Bcl6 is a subset defining transcription factor of Lymphoid Tissue inducer-like ILC3
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA951730 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24055260_1.fastq.gz | Fastqsanger.gz | |||
| SRR24055260_2.fastq.gz | Fastqsanger.gz | |||
| SRR24055261_1.fastq.gz | Fastqsanger.gz | |||
| SRR24055261_2.fastq.gz | Fastqsanger.gz | |||
| SRR24055262_1.fastq.gz | Fastqsanger.gz |
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Project description:Innate lymphoid cells (ILC) are tissue-resident effector cells with important roles in tissue homeostasis, protective immunity and inflammatory disease. Current nomenclature divides ILC into subsets based on the expression of master transcription factors and effector cytokine programs. In mucosal barrier tissues, group 3 ILC (ILC3) have been defined by the expression of the master transcription factor RORgt. However, ILC3 can be further subdivided into two major subsets – natural cytotoxicity receptor-expressing (NCR+) ILC3 and lymphoid tissue inducer (LTi)-like ILC3 which share type 3 effector modules but also exhibit significant ontological, transcriptional, phenotypic and functional heterogeneity. In particular, LTi-like ILC3 exhibit effector functions not typically associated with other RORgt-expressing lymphocytes, provoking the hypothesis that other master transcription factors may contribute to LTi-like ILC3 biology. Here we identify Bcl6 as an LTi-like ILC3 associated transcription factor in both mice and humans. Deletion of Bcl6 led to dysregulation of the LTi-like ILC3 transcriptional program and changes to subset-specific phenotypic markers and effector functions. Strikingly, loss of Bcl6 enhanced expression of the type 3 effector cytokines IL-17A and IL-17F in LTi-like ILC3, which was found to be in part dependent upon the commensal microbiota. Together these findings implicate Bcl6 as an ILC3 subset-defining transcription factor and part of a network that confers phenotype and function on LTi-like ILC3. Our study further provides a missing link to redefine analogous immune modules in innate and adaptive lymphocyte responses.
2023-10-31 | GSE228852 | GEO
Project description:Innate lymphoid cells (ILCs) are tissue-resident effector cells with roles in tissue homeostasis, protective immunity, and inflammatory disease. Group 3 ILCs (ILC3s) are classically defined by the master transcription factor RORγt. However, ILC3 can be further subdivided into subsets that share type 3 effector modules that exhibit significant ontological, transcriptional, phenotypic, and functional heterogeneity. Notably lymphoid tissue inducer (LTi)-like ILC3s mediate effector functions not typically associated with other RORγt-expressing lymphocytes, suggesting that additional transcription factors contribute to dictate ILC3 subset phenotypes. Here, we identify Bcl6 as a subset-defining transcription factor of LTi-like ILC3s in mice and humans. Deletion of Bcl6 results in dysregulation of the LTi-like ILC3 transcriptional program and markedly enhances expression of interleukin-17A (IL-17A) and IL-17F in LTi-like ILC3s in a manner in part dependent upon the commensal microbiota-and associated with worsened inflammation in a model of colitis. Together, these findings redefine our understanding of ILC3 subset biology.
| S-EPMC7615641 | biostudies-literature
Project description:Innate lymphoid cells (ILC) are similar to T helper (Th) cells in expression of cytokines and transcription factors. For example, RORγt is the lineage-specific transcription factor for both ILC3 and Th17 cells. However, the ILC counterpart for BCL6-expressing T follicular helper (Tfh) cells has not been defined. Here, we report that in the ILC compartment, BCL6 is selectively co-expressed with not only CXCR5, but also RORγt and CCR6 in ILC3 from multiple tissues. BCL6-deficient ILC3 produce enhanced levels of IL-17A and IL-22. More importantly, phenotypic and single-cell ATAC-seq analysis show that absence of BCL6 in mature ILC3 increases the numbers of ILC1 and transitional cells co-expressing ILC3 and ILC1 marker genes. A lineage-tracing experiment further reveals BCL6+ ILC3 to ILC1 trans-differentiation under steady state. Lastly, microbiota promote BCL6 expression in colonic CCR6+ ILC3, and thus reinforce their stability. Collectively, our data have demonstrated that CCR6+ ILC3 have both Th17 and Tfh programs and that BCL6 expression in these cells functions to maintain their lineage identity.
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Project description:Innate lymphoid cells (ILC) are similar to T helper (Th) cells in expression of cytokines and transcription factors. For example, RORγt is the lineage-specific transcription factor for both ILC3 and Th17 cells. However, the ILC counterpart for BCL6-expressing T follicular helper (Tfh) cells has not been defined. Here, we report that in the ILC compartment, BCL6 is selectively co-expressed with not only CXCR5, but also RORγt and CCR6 in ILC3 from multiple tissues. BCL6-deficient ILC3 produce enhanced levels of IL-17A and IL-22. More importantly, phenotypic and single-cell ATAC-seq analysis show that absence of BCL6 in mature ILC3 increases the numbers of ILC1 and transitional cells co-expressing ILC3 and ILC1 marker genes. A lineage-tracing experiment further reveals BCL6+ ILC3 to ILC1 trans-differentiation under steady state. Lastly, microbiota promote BCL6 expression in colonic CCR6+ ILC3, and thus reinforce their stability. Collectively, our data have demonstrated that CCR6+ ILC3 have both Th17 and Tfh programs and that BCL6 expression in these cells functions to maintain their lineage identity.
