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Specificity through cooperation: BATF–IRF interactions control immune-regulatory networks

Nature Reviews Immunology volume 13, pages 499–509 (2013)Cite this article

Subjects

Key Points

  • Basic leucine zipper transcription factor ATF-like (BATF), BATF2 and BATF3 are basic leucine zipper (bZIP) proteins that form heterodimers with JUN proteins.

  • Initially, BATF family members were thought to function only as inhibitors of activator protein 1 (AP-1)-driven transcription, but recent studies using Batf-, Batf2- and Batf3-knockout mice have uncovered unique positive transcriptional activities for these factors in B cells, T cells and dendritic cells (DCs).

  • BATF leucine zipper motifs interact with interferon-regulatory factor 4 (IRF4) and IRF8 at AP-1–IRF consensus elements (AICEs). The discovery of the BATF–IRF interaction adds additional flexibility to the actions of IRF4 and IRF8, which were previously known to interact with ETS factors such as PU.1 and SPIB for binding DNA.

  • BATF3 is required for the development of CD8α+ classical DCs (cDCs), which prime CD8+ T cell responses by cross-presentation. Thus, Batf3−/− mice fail to reject immunogenic syngeneic tumours and have impaired virus-specific CD8+ T cell responses.

  • Lymphoid-resident CD8α+ DCs and non-lymphoid CD103+CD11b− DCs are developmentally related and are both BATF3-dependent. The equivalent human DC subset expresses DC natural killer lectin group receptor 1 (DNGR1) and blood DC antigen 3 (BDCA3) and is also BATF3-dependent.

  • BATF is required for the production of interleukin-17 (IL-17), IL-21, IL-22 and IL-23 receptor in T helper 17 (TH17) cells. In TH17 cells, BATF is thought to function as a 'pioneer factor' with IRF4 to mediate chromatin remodelling.

  • Batf−/− mice have a defect in their production of isotype-switched antibodies owing to defective class-switch recombination in their B cells and a failure of their T cells to differentiate into T follicular helper (TFH) cells. In B cells, BATF is required for the expression of activation-induced cytidine deaminase (AID) and for normal intervening heavy-chain region and constant heavy-chain region (IH–CH) germline transcription of all isotype-switch regions. In TFH cells, BATF controls the expression of MAF, B cell lymphoma 6 (BCL-6) and IL-21, which are crucial for the development of functional TFH cells.

  • BATF1, BATF2 and BATF3 proteins have compensatory actions with each other in several immune cell lineages; for example, C57BL/6 Batf3−/− mice retain a population of CD103+ cDCs in the skin-draining lymph nodes that is absent in C57BL/6 Batf−/− Batf3−/− mice. Similarly, TH2 cells that are deficient in both BATF and BATF3 lack IL-10 production, unlike Batf−/− or Batf3−/− TH2 cells.

Abstract

Basic leucine zipper transcription factor ATF-like (BATF), BATF2 and BATF3 belong to the activator protein 1 (AP-1) family of transcription factors, which regulate numerous cellular processes. Initially, BATF family members were thought to function only as inhibitors of AP-1-driven transcription, but recent studies have uncovered that these factors have unique, non-redundant and positive transcriptional activities in dendritic cells, B cells and T cells. The question of how BATF and BATF3 — which lack a transcriptional activation domain, unlike the AP-1 factors FOS and JUN — can exert unique positive transcriptional specificity has now been answered by the discovery that BATF molecules interact with members of the interferon-regulatory factor (IRF) family. The capacity of the BATF leucine zipper regions to mediate dimerization with AP-1 factors and also to define cooperative interactions with heterologous factors explains both the positive transcriptional activity of BATF proteins and how they activate distinct sets of target genes compared with FOS.

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Figure 1: BATF, BATF2 and BATF3 are bZIP proteins that form heterodimers with JUN proteins.
Figure 2: BATF3 is required for the development of CD8α+ cDCs.
Figure 3: BATF is required for CSR in B cells and for the development of functional TFH, TH17 and TH2 cells.
Figure 4: BATFs and IRFs interact at AICEs.
Figure 5: BATF proteins have compensatory actions with each other and overlapping actions with IRF4 and IRF8.

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Acknowledgements

The authors thank the members of the Murphy laboratory, as well as H. Singh, W. Leonard and D. Littman for helpful discussions.

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  1. Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, 63110, Missouri, USA

    Theresa L. Murphy, Roxane Tussiwand & Kenneth M. Murphy

  2. Howard Hughes Medical Institute, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, 63110, Missouri, USA

    Kenneth M. Murphy

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The initiation of a CD8+ T cell response to an antigen that is presented by MHC class I molecules but that is not endogenous to antigen-presenting cells (APCs). This exogenous antigen must be taken up by APCs and then re-routed to the MHC class I pathway of antigen presentation.

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ChIP–Seq

Chromatin immunoprecipitation followed by next-generation sequencing; a technique that is used to identify the in vivo DNA-binding sites of proteins. After the crosslinking of proteins to DNA, isolation and fragmentation of the chromatin, genomic regions that are bound by the protein of interest are isolated using specific antibodies. The immunoprecipitated DNA is then sequenced.

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Murphy, T., Tussiwand, R. & Murphy, K. Specificity through cooperation: BATF–IRF interactions control immune-regulatory networks. Nat Rev Immunol 13, 499–509 (2013). https://doi.org/10.1038/nri3470

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