Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

BATF–JUN is critical for IRF4-mediated transcription in T cells


Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response1,2. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity3, allowing IRF4 to regulate genes containing ETS–IRF composite elements (EICEs; 5′-GGAAnnGAAA-3′)1. Here we show that in mouse CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1–IRF4 composite (5′-TGAnTCA/GAAA-3′) motifs that we denote as AP1–IRF composite elements (AICEs). Moreover, BATF–JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in TH17 differentiated cells. Importantly, BATF binding was diminished in Irf4−/− T cells and IRF4 binding was diminished in Batf−/− T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Preferential IRF4 binding to AP1 motifs in T cells.
Figure 2: Functionally important IRF4 binding to AP1 sites.
Figure 3: Cooperative IRF4/BATF/JUN binding.
Figure 4: Cooperative action of IRF4, BATF, and JUN.

Accession codes

Primary accessions

Gene Expression Omnibus


  1. Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623–655 (2001)

    Article  CAS  Google Scholar 

  2. Lohoff, M. & Mak, T. W. Roles of interferon-regulatory factors in T-helper-cell differentiation. Nature Rev. Immunol. 5, 125–135 (2005)

    Article  CAS  Google Scholar 

  3. Brass, A. L., Kehrli, E., Eisenbeis, C. F., Storb, U. & Singh, H. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev. 10, 2335–2347 (1996)

    Article  CAS  Google Scholar 

  4. Grossman, A. et al. Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23–p25. Genomics 37, 229–233 (1996)

    Article  CAS  Google Scholar 

  5. Grumont, R. J. & Gerondakis, S. Rel induces interferon regulatory factor 4 (IRF-4) expression in lymphocytes: modulation of interferon-regulated gene expression by Rel/nuclear factor κB. J. Exp. Med. 191, 1281–1292 (2000)

    Article  CAS  Google Scholar 

  6. Escalante, C. R. et al. Crystal structure of PU.1/IRF-4/DNA ternary complex. Mol. Cell 10, 1097–1105 (2002)

    Article  CAS  Google Scholar 

  7. Pernis, A. B. The role of IRF-4 in B and T cell activation and differentiation. J. Interferon Cytokine Res. 22, 111–120 (2002)

    Article  CAS  Google Scholar 

  8. Lohoff, M. et al. Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc. Natl Acad. Sci. USA 99, 11808–11812 (2002)

    Article  ADS  CAS  Google Scholar 

  9. Tominaga, N. et al. Development of Th1 and not Th2 immune responses in mice lacking IFN-regulatory factor-4. Int. Immunol. 15, 1–10 (2003)

    Article  CAS  Google Scholar 

  10. Rengarajan, J. et al. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J. Exp. Med. 195, 1003–1012 (2002)

    Article  CAS  Google Scholar 

  11. Hu, C. M., Jang, S. Y., Fanzo, J. C. & Pernis, A. B. Modulation of T cell cytokine production by interferon regulatory factor-4. J. Biol. Chem. 277, 49238–49246 (2002)

    Article  CAS  Google Scholar 

  12. Staudt, V. et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192–202 (2010)

    Article  CAS  Google Scholar 

  13. Brüstle, A. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nature Immunol. 8, 958–966 (2007)

    Article  Google Scholar 

  14. Kwon, H. et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31, 941–952 (2009)

    Article  CAS  Google Scholar 

  15. Schraml, B. U. et al. The AP-1 transcription factor Batf controls TH17 differentiation. Nature 460, 405–409 (2009)

    Article  ADS  CAS  Google Scholar 

  16. Echlin, D. R., Tae, H. J., Mitin, N. & Taparowsky, E. J. B-ATF functions as a negative regulator of AP-1 mediated transcription and blocks cellular transformation by Ras and Fos. Oncogene 19, 1752–1763 (2000)

    Article  CAS  Google Scholar 

  17. Dorsey, M. J. et al. B-ATF: a novel human bZIP protein that associates with members of the AP-1 transcription factor family. Oncogene 11, 2255–2265 (1995)

