The AP-1 transcription factor Batf controls T(H)17 differentiation - PubMed (original) (raw)

. 2009 Jul 16;460(7253):405-9.

doi: 10.1038/nature08114. Epub 2009 Jul 5.

Kai Hildner, Wataru Ise, Wan-Ling Lee, Whitney A-E Smith, Ben Solomon, Gurmukh Sahota, Julia Sim, Ryuta Mukasa, Saso Cemerski, Robin D Hatton, Gary D Stormo, Casey T Weaver, John H Russell, Theresa L Murphy, Kenneth M Murphy

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The AP-1 transcription factor Batf controls T(H)17 differentiation

Barbara U Schraml et al. Nature. 2009.

Abstract

Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity. Here we show that Batf is required for the differentiation of IL17-producing T helper (T(H)17) cells. T(H)17 cells comprise a CD4(+) T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity. Batf(-/-) mice have normal T(H)1 and T(H)2 differentiation, but show a defect in T(H)17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf(-/-) T cells fail to induce known factors required for T(H)17 differentiation, such as RORgamma t (encoded by Rorc) and the cytokine IL21 (refs 14-17). Neither the addition of IL21 nor the overexpression of RORgamma t fully restores IL17 production in Batf(-/-) T cells. The Il17 promoter is BATF-responsive, and after T(H)17 differentiation, BATF binds conserved intergenic elements in the Il17a-Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in T(H)17 differentiation.

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Figures

Figure 1

Figure 1. Loss of IL-17 production in Batf−/− T cells

a, DO11.10+CD4+ T cells from CD2-N-FLAG-Batf transgenic mice or littermates were cultured with OVA/APCs under TH2 conditions for 7 days, and stained with antibodies to CD4 and FLAG. b,Batf+/+ and Batf−/− CD4+CD62L+CD25 T cells cultured under TH17 conditions were restimulated with PMA/ionomycin on days 7 (left panel) or 3 (middle and right panels) and stained for IL-17, IFN-γ, IL-2 and IL-10. c, IL-17 and IFN-γ expression in DO11.10+CD4+ T cells from Batf+/+Batf +/− and Batf−/− mice activated with OVA/APCs under TH17 conditions. Data are representative of at least 2 independent experiments.

Figure 2

Figure 2. Batf−/− mice are resistant to EAE

a,Batf+/+ (n=12) and Batf−/− (n=13) mice were immunized with MOG33–35 peptide. (Mean clinical EAE scores +/− s.e.m, representative of two independent experiments). b, 13 days after EAE induction, CNS-infiltrating lymphocytes were stimulated with PMA/ionomycin, gated on CD4+ cells and stained for intracellular IL-17 and IFNγ (Clinical scores are in parentheses, data are representative of 2–3 mice per group). c,Batf+/+ and Batf−/− mice were injected with control PBS buffer (n=5) or 1×107_Batf+/+_ CD4+ T cells (n=6) four days prior to EAE induction. Mean clinical scores are shown.

Figure 3

Figure 3. Batf controls multiple TH17-associated genes

a, IL-21 expression in Batf+/+ or Batf−/− T cells cultured under TH17 conditions determined by qRT-PCR and ELISA. (mean + s.d. 3 mice). b, IL-17 and IFN-γ expression of CD4+CD62L+CD25− T cells cultured in a in the presence or absence of IL-21. c, Microarray analysis of anti-CD3/CD28-activated T cells at 72h, presented as heat maps of genes 5-fold-induced in Batf+/+ T cells under TH17 conditions. d, IL-17 and IL-22 expression in Batf+/+ or Batf−/− CD4+ T cells activated under TH17 conditions for 3 days. e, Anti−CD3/CD28-activated Batf+/+ or Batf−/− CD4+ T cells were left uninfected or infected with RORγt-GFP-RV or control-GFP-RV, and stained for IL-17.

Figure 4

Figure 4. Batf directly regulates IL-17 expression

a,Batf+/+ and Batf−/− CD4+ T cells cultured under TH17 conditions were infected with hCD4-pA-GFP-RV-IL-17p reporter virus. GFP expression after PMA/ionomycin restimulation is shown. b, Batf+/+ and Batf−/− CD4+ T cells cultured under TH17 conditions for 5 days were subjected to ChIP analysis of the indicated regions using anti-Batf antibody (mean + s.d.). c, d, f, EMSA supershift analysis of TH17 whole cell extracts using a consensus AP-1 (c, f) or the IL-17(−155 to − 187) probe (d). (Batf+/+ (WT), Batf−/− (KO), CD2-N-FLAG-Batf transgenic (TG), IL-17(−155 to − 187) and RORE probes were used as competitors).

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