Summary
Bach2 is a basic region‐leucine zipper (bZip) transcription factor that forms heterodimers with small Maf oncoproteins and binds to target genes, thus repressing their expression. Bach2 is ...required for class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes in activated B cells. Bach2 represses the expression of Prdm1 encoding Blimp‐1 repressor and thereby inhibits terminal differentiation of B cells to plasma cells. This causes a delay in the induction of Prdm1, thereby securing a time window for the expression of Aicda encoding activation‐induced cytidine deaminase (AID) required for both CSR and SHM. Based on the characteristics of a gene regulatory network (GRN) involving Bach2 and Prdm1 and its dynamics, a ‘delay‐driven diversity’ model was introduced to explain the responses of activated B cells. Bach2 is also required for the proper differentiation and function of peripheral T cells. In the absence of Bach2, CD4+ T cells show increased differentiation to effector cells producing higher levels of Th2‐related cytokines, such as IL‐4 and IL‐10, and a reduction in the generation of regulatory T cells. Bach2 represses many genes in T cells, including Prdm1, suggesting that the Bach2‐Prdm1 pathway is also important in maintaining the homeostasis of T cells. Furthermore, Bach2 is essential for the function of alveolar macrophages. Therefore, Bach2 orchestrates both acquired and innate immunity at multiple points. Its connection with disease is also reviewed in this report.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Two transcription factors, Pax5 and Blimp‐1, form a gene regulatory network (GRN) with a double‐negative loop, which defines either B‐cell (Pax5 high) or plasma cell (Blimp‐1 high) status as a binary ...switch. However, it is unclear how this B‐cell GRN registers class switch DNA recombination (CSR), an event that takes place before the terminal differentiation to plasma cells. In the absence of Bach2 encoding a transcription factor required for CSR, mouse splenic B cells more frequently and rapidly expressed Blimp‐1 and differentiated to IgM plasma cells as compared with wild‐type cells. Genetic loss of Blimp‐1 in Bach2−/− B cells was sufficient to restore CSR. These data with mathematical modelling of the GRN indicate that Bach2 achieves a time delay in Blimp‐1 induction, which inhibits plasma cell differentiation and promotes CSR (Delay‐Driven Diversity model for CSR). Reduction in mature B‐cell numbers in Bach2−/− mice was not rescued by Blimp‐1 ablation, indicating that Bach2 regulates B‐cell differentiation and function through Blimp‐1‐dependent and ‐independent GRNs.
The transcription factor Bach2 is an important component of a regulatory network that determines whether B cells will undergo terminal differentiation to IgM‐secreting cells or undergo class switch DNA recombination.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
The extracellular matrix (ECM) is the basis for virtually all cellular processes and is also related to tumor metastasis. Fibronectin (FN), a major ECM macromolecule expressed by different ...cell types and also present in plasma, consists of multiple functional modules that bind to ECM-associated, plasma, and cell-surface proteins such as integrins and FN itself, thus ensuring its cell-adhesive and modulatory role. Here we show that FN constitutes an immune checkpoint. Thus, FN was identified as a physiological ligand for a tumor/leukemia/lymphoma- as well as autoimmune-associated checkpoint, ILT3/LILRB4 (B4, CD85k). Human B4 and the murine ortholog, gp49B, bound FN with sub-micromolar affinities as assessed by bio-layer interferometry. The major B4-binding site in FN was located at the N-terminal 30-kDa module (FN30), which is apart from the major integrin-binding site present at the middle of the molecule. Blockade of B4–FN binding such as with B4 antibodies or a recombinant FN30-Fc fusion protein paradoxically ameliorated autoimmune disease in lupus-prone BXSB/Yaa mice. The unexpected nature of the B4–FN checkpoint in autoimmunity is discussed, referring to its potential role in tumor immunity.
Fibronectin functions as an immune checkpoint molecule
BTB and CNC homology 2 (Bach2) is a transcriptional repressor that is required for the formation of the germinal center (GC) and reactions, including class switch recombination and somatic ...hypermutation of Ig genes in B cells, within the GC. Although BCR-induced proliferation is essential for GC reactions, the function of Bach2 in regulating B cell proliferation has not been elucidated. In this study, we demonstrate that Bach2 is required to sustain high levels of B cell proliferation in response to BCR signaling. Following BCR engagement in vitro, B cells from
-deficient (
) mice showed lower incorporation of BrdU and reduced cell cycle progression compared with wild-type cells.
B cells also underwent increased apoptosis, as evidenced by an elevated frequency of sub-G
cells and early apoptotic cells. Transcriptome analysis of BCR-engaged B cells from
mice revealed reduced expression of the antiapoptotic gene
encoding Bcl-x
and elevated expression of cyclin-dependent kinase inhibitor (CKI) family genes, including
,
, and
Reconstitution of Bcl-x
expression partially rescued the proliferation defect of
B cells. Chromatin immunoprecipitation experiments showed that Bach2 bound to the CKI family genes, indicating that these genes are direct repression targets of Bach2. These findings identify Bach2 as a requisite factor for sustaining high levels of BCR-induced proliferation, survival, and cell cycle progression, and it promotes expression of Bcl-x
and repression of CKI genes. BCR-induced proliferation defects may contribute to the impaired GC formation observed in
mice.
