Article

The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Nature Immunology (Impact Factor: 24.97). 06/2011; 12(6):536-43. DOI: 10.1038/ni.2037
Source: PubMed

ABSTRACT The transcription factor BATF controls the differentiation of interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) by regulating expression of the transcription factor RORγt itself and RORγt target genes such as Il17. Here we report the mechanism by which BATF controls in vivo class-switch recombination (CSR). In T cells, BATF directly controlled expression of the transcription factors Bcl-6 and c-Maf, both of which are needed for development of follicular helper T cells (T(FH) cells). Restoring T(FH) cell activity to Batf(-/-) T cells in vivo required coexpression of Bcl-6 and c-Maf. In B cells, BATF directly controlled the expression of both activation-induced cytidine deaminase (AID) and of germline transcripts of the intervening heavy-chain region and constant heavy-chain region (I(H)-C(H)). Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo.

1 Follower
 · 
516 Views
 · 
3 Downloads
  • Source
    • "The mechanism by which FOXO1 affects Tfh differentiation appears to include its role in the regulation of Icos and Bcl6, but in addition, other transcription factors that have been implicated in Tfh differentiation. BATF is required for Tfh differentiation and appears to directly control Bcl6 (Betz et al., 2010; Ise et al., 2011). Within a 35 kb region of the genome that includes only the Batf gene, there is a single and very strong FOXO1 peak (rank 411 of 4333), and this peak is located within 100 bp upstream of the Batf TSS (Figure S5). "
    [Show abstract] [Hide abstract]
    ABSTRACT: T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 02/2015; 42(2):239-51. DOI:10.1016/j.immuni.2015.01.017 · 19.75 Impact Factor
  • Source
    • "This partnership was also observed in cytokine stimulated B-cells (19,20). BATF plays an essential role in both T- and B-cells during humoral immune responses, with a requirement in the germinal centre and the regulation of class-switch recombination via AICDA (22,23). However, in the context of B-cell malignancy BATF is consistently associated with ABC-DLBCL, representative of a post-germinal centre state, rather than GCB-DLBCL (24); BATF thus provides a potential alternate partner for IRF4 in this context. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interferon regulatory factor 4 (IRF4) is central to the transcriptional network of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), an aggressive lymphoma subgroup defined by gene expression profiling. Since cofactor association modifies transcriptional regulatory input by IRF4, we assessed genome occupancy by IRF4 and endogenous cofactors in ABC-DLBCL cell lines. IRF4 partners with SPIB, PU.1 and BATF genome-wide, but SPIB provides the dominant IRF4 partner in this context. Upon SPIB knockdown IRF4 occupancy is depleted and neither PU.1 nor BATF acutely compensates. Integration with ENCODE data from lymphoblastoid cell line GM12878, demonstrates that IRF4 adopts either SPIB- or BATF-centric genome-wide distributions in related states of post-germinal centre B-cell transformation. In primary DLBCL high-SPIB and low-BATF or the reciprocal low-SPIB and high-BATF mRNA expression links to differential gene expression profiles across nine data sets, identifying distinct associations with SPIB occupancy, signatures of B-cell differentiation stage and potential pathogenetic mechanisms. In a population-based patient cohort, SPIBhigh/BATFlow-ABC-DLBCL is enriched for mutation of MYD88, and SPIBhigh/BATFlow-ABC-DLBCL with MYD88-L265P mutation identifies a small subgroup of patients among this otherwise aggressive disease subgroup with distinct favourable outcome. We conclude that differential expression of IRF4 cofactors SPIB and BATF identifies biologically and clinically significant heterogeneity among ABC-DLBCL.
    Nucleic Acids Research 05/2014; 42(12). DOI:10.1093/nar/gku451 · 9.11 Impact Factor
  • Source
    • "Deletion of the silencer elements drastically increases AID expression, without inducing transcription in non-B cells, bolstering the notion of extensive checks to AID expression (26). Region 3, approximately 25 kb downstream of Aicda, is necessary to sustain physiological levels of AID expression, likely through a BATF-binding site (22, 27, 28). Region 4 is approximately 8 kb upstream of the Aicda transcriptional initiation site and contains enhancers that bind NF-κB, STAT6, and SMAD3/4, factors that are stimulated by B cell activation (22). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Secondary diversification of the antibody repertoire upon antigenic challenge, in the form of immunoglobulin heavy chain (IgH) class-switch recombination (CSR) endows mature, naïve B cells in peripheral lymphoid organs with a limitless ability to mount an optimal humoral immune response, thus expediting pathogen elimination. CSR replaces the default constant (CH) region exons (Cμ) of IgH with any of the downstream CH exons (Cγ, Cε, or Cα), thereby altering effector functions of the antibody molecule. This process depends on, and is orchestrated by, activation-induced deaminase (AID), a DNA cytidine deaminase that acts on single-stranded DNA exposed during transcription of switch (S) region sequences at the IgH locus. DNA lesions thus generated are processed by components of several general DNA repair pathways to drive CSR. Given that AID can instigate DNA lesions and genomic instability, stringent checks are imposed that constrain and restrict its mutagenic potential. In this review, we will discuss how AID expression and substrate specificity and activity is rigorously enforced at the transcriptional, post-transcriptional, post-translational, and epigenetic levels, and how the DNA-damage response is choreographed with precision to permit targeted activity while limiting bystander catastrophe.
    Frontiers in Immunology 03/2014; 5:120. DOI:10.3389/fimmu.2014.00120
Show more

Preview

Download
3 Downloads
Available from