Bach2 Controls T Follicular Helper Cells by Direct Repression of Bcl-6

Lahmann, Annette; Kuhrau, Julia; Fuhrmann, Franziska; Heinrich, Frederik; Bauer, Laura L.; Mashreghi, Mir‐Farzin; Hutloff, Andreas

doi:10.4049/jimmunol.1801400

Cited by 47 publications

(61 citation statements)

References 60 publications

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“…Other studies have confirmed the association between some intronic SNPs and immunemediated diseases including celiac disease, type 1 diabetes, RA, and autoimmune Addison's disease [20,22]. Bach2 is downregulated and low expressed in Tfh cells [25,26]. Bach2 is a crucial negative regulator of Tfh cells to remain its steady state and restrain its pathogenic accumulation [25].…”

Section: The Effect Of Bach2 On Th17mentioning

confidence: 90%

“…Bach2 is downregulated and low expressed in Tfh cells [25,26]. Bach2 is a crucial negative regulator of Tfh cells to remain its steady state and restrain its pathogenic accumulation [25]. It critically regulates Tfh cell differentiation.…”

Section: The Effect Of Bach2 On Th17mentioning

confidence: 99%

“…And Bach2-deficient Tfh cells were altered to the IL-4producing subset, which induced IgG1 and IgE isotype switching of B cells [26]. Overexpression of Bach2 resulted in a fast loss of Tfh cell phenotype and subsequent breakdown of the GC response [25]. In GC B cells, Bach2 is known to directly repress the transcription factor Blimp-1 and negatively regulates its expression, while Blimp-1 antagonizes Bcl-6 [28,29].…”

Section: The Effect Of Bach2 On Th17mentioning

confidence: 99%

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The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases

Yang

Chen

Zhao

et al. 2019

Mediators of Inflammation

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The transcription factor Bach2 which is predominantly expressed in B and T lymphocytes represses the expression of genes by forming heterodimers with small Maf and Batf proteins and binding to the corresponding sequence on the DNA. In this way, Bach2 serves as a highly conserved repressor which controls the terminal differentiation and maturation of both B and T lymphocytes. It is required for class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes in activated B cells, and its function in B cell differentiation has been well-described. Furthermore, emerging data show that Bach2 regulates transcriptional activity in T cells at super enhancers or regions of high transcriptional activity, thus stabilizing immunoregulatory capacity and maintaining T cell homeostasis. Bach2 is also critical for the formation and function of CD4+ T cell lineages (Th1, Th2, Th9, Th17, T follicular helper (Tfh), and regulatory T (Treg) cells). Genetic variations within Bach2 locus are associated with numerous immune-mediated diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), chronic pancreatitis (CP), type 2 chronic airway inflammation, inflammatory bowel disease (IBD), and type 1 diabetes. Here, we reveal a critical role of Bach2 in regulating T cell biology and the correlation with these immune-mediated diseases.

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Section: The Effect Of Bach2 On Th17mentioning

confidence: 90%

Section: The Effect Of Bach2 On Th17mentioning

confidence: 99%

Section: The Effect Of Bach2 On Th17mentioning

confidence: 99%

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The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases

Yang

Chen

Zhao

et al. 2019

Mediators of Inflammation

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“…Moreover, FOXO1 is not the only factor affecting Tfh‐cell differentiation in the presence of activated PI3Kδ (Figure ). Recent studies defined a role for the transcription factor BACH2 in antagonizing Tfh‐cell formation through suppression of Bcl6 , directly binding its promoter and displacing a BATF/IRF4 complex, as well as suppressing expression of CXCR5 . BACH2, like FOXO1, is inactivated by phosphorylation by AKT, suggesting lower BACH2 activity in Pik3cd E1020K/+ T cells further promotes a Tfh‐cell program.…”

Section: Pi3k Signaling Pathways Orchestrating T Follicular Helper Cellsmentioning

confidence: 99%

“…BACH2 represses both Prdm 1 and Bcl6 and its inactivation promotes the generation of multiple effector cell lineages and decreases Treg formation (Figure ). Indeed, Tfh cells express only low levels of BACH2, suggesting that balanced activity of this transcriptional repressor facilitates distinct types of T‐helper–cell development. Finally, phosphorylation of the histone methyltransferase EZH2 by AKT inhibits EZH2‐mediated promotion of memory cell and drives effector cell generation …”

