IFNg-producing Tfh cells control the differentiation of lung resident memory B cells
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ABSTRACT:
PROVIDER: PRJNA859180 | ENA |
REPOSITORIES: ENA
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Project description:T follicular helper (Tfh) cells are a specific subset of CD4 T cells that localize in the B cell follicle and are essential for the Germinal Center (GC) response. Under polarizing environments, Tfh cells produce IFN-g. Beyond promoting class switching, the role played by IFN-g-producing Tfh cells remains largely unexplored. Using an influenza infection model, we show here that interactions with IFN-γ producing Tfh cells during the peak of the response skew the GC B cell response towards the memory differentiation pathway. Consequently, lung-memory B cells fail to differentiate without IFN-γ producing Tfh cells. Collectively, our results support a model in which temporary changes in cytokine production by Tfh cells dynamically control the outcome of the GC response.
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Project description:T follicular helper (Tfh) cells, which reside in the B cell follicles and help Ig class switching, express the master transcription factor BCL-6 and signature cytokine IL-21. Tfh cells are also capable of expressing IFN-g, however, whether IFN-g-producing Tfh population represents a unique Tfh subset and how they develop are unknown. While T-bet is the master regulator for IFN-g production in Th1 cells, Tfh cells express no or very low levels of T-bet. Here, by using a T-bet-fate-mapping mouse strain, we report that all the IFN-g-producing Tfh cells identified after immunization have previously expressed T-bet. DNase I hypersensitivity analysis indicates that the Ifng gene locus is partially accessible in this ‘ex-T-bet’ population but inaccessible in Tfh cells without a history of T-bet expression. Furthermore, multi-color tissue imaging shows that some “ex-T-bet” Tfh cells reside in germinal centers and express IFN-gin situ. Finally, IFN-g-expressing Tfh cells are absent in T-bet-deficient mice and the Ifng gene is inaccessible in T-bet-deficient Tfh cells. Thus, transient expression of T-bet epigenetically imprints the Ifng locus for cytokine production in Tfh cells. Our results also indicate that Tfh cells are composed of different subsets and they may use genetic programs similar to those of classical non-Tfh T helper cells in order to acquire unique cytokine producing capacity.RNA-Seq analysis of gene expression in splenic CD4+CD44highCD25- T cell subsets. RNA-Seq analysis of gene expression in antigen-specific Tfh cells and non-Tfh cells that have a history of T-bet expression. DNase 1-Seq of T-bet expressed and un-expressed Tfh cells and non-Tfh cells.
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Project description:Global gene expression profile of PD1+ Tfh cells, CD62L+ Tfh cells, non-Tfh effector cells
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Project description:By using RNA-sequencing assay on sorted Sostdc1-EGFP- Tfh, Sostdc1+ Tfh and Non-Tfh cells and single cell RNA-seq assay on sorted CD4+CD44+T cells from Sostdc1-EGFP reporter mice, support the conclusion that Sostdc1+ Tfh cells are a distinct subpopulation of Tfh cells.After performing the RNA-seq assessment and ATAC-seq on Tfr and Treg cells from WT and Sostdc1 KO mice,demonstrated that Sostdc1 ablation predominantly augmented β-catenin-controlled transcriptome, which in turn resulted in Tfr cell failure.
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Project description:CD4 T cell help is critical for both the generation and maintenance of germinal centers, and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. SAP (SH2D1A) expression in CD4 T cells is essential for germinal center development. However, SAP-deficient mice have only a moderate defect in TFH differentiation as defined by common TFH surface markers. CXCR5+ TFH cells are found within the germinal center as well as along the boundary regions of T/B cell zones. Here we show that germinal center associated T cells (GC TFH) can be identified by their co-expression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. Here we show GC TFH are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH subset and SAP- TFH are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that utilizes SAP signaling, is specifically required for IL-4 production by GC TFH. GC TFH cells require IL-4 and IL-21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by germinal center CD4 T cells but not in TFH and GC TFH differentiation. Analysis of in vivo polyclonal GC Tfh vs Tfh vs Non-Tfh eight days after LCMV viral infection. Analysis of in vivo follicular helper CD4 T cells (CXCR5high GL7low), versus germinal center follicular helper CD4 T cells (CXCR5hi GL7hi), versus non-follicular helper CD4 T cells (CXCR5low) eight days after viral infection.
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Project description:Follicular helper T (Tfh) cells have been implicated in controlling rejection after allogeneic kidney transplantation, but the precise subsets, origins and functions of Tfh cells in this process have not been fully characterized. Here we show that a subset of effector Tfh cell marked by previous IL- 21 production is potently induced during allogeneic kidney transplantation and is inhibited by immunosuppressive agents. Single-cell RNAseq revealed that these lymph node effector Tfh cells have transcriptional and clonal overlap with IL-21 producing kidney infiltrating Tfh cells, implicating common origins and developmental trajectories. To investigate the precise functions of IL-21 producing effector Tfh cells in lymph nodes and allografts, we used a mouse model to selectively eliminate these cells and assessed allogeneic B cell clonal dynamics using a single B cell culture system. We found that IL-21 producing effector Tfh cells were essential for transplant rejection by regulating donor-specific germinal center B cell clonal dynamics both systemically in the draining lymph node and locally within kidney grafts. Thus, IL-21 producing effector Tfh cells have multifaceted roles in antibody-mediated rejection after kidney transplantation by promoting B cell alloimmunity.
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Project description:T follicular helper (Tfh) cells, essential for germinal center reactions, are not identical, with different phenotypes reported. Whether, when and how they generate memory cells are still poorly understood. Here, through single-cell RNA-sequencing analysis of CXCR5+Bcl6+ Tfh cells generated under different conditions, we discovered, in addition to PD-1hi effector Tfh cells, a CD62L+PD1low subpopulation. CD62L-expressing Tfh cells developed independently from PD-1+ cells, and not in direct contact with B cells. More importantly, CD62L+ Tfh cells expressed memory- and stemness-associated genes; with more superior long-term survival, they readily generated PD-1hi cells in the recall response. Finally, KLF2 and IL7R, also highly expressed by CD62L+ Tfh cells, were required to regulate their development. Our work thus demonstrates a novel Tfh memory-like cell subpopulation, which may benefit our understanding on immune responses and diseases.
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Project description:Follicular helper T (Tfh) cells access the B cell follicle to promote antibody responses, and are particularly important for germinal center (GC) reactions. However, the molecular mechanisms of how Tfh cells are physically associated with GCs are incompletely understood. Here we report that the sphingosine-1-phosphate receptor 2 (S1PR2) gene is highly expressed in a subpopulation of Tfh cells that localizes in GCs. S1PR2-deficient Tfh cells exhibited reduced accumulation in GCs due to their impaired retention. T cells deficient in both S1PR2 and CXCR5 were ineffective in supporting GC responses compared to T cells deficient only in CXCR5. These results suggest that S1PR2 and CXCR5 cooperatively regulate localization of Tfh cells in GCs to support GC responses. Venus-high Tfh, Venus-low Tfh, PD1-intermediate Th, PD1-low Th and naïve CD4+ T cells were sorted on FACSAria from immunized S1pr2V/+ mice or control mice for RNA extraction and hybridization on Affimetrix microarrays.
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