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Tregs to Boost Th9 Immunity Through Regulation of Histone Acetylation

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Tregs to Boost Th9 Immunity Through Regulation of Histone Acetylation ARTICLE Received 27 Jun 2015 | Accepted 4 Aug 2015 | Published 14 Sep 2015 DOI: 10.1038/ncomms9266 OPEN GITR subverts Foxp3 þ Tregs to boost Th9 immunity through regulation of histone acetylation Xiang Xiao1,*, Xiaomin Shi1,*, Yihui Fan1, Xiaolong Zhang1, Minhao Wu1, Peixiang Lan1, Laurie Minze1, Yang-Xin Fu2, Rafik M. Ghobrial1,3, Wentao Liu1 & Xian Chang Li1,3 Glucocorticoid-induced TNFR-related protein (GITR) is a costimulatory molecule with diverse effects on effector T cells and regulatory T cells (Tregs), but the underlying mechanism remains poorly defined. Here we demonstrate that GITR ligation subverts the induction of Foxp3 þ Tregs and directs the activated CD4 þ T cells to Th9 cells. Such GITR-mediated iTreg to Th9 induction enhances anti-tumour immunity in vivo. Mechanistically, GITR upregulates the NF-kB family member p50, which recruits histone deacetylases to the Foxp3 locus to produce a ‘closed’ chromatin structure. Furthermore, GITR ligation also activates STAT6, and STAT6 renders Il9 locus accessible via recruitment of histone acetyltransferase p300, and together with inhibition of Foxp3, GITR induces strong Th9 responses. Thus, Th9 cells and iTregs are developmentally linked and GITR can subvert tolerogenic conditions to boost Th9 immunity. 1 Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center, 6670 Bertner Avenue, Houston, Texas 77030, USA. 2 Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA. 3 Department of Surgery, Weill Cornell Medical College of Cornell University, New York, New York 10065, USA. * These authors contributed equally to this work. Correspondence and requests for materials shouldbe addressed to X.C.L. (email: [email protected]). NATURE COMMUNICATIONS | 6:8266 | DOI: 10.1038/ncomms9266 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms9266 þ þ nduction of Foxp3 Tregs from naive CD4 T cells in the a TGF-β + IL-2 periphery (induced regulatory T cells (iTregs)) is a key WT tolerogenic approach1, but the exact mechanisms and the CtrlIgG DTA-1 Gitr Ligand I 4 cellular fate of iTregs in vivo are poorly understood. In certain 10 0.05 0.01 0.57 0.51 29.0 0.41 37.6 0.43 models, iTregs can be induced and contribute to immune 103 2,3 tolerance , whereas in others, iTregs lack regulatory functions 102 and may even contribute to tissue pathology4,5. Moreover, the 0 1.20 65.6 4.50 3.17 IL-9 tumour microenvironment is believed to favour iTregs, which in 0 102 103 104 105 turn, facilitate tumour evasion6. Thus, understanding the fate- Foxp3 decision of iTregs is a therapeutically important issue. Naive CD4 þ T cells can also differentiate into functionally b 40 distinct T helper subsets upon activation (for example, Th1, Th2, 80 Th17, Th9), as shown by differences in the cytokines they 60 30 produce7. This process is transcriptionally regulated and involves 40 20 8 various cytokines and costimulatory signals . Th9 cells are a newly 20 10 described T-helper subset9,10; they play an important role in IL-9+ cells (%) Foxp3+ cells (%) 0 0 protective immunity11, as well as in allergic inflammation12,13, Ctrl 1 3 10 20 Ctrl 1 3 10 20 autoimmune diseases14–16 and importantly, in anti-tumour DTA-1 (μg ml–1) DTA-1 (μg ml–1) immunity17,18. Thus, understanding how Th9 cells are induced c TGF-β + IL-2 and regulated is a clinically relevant issue. In contrast to other T OT-II helper subsets, Th9 induction requires a constellation of Ctrl IgG DTA-1 Gitr ligand transcription factors, which include SMAD2/3, PU.1, IRF4, 105 0.28 0.02 0.67 0.27 33.7 1.31 40.7 1.27 STAT5, STAT6, NFAT, GATA1, GATA3, Notch, as well as 104 BATF, RelB/p52 (refs 19,20), and a single ‘master’ transcription 103 102 factor has yet been identified in Th9 induction. Furthermore, IL-9 multiple other cell types including Th2, Th17, natural Tregs and 0 0.47 63.5 10.8 9.82 3 4 5 even innate immune cells have been shown to be capable of 0 10 10 10 expressing interleukin (IL)-9 in various models21–24,suggestingthe Foxp3 complexity of Th9 induction and potential plasticity of Th9 cells. þ d Activated CD4 T cells express multiple TNFR superfamily 80 50 costimulatory molecules, including glucocorticoid-induced 60 40 TNFR-related protein (GITR), but its contributions to the 30 40 intricate programs of T-helper cell differentiation process are 20 þ less well studied. On one hand, naive CD4 T cells do not 20 10 IL-9+ cells (%) express GITR under resting state, but GITR is rapidly induced Foxp3+ cells (%) 0 0 following T-cell receptor stimulation. On the other hand, Ctrl 1 3 10 20 Ctrl 131020 Foxp3 þ Tregs constitutively expressed GITR on the cell DTA-1 (μg ml–1) DTA-1 (μg ml–1) surface25. Studies using GITR-deficient mice or an agonist anti- GITR antibody have shown an immune stimulatory role for e GITR in the context of viral infections, tumour immunity and IgG 66.8 0.25 66.5 0.59 66.6 0.40 65.2 0.88 autoimmune diseases26,27. But it has been difficult to determine the key cell types through which GITR mediates its effects. 