BACH2 Controls Seeding and Establishment of Long-Lived HIV-1 Reservoir in CD4+ T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1153621 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30458636_1.fastq.gz | Fastqsanger.gz | |||
| SRR30458636_2.fastq.gz | Fastqsanger.gz | |||
| SRR30458637_1.fastq.gz | Fastqsanger.gz | |||
| SRR30458637_2.fastq.gz | Fastqsanger.gz |
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Project description:Despite antiretroviral therapy, HIV mainly persists in memory CD4+ T cells in people living with HIV. Most long-lived viral reservoir cells are infected near the time of therapy initiation. A better understanding of the early events in reservoir seeding presents opportunities for preventing latent reservoir formation. Here, we demonstrated that CD4+ T cells expressing CCR5, permissive to HIV-1 infection, are effector or terminally differentiated cells. BACH2 is expressed by a small subset of CCR5+ cells and reverses their terminal differentiation. BACH2-mediated memory differentiation is impeded due to heightened inflammation before treatment initiation. Mice with a BACH2 knockout human immune system has a reduced frequency of HIV-1 reservoir cells and do not experience virus rebound after treatment discontinuation. Our study reveals that BACH2 is essential to the seeding of long-lived HIV-1 reservoir and demonstrates the potential of targeting BACH2 at the time of treatment initiation to eliminate HIV-1 reservoirs in T cells.
2024-11-01 | GSE275936 | GEO
Project description:The transcription factor Bach2 serves as a crucial regulator of the germinal center (GC) reaction, which is required for production of high-affinity antibodies and establishment of long-lived B cell memory. However, the stage at which Bach2 controls the GC programs and the precise mechanism underlying these processes remain poorly understood. In this study, we show that genetic ablation of Bach2 in GC B cells of mice impairs their survival and maintenance, and memory B cell formation. These defects can be rescued by enforced expression of anti-apoptotic gene Bcl2. As expected, Bach2-deficient GC B cells are defective in antibody affinity maturation, but have normal somatic hyper mutation and class switch recombination of immunoglobulin genes. Mechanistically, Bach2 controls the GC programs by directly repressing pro-apoptotic gene Bim and a set of genes involved in cell stress response and metabolic processes. Thus, our work reveals the precise roles of Bach2 in the GC biology, and demonstrates that Bach2 acts as a crucial survival regulator of GC B cells, providing a key mechanism underlying GC B maintenance and B cell memory formation.
2022-06-05 | GSE205400 | GEO
Project description:Bach2 codes for a transcriptional regulator exerting major influences on T cell mediated immune regulation. Effector CTLs derived from in vitro activation of murine CD8+ T cells showed increased proliferative and cytolytic capacity in the absence of BACH2. Before activation, BACH2-deficient CD8+ T cells had a higher abundance of memory and reduced abundance of naïve cells compared to wild-type. CTLs derived from central memory T cells were more potently cytotoxic than those derived from naïve T cells, but even within separated subsets, BACH2-deficiency conferred a cytotoxic advantage. Immunofluorescence and electron microscopy revealed larger granules in BACH2-deficient compared to wild-type CTLs, and proteomic analysis showed an increase in granule content, including perforin and granzymes. Thus, the enhanced cytotoxicity observed in effector CTLs lacking BACH2 arises not only from differences in their initial differentiation state but also inherent production of enlarged cytolytic granules. These results demonstrate how a single gene deletion can produce a CTL super-killer.
2022-09-02 | PXD036457 | Pride
Project description:During HIV infection, a latent viral reservoir is formed that persists during antiretroviral therapy (ART) and is maintained by a heritable state of transcriptional repression. Recent findings indicate that much of the reservoir originates from infections occurring in the weeks near the time of ART initiation, raising the important possibility that interventions during this period might prevent reservoir seeding and substantially reduce reservoir size. Based on this concept, we tested the ability of compounds that target epigenetic machinery to prevent the establishment of latent HIV infection in primary CD4 T cells. We identified class 1 histone deacetylase inhibitors (HDACi) as potent agents of latency prevention, an activity distinct from latency reversal. Inhibiting HDACs in productively infected cells caused extended maintenance of HIV expression, even after HDACi withdrawal, and this activity was associated with persistently elevated H3K9 acetylation and reduced H3K9 methylation at the viral LTR promoter region. HDAC inhibition in HIV-infected CD4 T cells during effector-to-memory transition led to a striking change in the memory subset distribution indicating reprogramming of cell identity. Through knockout of individual HDACs and use of HDAC-selective inhibitors, we determined that HDAC1 and HDAC3 play crucial and distinct roles in proviral silencing initiation. Overall, this work indicates that a network of HDACs regulate a critical gateway process for HIV latency establishment and are required for the development of CD4 T-cell memory subsets that preferentially harbor long-lived, latent provirus. Epigenetic reprogramming by clinical targeting of HDACs during ART initiation may represent a novel way to prevent seeding of the HIV reservoir in vivo
2023-08-08 | GSE199946 | GEO
Project description:T cell antigen receptor (TCR) signaling drives distinct responses depending upon the differentiation state and context of CD8+ T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity following viral infection. BACH2 was recruited to enhancers where it limited expression of TCR-driven genes by attenuating the availability of activator protein 1 (AP-1) sites to Jun family signal-dependent TFs. In naïve cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs.