Plasmablasts and plasma cells (PBs and PCs) producing pathogenic auto-antibodies in patients with systemic autoimmune diseases could be a better target for specific therapies for the disease than ...general immunosuppression or pan- or activated B-cell targeting. Our previous study indicated that leukocyte immunoglobulin-like receptor (LILR) B4 (B4, also known as ILT3/LIR-5/CD85k), a tolerogenic receptor in antigen-presenting cells, is ectopically expressed on the PB/PC surface in healthy individuals. Here, we show that the enlarged population size of PBs/PCs with augmented B4 expression is characteristic in non-treated systemic lupus erythematosus (SLE). Paradoxically, the transcription frequency of the anti-double-strand DNA immunoglobulin-coding V
sequence in the B4
population of non-treated SLE was significantly higher than that in B4
cells. B4
and B4
PBs/PCs were suggested to be developmentally equivalent based on the simultaneous generation of these populations upon activation of memory B cells in vitro B4 expression was found to be induced efficiently by IL-2, while IFN-α effectively induced B4
PBs/PCs in vitro Utilizing the elevated B4 will support opening a new avenue for identifying the mechanism for generation of, and additional molecular markers for, pathogenic cells.
Pulmonary alveolar proteinosis (PAP) is a disease resulting from a dysfunction of the alveolar macrophages (AMs) where excess surfactant protein accumulates in the alveolar spaces. We previously ...reported that Bach2 KO mice developed PAP due to a defect in the handling of lipids by AMs. To investigate the functions of Bach1 and Bach2, which are regulated by oxidative stress, in the AMs and in lung homeostasis, we generated mice that lacked both Bach1 and Bach2 (Bach1/2 DKO mice). The Bach1/2 DKO mice showed more severe PAP phenotype than Bach2 KO mice with abnormal AMs, whereas the Bach1 KO mice did not develop any pulmonary disease. The PAP-like disease in the Bach1/2 DKO and Bach2 KO mice was not ameliorated by antioxidant, suggesting that ROS was not involved in the onset of PAP in the absence of Bach1 and Bach2. A microarray and a chromatin immunoprecipitation sequence analysis revealed that Bach1 and Bach2 directly repress the common set of genes involved in the inflammatory response, and that Bach2 is a major contributor to this repression. These results suggest that Bach1 and Bach2 work in a complementary manner to maintain the normal function of the AMs and surfactant homeostasis in the lung.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Mesenchymal stem cells support antibody production by plasma cells
Abstract
Plasma cells (PCs) acquiring long lifespans in the bone marrow (BM) play a pivotal role in the humoral arm of immunological ...memory. The PCs reside in a special BM niche and produce antibodies against past-encountered pathogens or vaccine components for a long time. In BM, cysteine-X-cysteine (CXC) chemokine receptor type 4 (CXCR4)-expressing PCs and myeloid cells such as dendritic cells are attracted to and held by CXC chemokine ligand 12 (CXCR12)-secreting stromal cells, where survival of the PCs is supported by soluble factors such as IL-6 and APRIL (a proliferation-inducing ligand) produced by neighboring myeloid cells. Although these stromal cells are also supposed to be involved in the support of the survival and antibody production, the full molecular mechanism has not been clarified yet. Here, we show that BM PDGFRα+Sca-1+-enriched mesenchymal stem cells (MSCs), which can contribute as stromal cells for hematopoietic stem cells, also support in vitro survival of and antibody production by BM PCs. IL-6 produced by MSCs was found to be involved in the support. Immunohistochemistry of BM sections suggested a co-localization of a minor population of PCs with PDGFRα+Sca-1+ MSCs in the BM. We also found that the sort-purified MSC preparation was composed of multiple cell groups with different gene expression profiles, as found on single-cell RNA sequencing, to which multiple roles in the in vitro PC support could be attributed.
Mature lymphoid cells express the transcription repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B ...lineage, commencing from the common lymphoid progenitor (CLP) stage, with Bach1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and Bach1 repressed the expression of genes important for myeloid cells ('myeloid genes'). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2(hi) CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with Bach1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor ...(GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling.
Elucidation of how the differentiation of hematopoietic stem and progenitor cells (HSPCs) is reconfigured in response to the environment is critical for understanding the biology and disorder of ...hematopoiesis. Here we found that the transcription factors (TFs) Bach2 and Bach1 promoted erythropoiesis by regulating heme metabolism in committed erythroid cells to sustain erythroblast maturation and by reinforcing erythroid commitment at the erythro-myeloid bifurcation step. Bach TFs repressed expression of the gene encoding the transcription factor C/EBPβ, as well as that of its target genes encoding molecules important for myelopoiesis and inflammation; they achieved the latter by binding to their regulatory regions also bound by C/EBPβ. Lipopolysaccharide diminished the expression of Bach TFs in progenitor cells and promoted myeloid differentiation. Overexpression of Bach2 in HSPCs promoted erythroid development and inhibited myelopoiesis. Knockdown of BACH1 or BACH2 in human CD34
HSPCs impaired erythroid differentiation in vitro. Thus, Bach TFs accelerate erythroid commitment by suppressing the myeloid program at steady state. Anemia of inflammation and myelodysplastic syndrome might involve reduced activity of Bach TFs.
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