NFATc1/αA and Blimp-1 support the follicular and effector phenotype of Tregs
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ABSTRACT:
PROVIDER: PRJNA721959 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14238847.fastq.gz | Fastqsanger.gz | |||
| SRR14238848.fastq.gz | Fastqsanger.gz | |||
| SRR14238849.fastq.gz | Fastqsanger.gz |
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Project description:CD4+CXCR5+Foxp3+ T follicular regulatory (TFR) cells control the germinal center responses. Like follicular helper T-cells, they express high levels of Nuclear Factor of Activated T-cells c1, predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of TFR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a TFR migrates into the GC and how effectively it controls antibody production. NFATc1/αA is necessary to overcome TFR-expressed B lymphocyte-induced maturation protein (Blimp-1), which can directly repress Cxcr5. Blimp-1 then reinforces the recruitment of NFATc1 to Cxcr5 by protein-protein interaction and by those means cooperates with NFATc1 for Cxcr5 transactivation. On the contrary, Blimp-1 is necessary to counterbalance NFATc1/αA, which strengthens the follicular development of Tregs, but bears the inherent risk of causing an ex-Treg phenotype.
2022-01-01 | GSE172075 | GEO
Project description:CD4+CXCR5+Foxp3+ T-follicular regulatory (TFR) cells control the germinal center responses. Like T-follicular helper cells, they express high levels of Nuclear Factor of Activated T-cells c1, predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of TFR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a TFR migrates into the GC and how effectively it controls antibody production. As one type of effector Treg, TFR cells express B lymphocyte-induced maturation protein-1 (Blimp-1). Blimp-1 can directly repress Cxcr5 and NFATc1/αA is necessary to overcome this Blimp-1-mediated repression. Interestingly, Blimp-1 even reinforces the recruitment of NFATc1 to Cxcr5 by protein-protein interaction and by those means cooperates with NFATc1 for Cxcr5 transactivation. On the contrary, Blimp-1 is necessary to counterbalance NFATc1/αA and preserve the Treg identity. This is because although NFATc1/αA strengthens the follicular development of Tregs, it bears the inherent risk of causing an ex-Treg phenotype.
| S-EPMC8770984 | biostudies-literature
Project description:Post-translational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is mostly unexplored. The NFAT transcription factors play an essential role in antigen receptor-mediated gene regulation. SUMOylation of NFATc1 represses IL-2 in vitro, but its role in T cell-mediated immune responses in vivo is not clear. To this end, we generated a novel Nfatc1 transgenic mouse, which prevents SUMO modification of NFATc1. Avoidance of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. An elevated IL-2 production promoted Treg expansion and suppressed autoreactive or alloreactive T cells. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Then, Blimp-1 repressed IL-2 itself and the as well induced, proliferation-associated survival factor Bcl2A1. Collectively, we demonstrate that prevention of NFATc1 SUMOylation fine-tunes T-cell responses towards lasting tolerance. Thus, targeting NFATc1 SUMOylation presents a novel and promising strategy to treat T cell-mediated inflammatory diseases.
2020-07-01 | GSE148087 | GEO
Project description:Post-translational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is mostly unexplored. NFATc1 is a transcription factor of the family of ‘Nuclear Factors of Activated T-cells’ which plays an essential role in antigen receptor-mediated gene regulation. It is expressed in multiple isoforms of which the longer isoforms can be modified by SUMOylation. SUMO modification of NFATc1 represses IL-2 in vitro, but its role in T cell-mediated immune responses in vivo is not clear. To this end, we generated a novel Nfatc1 transgenic mouse with lysine to arginine mutations, which abolish the SUMO modification within NFATc1’s C-terminal domain. Inhibition of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. This was due to elevated IL-2 production that promoted Treg expansion and suppressed autoreactive or alloreactive T cells. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Blimp-1 also repressed IL-2 itself and the as well induced survival factor Bcl2A1. Still, lack of NFATc1 sumoylation fine-tunes T-cell responses towards lasting tolerance implying a novel approach to treat inflammatory diseases.
