establish chronic infections. Recent work from our group has shown that this unbalance is observed also at the level of CD4 T cells responses, with subcutaneous LCMV infection leading almost exclusively to TH1 but no TFH differentiation. Here, we report that LCMV-induced TH1 cells are heterogeneous and comprise a Tcf-1+ subset and a GzmB+ subset. We found that none of the subsets is dependent on the major TH1-polarizing cytokine IL-12. Instead, IFN-gamma (IFN-g) was found to promote the development of GzmB+ cells and to suppress the commitment of the Tcf-1+ population into fully differentiated TFH. As a result, blockade of IFN-g led to a rescue in the TFH population, germinal center B cells and antibody responses. Our results shed light on new mechanisms underlying the inefficient nAbs production in response to non-cytopathic viruses such as LCMV and are promising for the design of new vaccination strategies.

2025-03-25 | GSE250209 | GEO

Gene expression data from LCMV-specific WT and Tcf7-/- follicular T helper cells

Project description:We did microarray experiments to elucidate the transcriptome changes due to TCF-1 deficiency in Tfh cells. These data clearly demonstrate that Tfh-associated genes were down-regulated in TCF-1-null Tfh cells, whereas Th1-associated signatures were up-regulated, indicating that TCF-1 initiates the Tfh fate by directly strengthening Tfh signatures while suppressing Th1-associated genes. We first sorted WT and TCF-1-null Tfh cells (2 samples per group, each sample was pooled from 4 mice) at day 8 after LCMV Armstrong infection. Then, we extracted RNA, which were subsequently sent to microarray analysis.

2015-07-24 | E-GEOD-65693 | biostudies-arrayexpress

Gene expression data from LCMV-specific WT and Tcf7-/- follicular T helper cells

2015-07-24 | GSE65693 | GEO

ZIKV infection induces robust Th1-like Tfh cell and long-term protective antibody responses in immunocompetent mice

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

Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection

Project description:CD4 T cells responses induced by LM61 immunization are heterogeneous in phenotype. The majority consists of Th1 cells, but there is also a consistent population of Tfh-differentiated cells and a minor population of Treg cells. Tfh-differentiated cells, alongside Th1 cells expand upon LCMV challenge.

2021-11-09 | GSE161356 | GEO

Transcriptome analysis of early differentiating Tfh vs Th1 cells

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)

2015-07-27 | E-GEOD-67334 | biostudies-arrayexpress

TCF1 is required for the differentiation of T follicular helper (TFH) cells during viral infections

Project description:TFH and Th1 cells generated after viral or intracellular bacterial infections are critical for the control of infections and the development of immunological memories. However, the mechanisms that govern the choice of activated CD4 T cells to the two alternative fates remain unclear. Here, we found that reciprocal expression of TCF1 and Blimp1 between viral-specific TFH and Th1 cells started early after infection. TCF1 was intrinsically required for the differentiation of TFH cells. In the absence of TCF1, TFH cells failed to maintain their transcriptional and metabolic signatures, distinct from those in Th1 cells. Mechanistically, TCF1 functioned through forming negative feedback loops with IL-2 and Blimp1 signaling. Thus, we have demonstrated an essential role of TCF1 in TFH-cell differentiation. Tcf7 deficient and WT SMARTA CD4 T cells were isolated from mice 8 days after Lymphocytic Choriomeningitis Virus (LCMV) infection. TFH and Th1 cells were separated by FACS.

2015-09-18 | E-GEOD-65660 | biostudies-arrayexpress

Expression data from virus-specific mouse Th1 and Tfh CD4 T cell subsets after LCMV infection

Project description:CD4 T follicular helper (Tfh) cells provide the required signals to B cells for germinal center reactions that are necessary for longlived antibody responses. However, it remains unclear whether there are CD4+ memory T cells committed to the Tfh lineage after antigen clearance. Using adoptive transfer of antigen-specific memory CD4+ subpopulations (based on CXCR5 and Ly6c expression)in the LCMV infection model, we found that there are distinct memory CD4+ T cell populations with commitment to the Tfh and Th1 lineages. Our conclusions are based on gene expression profiles, epigenetic studies and phenotypic and functional analysis. The gene expression profiles of virus-specific CD4 T cell subets at effector and memory stages is presented here. The SMARTA TCR transgenic / adptive transfer system was used to identify and sort subsets of antigen-specific CD4 T cells (based on their expression of Ly6c and CXCR5) elicited after acute infection with LCMV (Arm).

2013-04-22 | E-GEOD-43863 | biostudies-arrayexpress

Genome-wide maps of chromatin state in naïve CD4+ T cells, WT/EZH2-null TFH and TH1 cells

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.

2018-12-31 | GSE120532 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type and Bcl6-/- helper T cell Transcriptomes

Project description:Virus infection induces T follicular helper (TFH) and T helper 1 (TH1) cells. Although TFH cells are important in anti-viral humoral immunity, the role of TH 1 cells is still elusive. IgG2 antibodies predominate in the response to vaccination with inactivated Influenza A virus (IAV) and were responsible for protective immunity to lethal challenge with pathogenic H5N1 and pandemic H1N1 IAVs even in mice lacking TFH cells owing to B or T cell-specific ablation of the Bcl6. We demonstrate that IL-21 and IFN-γ secreted from TH1 cells were essential for greater persistence and higher titers of IgG2 protective antibodies. These results suggest that TH1 induction could be a promising strategy to induce effective neutralizing antibodies against emerging influenza viruses.

2016-10-12 | GSE85316 | GEO

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