IFNg-producing Tfh cells control the differentiation of lung resident memory B cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE208322 | GEO | 2023/07/06
REPOSITORIES: GEO
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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.
2018-09-17 | GSE102959 | GEO
Project description:Type I interferons (IFNs) play an essential role in antiviral immunity, correlate with severity of systemic autoimmune disease, and are likely to represent a key component of mRNA vaccine-adjuvanticity. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood due to pleiotropic effects in multiple cell types. Here, we demonstrate that a succinct type I IFN response promotes GC formation and associated IgG subclass distribution primarily through signaling in cDCs and B cells. Type I IFN signaling in cDCs, distinct from cDC1, stimulates development of separable Tfh and Th1 cell subsets. However, Th cell-derived IFN-g induces T-bet expression and IgG2c isotype switching prior to this bifurcation and has no evident effects once GCs and bona fide Tfh cells developed. This pathway acts in synergy with early B cell-intrinsic type I IFN signaling, which reinforces T-bet expression in B cells and leads to a selective amplification of the IgG2c+ GC B cell response. Despite the strong Th1 polarizing effect of type I IFNs, the Tfh cell subset develops into IL-4 producing cells that control the overall magnitude of the GCs and promote generation of IgG1+ GC B cells. Thus, type I IFNs act on B cells and cDCs to drive GC formation and to coordinate IgG subclass distribution through parallel Th1 and Tfh cell-dependent pathways.
2022-07-08 | GSE201551 | GEO
Project description:Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation, and guide their differentiation and Ig isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-g. IL-21 and IFN-g are co-expressed by Tfh cells during acute and chronic infections, but transcriptional regulation of these cytokines in the GC is incompletely understood. We show that the Th1 transcriptional regulators T-bet and STAT4 are co-expressed with Bcl6 in Tfh cells following acute murine lymphocytic choriomeningitis virus infection, albeit with temporal decline in T-bet expression as the GC response evolved. T-bet was important for Tfh cell production of IFN-g, but not IL-21, and for the generation of a robust germinal center reaction. STAT4, phosphorylated in Tfh cells upon infection, was required for their expression of T-bet and Bcl6, and that of IFN-g and IL-21. These data indicate that T-bet is concomitantly expressed with Bcl6 in Tfh cells and is required alongside STAT4 phosphorylation to coordinate Tfh cell IL-21 and IFN-g production, and for promotion of the GC response following acute viral challenge.
2017-11-22 | GSE105807 | GEO
Project description:Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation, and guide their differentiation and Ig isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-g. IL-21 and IFN-g are co-expressed by Tfh cells during acute and chronic infections, but transcriptional regulation of these cytokines in the GC is incompletely understood. We show that the Th1 transcriptional regulators T-bet and STAT4 are co-expressed with Bcl6 in Tfh cells following acute murine lymphocytic choriomeningitis virus infection, albeit with temporal decline in T-bet expression as the GC response evolved. T-bet was important for Tfh cell production of IFN-g, but not IL-21, and for the generation of a robust germinal center reaction. STAT4, phosphorylated in Tfh cells upon infection, was required for their expression of T-bet and Bcl6, and that of IFN-g and IL-21. These data indicate that T-bet is concomitantly expressed with Bcl6 in Tfh cells and is required alongside STAT4 phosphorylation to coordinate Tfh cell IL-21 and IFN-g production, and for promotion of the GC response following acute viral challenge.
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Project description:Follicular helper CD4 T (Tfh) cells provide B cells with signals that are important for the generation of high-affinity Abs and immunological memory and, therefore, are critical for the protective immunity elicited by most human vaccines. In this study we sought to define the gene expression signature of bona fide GC Tfh and Tfh cells. The CD4+ T cell subsets CD45RO+CXCR5-, CD45RO+CXCR5int (Tfh cells), and CD45RO+CXCR5hi (GC Tfh cells) were isolated from 6 tonsil samples for gene expression analysis.