0.16 0.30 0.01 0.37 Controversy over the relative role of GITR on effector versus 105 3.22 0.00 3.24 0.01 3.20 0.04 3.23 0.00 DTA-1 4 28 10 regulatory T cells in boosting T-cell immunity persists . 103 In the present study, we examined the mechanisms of GITR 102 þ 0 0.11 0.38 1.36 0.42 costimulation in regulating fate-decisions of CD4 T-helper Foxp3 0 103 104 0 102 103 104 105 0 103 104 0 103 104 cells, and found that under iTreg-polarizing conditions, GITR IFN-γ IL-17 IL-4 IL-22 ligation inhibits iTregs and selectively diverts the cells to a Th9 phenotype, which enhances anti-tumour immunity in vivo. Figure 1 | GITR ligation induces Th9 cells under iTreg-polarizing Mechanistically, we found that GITR signalling controls chro- conditions. Naive CD4 þ T cells were FACS sorted from WT B6 (a,b) and matin remodelling at the Foxp3 and Il9 loci via regulation of OT-II (c,d) Foxp3gfp reporter mice and activated under iTreg-polarizing histone acetylation and deacetylation status, and consequently the conditions. Anti-GITR agonistic antibody (DTA-1, 10 mgmlÀ 1) or His-GITR suppression of iTregs and induction of Th9 cells. Ligand (200 ng ml À 1, along with anti-His mAb) were used to ligate the GITR receptor on activated CD4 þ T cells. Three days later, cells were harvested and analysed for Foxp3 and cytokines expression by flow Results cytometry. (a,c) Colour FACS plots depicting Foxp3- and IL-9-producing GITR promotes Th9 cells under iTreg-inducing conditions.To cells. Numbers in the quadrants indicate the percentage of cells. Data are determine the role of GITR signalling in regulation of fate-deci- representative of five independent experiments. (b,d) DTA-1 titrations and sions of CD4 þ T-helper cells, we FACS sorted naive CD4 þ their impact on induction of Foxp3 þ Tregs and Th9 cells, and graphs depict Foxp3 À T cells from Foxp3gfp reporter mice and activated them the percentage of cells that express Foxp3 (left) or IL-9 (right). Data are in vitro with anti-CD3/APC in the presence of transforming pooled from five independent experiments with triplicate cultures. growth factor (TGF)-b and IL-2 (iTreg-inducing conditions). As (e) Expression of other cytokines, as indicated in the x axis, by WT naive shown in Fig. 1a, a substantial fraction of naive CD4 þ T cells CD4 þ T cells polarized under iTreg conditions for 3 days with or without were converted to Foxp3 þ T cells 3 days after the culture GITR ligation. Data are representative of three independent experiments. (B65%). In these cultures, GITR was highly expressed by CD4 þ T cells as early as 24 h after activation and maintained for up to 5 2 NATURE COMMUNICATIONS | 6:8266 | DOI: 10.1038/ncomms9266 | www.nature.com/naturecommunications & 2015 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms9266 ARTICLE days (Supplementary Fig. 1). Interestingly, ligation of GITR on Foxp3 promoter, CNS1, and CNS2 regions, histone 3 (H3), as well the activated CD4 þ T cells, using either an agonist mAb DTA-1 as H3K27 and H3K9 were hyperacetylated in CD4 þ T cells or a His-tagged GITR ligand fusion protein (followed by cross- activated under iTreg conditions, and this histone hyper- linking with anti-His mAb), markedly inhibited the induction of acetylation was markedly inhibited by GITR stimulation, Foxp3 þ T cells (down to B4%). Unexpectedly, GITR ligation leading to hypoacetylation at H3 and H3K27 sites (Fig. 2c). resulted in strong induction of Th9 cells under such iTreg The acetylation status of H4 did not change with or without GITR polarizing conditions, and B30% of the activated CD4 þ T cells ligation. The methylation status of H3, including H3K9 and became IL-9 þ Th9 cells (Fig. 1a,b). In another set of experi- H3K27, did not show any differences in the Foxp3 locus in GITR ments, we activated the T-cell receptor transgenic OT-II cells with stimulated CD4 þ T cells activated under iTreg conditions their cognate antigen OVA presented by autologous APCs, and in (Fig. 2c, right panels). this setting, addition of TGF-b and IL-2 in the cultures induced The changes at the Il9 locus are mirror opposite of those at the 460% of the OT-II cells to become Foxp3 þ iTregs 3 days later Foxp3 locus following GITR stimulation (Fig.
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