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Project description:Innate lymphoid cells (ILC) are similar to T helper (Th) cells in expression of cytokines and transcription factors. For example, RORγt is the lineage-specific transcription factor for both ILC3 and Th17 cells. However, the ILC counterpart for BCL6-expressing T follicular helper (Tfh) cells has not been defined. Here, we report that in the ILC compartment, BCL6 is selectively co-expressed with not only CXCR5, but also RORγt and CCR6 in ILC3 from multiple tissues. BCL6-deficient ILC3 produce enhanced levels of IL-17A and IL-22. More importantly, phenotypic and single-cell ATAC-seq analysis show that absence of BCL6 in mature ILC3 increases the numbers of ILC1 and transitional cells co-expressing ILC3 and ILC1 marker genes. A lineage-tracing experiment further reveals BCL6+ ILC3 to ILC1 trans-differentiation under steady state. Lastly, microbiota promote BCL6 expression in colonic CCR6+ ILC3, and thus reinforce their stability. Collectively, our data have demonstrated that CCR6+ ILC3 have both Th17 and Tfh programs and that BCL6 expression in these cells functions to maintain their lineage identity.
2022-12-29 | GSE220434 | GEO
Project description:A cross tissue transcriptional comparison of human ILC3 isolated from non-inflamed lymph nodes (LN) and spleens, inflamed tonsils and the peripheral blood (PB). Using uniform gating and high-purity cell-sorting, ILC3 were sorted as Lineage(CD3,CD19,CD34,CD14,CD94)-CD45intCD127+CRTH2-CD117+. From LN, spleen, tonsils and PB, NKp44- ILC3 were isolated and, in addition, NKp44+ ILC3 were sorted from spleen and tonsils. RNA quality was measured on a RNA 6000 Pico Kit (Agilent Technologies) using a 2100 Bioanalyzer (Agilent Technologies). 100 pg high-quality RNA was isolated and cDNA was generated using the SMART-Seq (v3) Ultra Low Input RNA Kit (Clontech) with 15 cycles of amplification. Amplified and Covaris-fragmented cDNA was quality-checked on a High Sensitivity DNA chip (Agilent Technologies) and further processed according the TruSeq Nano DNA Library Preparation Kit (Illumina). Data was processed as follows: SMARTer adapters were trimmed with cutadapt and the resulting sequences were aligned to the human RefSeq transcriptome using 14 TopHat2 (Kim et al., 2013). Normalization and quantification was performed using Cufflinks (Trapnell et al., 2012). FPKM counts were determined per gene with HTSeq-count. Raw data has been deposited at the European Genome-Phenome Archive (www.ebi.ac.uk/ega) under accession EGAS00001002636.
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Project description:Innate lymphoid cells (ILCs) play important roles in health and tissue homeostasis. While the transcriptional networks that drive their development have been defined, the transcriptional requirements that support the phenotypes and functions of mature tissue-resident populations remain poorly understood. Here we employed combinatorial inducible deletion of core transcription factors (TFs) to test how co-operative and antagonistic networks operate to control function and identity. Utilizing single cell sequencing and epigenetic profiling we dissect the complex interplay between ROR family member TFs and T-bet in determining the function and phenotype of ILC3 and NCR-lineage ILCs, defining the ontogeny and surface phenotype across a continuum of ILC3s and mature ILC1s in the small intestine, alongside the differential requirements for ROR family TFs in the maintenance of effector functions and phenotype in mature ILCs. Combined, our data demonstrates how TF networks integrate in vivo to sustain effector functions and restrict alternative differentiation programmes.
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2023-12-07 | GSE243737 | GEO
Project description:For MS of BCL6 modification sites and interaction proteins, the gel band of BCL6 was excised and digested with trypsin. Immunocomplexes were identified on Thermo Scientific Orbitrap Fusion Lumos. The data for this project include raw data.
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Project description:Tfh cells are required for T cell help to B cells, and BCL6 is the defining transcription factor of Tfh cells. However, the functions of Bcl6 in Tfh have largely remained unclear. Here we defined the BCL6 cistrome in primary human germinal center Tfh cells to assess mechanisms of BCL6 regulation of CD4 T cells, comparing and contrasting BCL6 function in T and B cells. BCL6 primarily acts as a repressor in Tfh cells, and BCL6 binding was associated with control of Tfh cell migration and repression of alternative cell fates. Interestingly, although some BCL6 bound genes possessed BCL6 DNA binding motifs, many BCL6-bound loci were instead characterized by the presence of DNA motifs for AP1 or STAT. AP1 complexes are key positive downstream mediators of TCR signaling and external stimuli. We show that BCL6 can directly bind AP1, and BCL6 depends on AP1 for recruitment to BCL6 binding sites with AP1 motifs, suggesting that BCL6 subverts AP1 activity. These findings reveal that BCL6 has broad and multifaceted effects on Tfh biology, and provide insight into how this master regulator mediates distinct cell-context dependent phenotypes.
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