2013-11-12 | E-GEOD-50391 | biostudies-arrayexpress
Project description:Follicular T helper cells (Tfh) are critical for providing help to B cells for germinal center (GC) formation. Mutations affecting SAP prevent GC formation due to defective T:B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent “Tfh-like” cells that expressed IL-21, Tfh markers, and Bcl6, and rescued GC formation in SAP-deficient hosts substantially better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wildtype, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, other Th cell populations could be reprogrammed to obtain Tfh characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3 and Rorc in Tfh-like and ex vivo Tfh cells, and Bcl6 in other Th cells, supporting the concept of plasticity between Tfh and other Th populations. We describe the in vitro differentiation of functionally competent IL-21-producing cells with Tfh-like properties. Importantly, transfer of low numbers of these cells induced GC formation in SAP-deficient hosts more effectively than other in vitro differentiated Th cells, suggesting they represent bona fide Tfh cell precursors. We have chosen the name “Tfh-like” cells for these in vitro differentiated IL-21 producing cells as they exhibit Tfh characteristics, but do not reside within B cell follicles. SAP-deficient Tfh-like cells were virtually indistinguishable from WT, yet nonetheless, failed to effectively contribute to Tfh cells and rescue GC formation in vivo. Evaluation of cytokine production as well as epigenetic chromatin modifications of genes encoding Th cell-specific transcription factors from either in vitro-generated Tfh-like cells or Tfh cells isolated directly ex vivo provided evidence for plasticity between Tfh-like and other Th cell populations. Our results provide insight into the requirements for differentiation and plasticity of Tfh cells, which are critical for the generation of effective long-term humoral immunity. RNA was prepared from subconfluent asynchronously proliferating cells using TRIZOL and purified by RNeasy MinElute Cleanup kit (Qiagen). Hybridization to Affymetrix GeneChip Mouse Genome 430 2.0 arrays was used to generate gene expression profiles of WT Tfh-like and SAP-deficient Tfh-like cells.
2011-12-06 | E-GEOD-32624 | biostudies-arrayexpress
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Project description:Follicular T helper cells (Tfh) are critical for providing help to B cells for germinal center (GC) formation. Mutations affecting SAP prevent GC formation due to defective T:B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent “Tfh-like” cells that expressed IL-21, Tfh markers, and Bcl6, and rescued GC formation in SAP-deficient hosts substantially better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wildtype, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, other Th cell populations could be reprogrammed to obtain Tfh characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3 and Rorc in Tfh-like and ex vivo Tfh cells, and Bcl6 in other Th cells, supporting the concept of plasticity between Tfh and other Th populations. We describe the in vitro differentiation of functionally competent IL-21-producing cells with Tfh-like properties. Importantly, transfer of low numbers of these cells induced GC formation in SAP-deficient hosts more effectively than other in vitro differentiated Th cells, suggesting they represent bona fide Tfh cell precursors. We have chosen the name “Tfh-like” cells for these in vitro differentiated IL-21 producing cells as they exhibit Tfh characteristics, but do not reside within B cell follicles. SAP-deficient Tfh-like cells were virtually indistinguishable from WT, yet nonetheless, failed to effectively contribute to Tfh cells and rescue GC formation in vivo. Evaluation of cytokine production as well as epigenetic chromatin modifications of genes encoding Th cell-specific transcription factors from either in vitro-generated Tfh-like cells or Tfh cells isolated directly ex vivo provided evidence for plasticity between Tfh-like and other Th cell populations. Our results provide insight into the requirements for differentiation and plasticity of Tfh cells, which are critical for the generation of effective long-term humoral immunity.
2011-12-06 | GSE32624 | GEO
Project description:Tight control of follicular helper T(Tfh) cells is required for optimal maturation of the germinal center (GC) response. The molecular mechansims controlling Tfh cell differentiation remain incompletely understood. Here we sought to to identfiy miRNAs that might regulate Tfh cell development and/or function. To identfiy miRNAs that are differentially expressed in Tfh cells, we performed Agilent microRNA microarray analysis comparing Tfh cells with the other main T cell subsets (naive T cells, non-Tfh effector or non-Tfh memory T cells, CD57+ Tfh cells and CD57- Tfh cells).
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