2016-05-09 | GSE77857 | GEO
Project description:Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a major impediment for HIV cure research. To address this, we developed single-cell viral ASAPseq to precisely define the unperturbed peripheral blood HIV-infected memory CD4+ T cell reservoir from antiretroviral treated people living with HIV (ART-PLWH) via the presence of integrated accessible proviral DNA in concert with epigenetic and cell surface protein profiling. We identified profound reservoir heterogeneity within and between ART-PLWH, characterized by novel and known surface markers within total and individual memory CD4+ T cell subsets. We further uncovered novel epigenetic profiles and transcription factor motifs enriched in HIV-infected cells that suggest infected cells with accessible provirus, irrespective of reservoir distribution, are poised for reactivation during ART treatment. Together, our findings reveal the extensive inter- and intrapersonal cellular heterogeneity of the HIV reservoir, and establish an initial multiomic atlas to develop targeted reservoir elimination strategies.
2022-10-21 | GSE199727 | GEO
Project description:We report here the broad transcriptomic program regulated by BACH2 transcription factor. We used a well suited in vitro model of B cell differentiation to evaluate transcriptomic program governed by BACH2 leading to Plasmocyte (PC) differentiation. In this model B cells were cultured with anti-BCR, CpG, CD40L and Interleukin-2 (IL2). This Interleukin triggers PC differentiation by directly repressing BACH2 expression. We artificially inhibit BACH2 expression by siRNA and found that this condition is sufficient to trigger PC differentiation without IL2. To understand global changes induced by enforced BACH2 downregulation we compared Chip-Sequencing data between activated B Cells and BACH2 deficient B cells (siBACH2). We found that BACH2 binds more than 3000 genes across the human genome. RNAsequencing comparing IL2 drivent committed cells and siBACH2 committed cells highlighs a large common trasncriptional program shared by both conditions and involved in B cell destiny. This study provides evidence that BACH2 is a guardian of B cell fate.
2017-08-29 | GSE102460 | GEO
Project description:Bone invigorates metastatic seeding
| PRJNA675666 | ENA
Project description:Through their functional diversification, CD4+ T cells play key roles in both driving and constraining immune-mediated pathology. Transcription factors are critical in the generation and maintenance of cellular diversity and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage specification1. Polymorphisms within the locus encoding a transcription factor BACH2 are associated with diverse immune-mediated diseases including asthma2, multiple sclerosis3, Crohn¹s disease4-5, coeliac disease6, vitiligo7 and type 1 diabetes8. A role for Bach2 in maintaining immune homeostasis, however, has not been established. Here, we define Bach2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programmes of multiple effector lineages in CD4+ T cells. Bach2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg cell dependent. Assessment of the genome-wide function of Bach2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, Bach2 constrained full effector differentiation within Th1, Th2 and Th17 cell lineages. These findings identify Bach2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity. The role of Bach2t to regulate immune homeostasis was investigated by mapping DNA binding profiles of Bach2 in iTreg condition. The function of Bach2 was also evaluated by comparing transcriptome in WT and Bach2-deficient iTreg cells and further comparison was done with transcriptome in naive, Th1, Th2, and Th17 conditions.
2013-06-27 | E-GEOD-45975 | biostudies-arrayexpress
Project description:Bach2 has been reported to regulate multiple immune cell development and function. Here we report that Bach2 is constitutively expressed in relatively immature NK subsets. Bach2 negatively regulates NK cell development and Bach2 deficiency results in NK cell with mature effector phenotype. Thus, Bach2 functions as a negative regulator of NK cell maturation and function.
2022-02-10 | GSE196530 | GEO