    CAS  PubMed  Google Scholar 

  18. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007)

    Article  ADS  CAS  Google Scholar 

  19. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007)

    Article  ADS  CAS  Google Scholar 

  20. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol. 8, 967–974 (2007)

    Article  CAS  Google Scholar 

  21. Zhang, X., Wrzeszczynska, M. H., Horvath, C. M. & Darnell, J. E., Jr Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation. Mol. Cell. Biol. 19, 7138–7146 (1999)

    Article  CAS  Google Scholar 

  22. Spolski, R., Kim, H. P., Zhu, W., Levy, D. E. & Leonard, W. J. IL-21 mediates suppressive effects via its induction of IL-10. J. Immunol. 182, 2859–2867 (2009)

    Article  CAS  Google Scholar 

  23. Pot, C. et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 183, 797–801 (2009)

    Article  CAS  Google Scholar 

  24. Lee, C. G. et al. A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells. Mol. Immunol. 46, 613–621 (2009)

    Article  CAS  Google Scholar 

  25. Chang, H. C. et al. PU.1 expression delineates heterogeneity in primary Th2 cells. Immunity 22, 693–703 (2005)

    Article  CAS  Google Scholar 

  26. Chang, H. C. et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nature Immunol. 11, 527–534 (2010)

    Article  ADS  CAS  Google Scholar 

  27. Altin, J. A., Goodnow, C. C. & Cook, M. C. IL-10+CTLA-4+ Th2 inhibitory cells form in a Foxp3-independent, IL-2-dependent manner from Th2 effectors during chronic inflammation. J. Immunol. 188, 5478–5488 (2012)

    Article  CAS  Google Scholar 

  28. Tussiwand, R. et al. Compensatory dendritic cell development mediated by BATF–IRF interactions. Nature (19 September 2012)

  29. Liao, W., Lin, J. X., Wang, L., Li, P. & Leonard, W. J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nature Immunol. 12, 551–559 (2011)

    Article  CAS  Google Scholar 

  30. Lin, J. X. et al. Critical role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function. Immunity 36, 586–599 (2012)

    Article  CAS  Google Scholar 

  31. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

    Article  Google Scholar 

  32. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008)

    Article  Google Scholar 

  33. Bailey, T. L. & Elkan, C. Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proc. Int. Conf. Intell. Syst. Mol. Biol. 2, 28–36 (1994)

    CAS  PubMed  Google Scholar 

Download references


This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH (P.L., R.S., W.L., L.W. and W.J.L.) and the Howard Hughes Medical Institute (T.L.M. and K.M.M.). We thank J.-X. Lin for valuable suggestions, critical comments and RNA-Seq data for pro-B/pre-B-enriched populations. We thank J. Zhu and Y. Wakabayashi, NHLBI DNA Sequencing Core, for excellent services, K. Ozato and Y. Hiroaki, NICHD, for Irf4−/− mice, and J. Thierry-Mieg and D. Thierry-Mieg, NCBI, for early analysis of ChIP-Seq data from ref. 14.

Author information

Authors and Affiliations



P.L. designed experiments, analysed data and wrote the paper. R.S. designed and performed experiments, analysed data and wrote the paper. W.L. and L.W. designed and performed experiments and analysed data. T.L.M. and K.M.M. provided reagents and made suggestions. W.J.L. designed experiments, analysed data and wrote the paper.

Corresponding authors

Correspondence to Peng Li or Warren J. Leonard.

Ethics declarations

Competing interests

W.J.L. and R.S. are inventors on NIH patents related to IL-21.

Additional information

Data sets (ChIP-Seq and RNA-Seq data) have been deposited in the Gene Expression Omnibus (GSE39756).

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-8 and Supplementary Tables 1-2. (PDF 1876 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Li, P., Spolski, R., Liao, W. et al. BATF–JUN is critical for IRF4-mediated transcription in T cells. Nature 490, 543–546 (2012).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing