Cell‐intrinsic functions of Bhlhe40 in activated B cells and TFH cells restrain the GC reaction and prevent lymphomagenesis
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ABSTRACT:
PROVIDER: PRJNA773937 | ENA |
REPOSITORIES: ENA
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Project description:The generation of high-affinity antibodies against pathogens and vaccines requires the germinal center (GC) reaction – a process that relies on a complex interplay between specialized effector subsets of B and CD4 T lymphocytes – GC B cells and T follicular helper (TFH) cells. Intriguingly, several key positive regulators of the GC reaction are common for both cell types. Here, we report that the transcription factor Bhlhe40 is a crucial cell-intrinsic negative regulator affecting both the B and T cell sides of the GC reaction. In activated CD4 T cells, Bhlhe40 was required to restrain proliferation thus limiting the number of TFH cells. In B cells, Bhlhe40 executed its function in the first days after immunization by selectively restricting the generation of the earliest GC B cells but not of early memory B cells or plasmablasts. Conditional Bhlhe40 inactivation confirmed cell-autonomous functions of Bhlhe40 in both GC B and TFH cells, while the GC phenotype was further enhanced upon loss of Bhlhe40 in both cell types. This negative regulation of the GC reaction by Bhlhe40 was of crucial importance, as Bhlhe40-deficient mice with progressing age succumbed to a B cell lymphoma characterized by the accumulation of monoclonal GC B-like cells and polyclonal TFH cells in various tissues.
2021-10-25 | GSE186457 | GEO
Project description:Microarray data on TH17 cells from Bhlhe40-GFP reporter mice We used microarrays to detail the global programme of gene expression in polarized Bhlhe40-GFPneg and Bhlhe40-GFPpos TH17 cells Purified naïve CD4 T cells from spleen were polarized under TH17 condition in vitro. On day 4, cells were stimulated with PMA and ionomycin, and sorted by their Bhlhe40-GFP expression prior to microarray analysis
2016-01-04 | E-GEOD-75407 | biostudies-arrayexpress
Project description:Microarray data on TH17 cells from Bhlhe40-GFP reporter mice We used microarrays to detail the global programme of gene expression in polarized Bhlhe40-GFPneg and Bhlhe40-GFPpos TH17 cells
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Project description:NK cells represent a cellular component of the mammalian innate immune system, and mount rapid responses against viral infection, including the secretion of the potent anti-viral effector cytokine IFN-g. Following mouse cytomegalovirus (MCMV) infection, Bhlhe40 was the most highly induced transcription factor in NK cells among the basic helix-loop-helix family. Bhlhe40 upregulation in NK cells depended upon IL-12 and IL-18 signals, with the promoter of Bhlhe40 enriched for STAT4 and the permissive histone H3K4me3, and STAT4-deficient NK cells showing an impairment of Bhlhe40 induction and diminished H3K4me3. Transcriptomic and protein analysis of Bhlhe40-deficient NK cells revealed a defect in IFN-g production during MCMV infection, resulting in diminished protective immunity following viral challenge. Finally, we provide evidence that Bhlhe40 directly promotes IFN-g by binding throughout the Ifng loci in activated NK cells. Thus, our study reveals how STAT4-mediated control of Bhlhe40 drives protective IFN-g secretion by NK cells during viral infection.
2023-09-13 | GSE242900 | GEO
Project description:Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state, and can expand during type 2 immunity. Whether shared mechanisms regulate macrophage proliferation in homeostasis and disease is unclear. We found that the transcription factor Bhlhe40 was cell-intrinsically required in large peritoneal macrophages (LPMs) for self-renewal and maintenance, but was not required in other resident macrophages. Bhlhe40 was selectively necessary in LPMs for proliferation, but not polarization, in response to IL-4. During a helminth infection, Bhlhe40 was required for normal LPM cell cycling. Bhlhe40 repressed the expression of Maf and Mafb and directly promoted expression of cell cycle-related transcripts to enable proliferation of LPMs. Genomic sites bound by Bhlhe40 in LPMs included some co-bound by the macrophage lineage-determining factor PU.1 and others uniquely bound by Bhlhe40, including Maf and cell cycle-related loci. Our findings demonstrate a tissue-specific control mechanism regulating resident macrophage proliferation in homeostasis and type 2 immunity.
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Project description:To assess the impact of hypoxia on global gene expression of beta cells, we performed bulk RNA-seq on mouse islets, human islets and MIN6 cells. Bhlhe40 was transcriptional repressor which was highly induced by hypoxia in beta cells. Thus, we established Bhlhe40 overexpressing MIN6 cells and performed RNA-seq to identify the targets of Bhlhe40.
2023-05-01 | GSE202603 | GEO
Project description:BHLHE40-AS1 was cloned into pBABE-Puro. Empty vector and pBABE-BHLHE40-AS1 were used to generate retrovirus and infect MCF10A cells. Transduced cells were selected with 1ug/mL puromycin for 2 weeks.
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Project description:The Germinal center is a dynamic microenvironment wherein B cells expressing high affinity antibody variants produced by hypermutation are selected for clonal expansion by limiting numbers of T follicular helper cells. Although a great deal is known about the mechanisms that control B cell selection in the germinal center, far less is understood about the clonal behavior of the T follicular helper cells that regulate this process. Here we report on the dynamic behavior of clones of T follicular helper cells during the germinal center reaction. We find that like germinal center B cells, T follicular helper cells undergo antigen dependent selection during the germinal center reaction resulting in differential proliferative expansion and contraction. Increasing the amount of antigen presented in the germinal center leads to increased T follicular cell division. Competition between T follicular helper cell clones is mediated by T cell receptor affinity for peptide-MHC ligand. Higher affinity T cells expanding preferentially in the germinal center show increased expression of genes downstream of the T cell receptor, genes required for metabolic reprogramming, cell division and cytokine production. These dynamic changes lead to dramatic remodeling of the functional T follicular cell repertoire during the germinal center reaction.
2020-03-19 | GSE147182 | GEO
Project description:Better understanding of the host responses to Mycobacterium tuberculosis (Mtb) infections is required to prevent tuberculosis and develop new therapeutic interventions. The host transcription factor BHLHE40 is essential for controlling Mtb infection, in part by repressing Il10 expression, where excess IL-10 contributes to the early susceptibility of Bhlhe40-/- mice to Mtb infection. Deletion of Bhlhe40 in lung macrophages and dendritic cells is sufficient to increase the susceptibility of mice to Mtb infection, but how BHLHE40 impacts macrophage and dendritic cell responses to Mtb is unknown. Here we report that BHLHE40 is required in myeloid cells exposed to GM-CSF, an abundant cytokine in the lung, to promote the expression of genes associated with a pro-inflammatory state and better control of Mtb infection. Loss of Bhlhe40 expression in murine bone marrow derived myeloid cells cultured in the presence of GM-CSF results in lower levels of pro-inflammatory associated signaling molecules IL-1b, IL-6, IL-12, TNFα, iNOS, IL-2, KC, and RANTES, as well as higher levels of the anti-inflammatory associated molecules MCP-1 and IL-10 following exposure to heat-killed Mtb. Deletion of Il10 in Bhlhe40-/- myeloid cells restored some, but not all, pro-inflammatory signals, demonstrating that BHLHE40 promotes pro-inflammatory responses via both IL-10-dependent and independent mechanisms. In addition, we show that macrophages and neutrophils within the lungs of Mtb-infected Bhlhe40-/- mice exhibit defects in iNOS production compared to infected WT mice, supporting that BHLHE40 promotes pro-inflammatory responses in innate immune cells, which may contribute to the essential role for BHLHE40 during Mtb infection in vivo.
2024-07-02 | GSE265840 | GEO
Project description:Using both global and conditional knockout mice, we demonstrated that the transcription factor Basic Helix-Loop-Helix Family Member E40 (BHLHE40/DEC1) is required in T cells for rejection of mouse syngeneic tumors upon immune checkpoint therapy (ICT) with anti-PD-1 or anti-CTLA-4 monoclonal antibody (mAb) treatment. Using single cell RNA sequencing (scRNAseq) we profiled intratumoral CD45+ cells from syngeneic mouse sarcomas that (a) grow progressively with control treatment in either Bhlhe40+/+ or Bhlhe40-/- tumor-bearing mice, (b) reject following anti-PD-1 or anti-CTLA-4 ICT in Bhlhe40+/+ tumor-bearing mice, or (c) grow progressively following anti-PD-1 or anti-CTLA-4 in Bhlhe40-/- mice. We performed two separate scRNAseq experiments with the same conditions but harvested tumors on either day 9 post-tumor transplant or day 11 post-tumor transplant. The groups were as follows: (1) Control mAb Bhlhe40+/+, (2) Control mAb Bhlhe40-/-, (3) anti-PD-1 Bhlhe40+/+, (4) anti-PD-1 Bhlhe40-/-, (5) anti-CTLA-4 Bhlhe40+/+, and (6) anti-CTLA-4 Bhlhe40-/-. scRNAseq of intratumoral immune cells in BHLHE40-deficient mice revealed differential ICT-induced immune cell remodeling. These BHLHE40-dependent gene expression alterations were associated with altered metabolism, NF-kB signaling, and IFN- response in subpopulations of intratumoral CD4+ and CD8+ T cells. Intratumoral T cells from tumor-bearing Bhlhe40-/- mice also had higher transcript expression of the inhibitory receptor gene Tigit, along with altered transcript expression of chemokine/chemokine receptor granzyme family members. Bhlhe40-/- CD4+ and CD8+ T cells also had reduced ICT-driven IFN- production. Furthermore, BHLHE40 was required for ICT-induced remodeling of macrophages from a CX3CR1+ CD206+ subpopulation to an iNOS+ subpopulation. While anti-PD-1 or anti-CTLA-4 ICT in tumor-bearing Bhlhe40-/- mice led to tumor outgrowth—several BHLHE40-dependent changes were specific to the ICT treatment that was administered.
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