Section: T‐helper–cell Differentiationmentioning

confidence: 99%

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

Preite

Gómez-Rodríguez

Cannons

et al. 2019

Immunological Reviews

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Phosphatidylinositol 3 kinases (PI3K) are a family of lipid kinases that are activated by a variety of cell-surface receptors, and regulate a wide range of downstream readouts affecting cellular metabolism, growth, survival, differentiation, adhesion, and migration. The importance of these lipid kinases in lymphocyte signaling has recently been highlighted by genetic analyses, including the recognition that both activating and inactivating mutations of the catalytic subunit of PI3Kδ, p110δ, lead to human primary immunodeficiencies. In this article, we discuss how studies on the human genetic disorder "Activated PI3K-delta syndrome" and mouse models of this disease (Pik3cd E1020K/+ mice) have provided fundamental insight into pathways regulated by PI3Kδ in T and B cells and their contribution to lymphocyte function and disease, including responses to commensal bacteria and the development of autoimmunity and tumors. We highlight critical roles of PI3Kδ in T follicular helper cells and the orchestration of the germinal center reaction, as well as in CD8 + T-cell function. We further present data demonstrating the ability of the AKT-resistant FOXO1 AAA mutant to rescue IgG1 class switching defects in Pik3cd E1020K/+ B cells, as well as data supporting a role for PI3Kδ in promoting multiple T-helper effector cell lineages. K E Y W O R D S APDS/PASLI, autoimmunity, immunodeficiency, phosphatidylinositol 3 kinase, T and B lymphocytes | 155 PREITE ET al. | AC TIVATED PI3K-DELTA SYNDROMEIn 2013-2014, three studies described immunodeficient patients with heterozygous gain-of-function autosomal-dominant mutations in PIK3CD, the gene encoding the catalytic subunit of PI3K p110δ. [3][4][5] At least 11 mutations have now been identified by whole exome sequencing, with the E1021K mutant being most prevalent. 2,6 Based on similar mutations in PI3Kα found in cancers and overgrowth syndromes, p110δ mutations were predicted to activate p110δ. 4,7 Indeed, increased PI3K activity and downstream readouts including increased PIP 3 levels, pAKT and pS6, have been observed in cells from these patients. 3,4 This novel PID has been named "Activated PI3K-delta syndrome" (APDS) or "p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency" (PASLI), hereafter referred to as APDS. Activated PI3K-delta syndrome is a combined immunodeficiency syndrome characterized by altered T-and B-cell development and responses. APDS is associated with frequent respiratory infections, progressive blood lymphopenia, mucosal lymphoid nodules, defective antibody responses, and lymphoma development. 2 Patients exhibit a paucity of naïve peripheral blood T cells with a large fraction of T cells displaying activation markers. In contrast, B-cell development is partially blocked, with increased transitional and few circulating memory B cells. 4,8,9 Recurrent respiratory infections are the most common feature of APDS. However, Epstein-Barr virus (EBV) and/ or cytomegalovirus (CMV) viremia occurs in a substantial fraction of patients, ...

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BACH2 regulates the function of human CD4⁺CD45RA⁻Foxp3^l° cytokine‐secreting T cells and promotes B‐cell response in systemic lupus erythematosus

Zheng

Huang

et al. 2019

Eur J Immunol

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Although CD4+CD45RA−Foxp3l° cytokine‐secreting T cells (Fr.III cells) have been reported to be increased in systemic lupus erythematosus (SLE), their function and effects on response of B cells are still unclear. Here, we dissect how BACH2 regulates Fr.III cells function and promotes B‐cell response in active SLE patients. We measured cytokines and BACH2 expression, and found that Fr.III cells from SLE patients produce much more inflammatory cytokines and were more able to promote B‐ cell proliferation, IgG, IgA, and TNF‐α production than controls in a co‐culture system. Fr.III cells expressed high levels of ICOS and CD154, but a low level of Tfr and BACH2, BACH2 expression was negatively correlated with SLE Disease Activity Index. Overexpressed of BACH2 in Fr.III cells, decreased cytokines expression and reduced B‐cell response. Furthermore, we identified a reduction of H3K27ac level binding at the BACH2 locus in the SLE Fr.III cells and SLE serum stimulation decreased H3K27ac binding at the BACH2 locus, which could be restored using trichostatin A (TSA). In conclusion, BACH2 was associated with SLE disease activity, regulated the function of Fr.III cells, and promoted B‐cells response. Targeting BACH2 may be a new immune intervention therapy of SLE.

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Bach2 Controls T Follicular Helper Cells by Direct Repression of Bcl-6

Cited by 47 publications

References 60 publications

The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases

The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

BACH2 regulates the function of human CD4⁺CD45RA⁻Foxp3^l° cytokine‐secreting T cells and promotes B‐cell response in systemic lupus erythematosus

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Bach2 Controls T Follicular Helper Cells by Direct Repression of Bcl-6

Cited by 47 publications

References 60 publications

The Critical Role of Bach2 in Shaping the Balance between CD4+ T Cell Subsets in Immune-Mediated Diseases

The Critical Role of Bach2 in Shaping the Balance between CD4+ T Cell Subsets in Immune-Mediated Diseases

T and B‐cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity

BACH2 regulates the function of human CD4+CD45RA−Foxp3l° cytokine‐secreting T cells and promotes B‐cell response in systemic lupus erythematosus

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Product

Resources

About

The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases

The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases

BACH2 regulates the function of human CD4⁺CD45RA⁻Foxp3^l° cytokine‐secreting T cells and promotes B‐cell response in systemic lupus erythematosus