2019-08-31 | GSE119313 | GEO
Project description:In lymphocytes, NFATc1 is the most prominent NFAT transcription factor which play a crucial role in the fate and activity of peripheral T and B cells. NFATc1 is synthesized in two prominent isoforms, the inducible short isoform NFATc1/aA and the constitutively expressed long isoform NFATc1/C. Several lines of evidence suggested that both isoforms differ markedly in their function. It was speculated that NFATc1/aA supports the proliferation and survival of lymphocytes, whereas NFATc1/C should support apoptosis and anergy induction. To proof this hypothesis we established WEHI 231 B lymphoma cells that stably (over-) express either NFATc1/aA or NFATc1/C. In preliminary experiments we could should that WEHI cells overexpressing NFATc1/aA were protected against apoptosis induction, while cells overexpressing NFATc1/C should a higher apoptosis rate. Transcriptom analysis of WEHI-231 cells overexpressing either NFATc1/aA or NFATc1/C were performed, along with a control group of WEHI-231 cells overexpressing the E.coli enzyme BirA Ligase (which is also present in all target cell lines since for further molecular assays the NFATc1 proteins were expressed as chimeric protein containing C-terminal bio-tags. The experimental results obtained indicate that the both NFATc1 proteins, NFATc1/aA and NFATc1/C, differ tremendously in their transcriptional properties.
2016-07-01 | E-MTAB-4665 | biostudies-arrayexpress
Project description:Analysis of in vivo antigen-specific (LCMV-specific, SMARTA TCR transgenic) follicular helper CD4 T cells (CXCR5high),versus non-follicular helper CD4 T cells (CXCR5low), eight days after viral infection. A paper including data analysis of these experiments has been accepted for publication (Robert J. Johnston et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of follicular helper CD4 T cell differentiation). Experiment Overall Design: Analysis of in vivo antigen-specific (LCMV-specific, SMARTA TCR transgenic) follicular helper CD4 T cells (CXCR5high), versus non-follicular helper CD4 T cells (CXCR5low), eight days after viral infection.
2009-08-07 | E-GEOD-16697 | biostudies-arrayexpress
Project description:Analysis of in vivo antigen-specific (LCMV-specific, SMARTA TCR transgenic) follicular helper CD4 T cells (CXCR5high),versus non-follicular helper CD4 T cells (CXCR5low), eight days after viral infection. A paper including data analysis of these experiments has been accepted for publication (Robert J. Johnston et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of follicular helper CD4 T cell differentiation).
2009-07-28 | GSE16697 | GEO
Project description:We identify c-Maf as an essential factor regulating adoption of RORgamma t+ and T follicular regulatory phenotypes in effector Tregs. Differential expression analysis demonstrates reduced signatures of both ROR gamma t+ Tregs and T follicular regulatory cells following regulatory T cell-specific c-Maf deletion.
2017-11-11 | GSE102491 | GEO
Project description:Expression of Blimp-1 was specifically deleted in dendritic cells (DCs) by breeding Blimp-1 flox and CD11c-CRE mice. MiRNA expression was evaluated and compared from DCs, CD4+ T cells and total B cells from spleens of control and Blimp-1 KO mice. Age-matched (6-10 weeks old) female mice from control and Blimp-1 KO mice were sacrificed and spleens were collected. CD11chi/MHCIIhi DCs, CD4+TCRb+ T cells and B220+ B cells were sorted by FACSaria. MiRNA was measured from the total RNA preparation.
2013-09-05 | E-GEOD-40587 | biostudies-arrayexpress
Project description:The goal of this study was to profile Blimp1 binding in E18.5 small intestine using a Blimp-1-eGFP knock-in allele, and to compare Blimp-1-eGFP genomic binding with Irf-1 genomic binding in normal small intestine. Changes in Irf-1 binding between wild type and Prdm1/Blimp-1 mutant small intestine were also assessed. ChIP-seq was performed for Blimp-1-eGFP in duplicate in E18.5 small intestine expressing the fusion protein using anti-GFP antibody. As a negative control a single anti-GFP ChIP was also performed in wild type small intestine. ChIP-seq for Irf-1 was performed in duplicate in both wild type and Prdm1/Blimp-1 mutant E18.5 small intestine using an anti-Irf-1 antibody. Duplicate IgG ChIP control in wild types was performed as a negative control. All samples had an associated input chromatin sample sequenced.
2015-07-10 | E-GEOD-66069 | biostudies-arrayexpress