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Jimmunol.1302943.Full.Pdf Published April 23, 2014, doi:10.4049/jimmunol.1302943 The Journal of Immunology Ezh2 Regulates Transcriptional and Posttranslational Expression of T-bet and Promotes Th1 Cell Responses Mediating Aplastic Anemia in Mice Qing Tong,*,† Shan He,†,‡ Fang Xie,† Kazuhiro Mochizuki,† Yongnian Liu,†,‡ Izumi Mochizuki,† Lijun Meng,‡,x Hongxing Sun,x Yanyun Zhang,x Yajun Guo,* Elizabeth Hexner,{ and Yi Zhang†,‡ Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome. IFN-g–producing Th1 CD4+ T cells mediate the immune destruction of hematopoietic cells, and they are central to the pathogenesis. However, the molecular events that control the development of BM-destructive Th1 cells remain largely unknown. Ezh2 is a chromatin-modifying enzyme that regulates multiple cellular processes primarily by silencing gene expression. We recently reported that Ezh2 is crucial for inflammatory T cell responses after allogeneic BM transplantation. To elucidate whether Ezh2 mediates pathogenic Th1 responses in AA and the mechanism of Ezh2 action in regulating Th1 cells, we studied the effects of Ezh2 inhibition in CD4+ T cells using a mouse model of human AA. Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM- destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure. Ezh2 inhibition resulted in significant decrease in the expression of Tbx21 and Stat4, which encode transcription factors T-bet and STAT4, respectively. Introduction of T-bet but not STAT4 into Ezh2-deficient T cells fully rescued their differentiation into Th1 cells mediating AA. Ezh2 bound to the Tbx21 promoter in Th1 cells and directly activated Tbx21 transcription. Unexpectedly, Ezh2 was also required to prevent proteasome-mediated degradation of T-bet protein in Th1 cells. Our results demonstrate that Ezh2 promotes the generation of BM-destructive Th1 cells through a mechanism of transcriptional and posttranscriptional regulation of T-bet. These results also highlight the therapeutic potential of Ezh2 inhibition in reducing AA and other autoimmune diseases. The Journal of Immunology, 2014, 192: 000–000. cquired aplastic anemia (AA) in humans is a fatal dis- patients with AA have a potent ability to lyse autologous CD34+ order characterized by bone marrow (BM) hypoplasia hematopoietic cells and inhibit formation of hematopoietic cell and blood pancytopenia (1, 2). Clinical studies indicate colonies (3). Accumulating evidence indicates that CD4+ Th1 by guest on September 30, 2021. Copyright 2014 Pageant Media Ltd. A that in most cases, AA is a disease caused by immune-mediated cells, which are characterized by production of high levels of destruction of hematopoietic stem cells and hematopoietic pro- IFN-g, play important roles in mediating bone marrow failure genitor cells (1, 2). A role for T cells in AA was first suggested by (BMF) (2, 4–8). IFN-g displays potent effects on suppressing their inhibition of hematopoietic cell colony formation in cultures hematopoiesis in vitro (2, 3). Immunosuppressive therapy and in vitro (2). Furthermore, CD4+ T cell clones isolated from the allogeneic BM transplantation (BMT) have significantly im- proved the survival of severe AA. However, relapse still occurs ∼ *International Joint Cancer Institute, Second Military Medical University, Shanghai in 35% of patients with AA when immunosuppressive therapy 200433, China; †Department of Internal Medicine, University of Michigan Medical is withdrawn (1, 2, 9). Furthermore, graft-versus-host disease ‡ School, Ann Arbor, MI, 48109; Department of Microbiology and Immunology, Fels remains a major barrier to the success of allogeneic BMT (10, http://classic.jimmunol.org Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA 19140; xInstitute of Health Sciences, Shanghai Institutes for Biological Sciences 11). Novel approaches are needed to improve the outcome of Chinese Academy of Sciences, Shanghai 200433, China; and {Department of Med- treatments for AA. icine and Abramson Cancer Center, University of Pennsylvania Perelman School of The transcription factor T-bet (encoded by Tbx21) is crucial for Medicine, Philadelphia, PA 19104 Th1 cell differentiation (12–15). T-bet is induced by TCR sig- Received for publication November 1, 2013. Accepted for publication March 19, 2014. naling and strongly upregulated by activation of the STAT1 tran- This work was supported by the American Cancer Society (to Y.Z.), the U.S. De- scription factor (16). T-bet binds to several enhancers and promoter Downloaded from partment of Defense (to Y.Z.) and National Institutes of Health Grant R01-CA- of the Ifng genes, activating its transcription (12, 16). T-bet also 172106-01 (to Y.Z.). promotes expression of the IL-12 receptor b2 chain (IL12Rb2), Q. T. and Y. Z. conceived and designed the project; Q.T., S.H., F.X., K.M., Y.L., I.M., resulting in greater IL-12 responsiveness and further elevated L.M., H.S., Y.Z., Y.G., E.H., and Y.Z. performed experiments and analyzed the data; Q. T. and Y. Z. wrote the manuscript. production of IFN-g (16). In addition, T-bet prevents Th2 differ- entiation by inhibiting Gata3 (16). T-bet is upregulated in pe- Address correspondence and reprint requests to Dr. Yi Zhang, Department of Micro- biology and Immunology, Fels Institute for Cancer Research and Molecular Biology, ripheral blood T cells from patients with AA, and it is a useful Temple University, Philadelphia, PA 19140. E-mail address: [email protected] marker for predicting the responsiveness of patients to immuno- The online version of this article contains supplemental material. suppressive therapy (17). Furthermore, experimental studies sug- Abbreviations used in this article: AA, aplastic anemia; BM, bone marrow; BMF, gested that T cells lacking T-bet were defective in induction of AA bone marrow failure; BMT, bone marrow transplantation; ChIP, chromatin immuno- in mice (6). These observations suggest that T-bet can be an at- precipitation; LN, lymph node; TSS, transcription start site. tractive target for modulating Th1 cell–mediated AA. However, Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 transcription factors are difficult drug targets (18). Thus, identifying www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302943 2 EPIGENETIC REGULATION OF Th1 CELLS MEDIATING APLASTIC ANEMIA the molecular pathways that control T-bet expression in Th1 cells Cell culture can lead to new strategies to control AA. Splenic and LN CD4+ T cells were prepared by MACS purification with Ezh2 is a histone methyltransferase that specifically catalyzes CD4 microbeads (Miltenyi Biotec), and the purity was usually 90–95%. trimethylation of histone H3 at lysine 27 (H3K27me3) (19). Ezh2 Th1-skewing culture conditions were set up as previously described (34– lo + forms polycomb repressive complex 2 together with other polycomb 36). In brief, CD44 CD4 naive T cells (Tn) were cultured in the presence group proteins Suz12 and Eed (19), which is crucial for maintaining of anti-CD3 (2 mg/ml; BioLegend) and anti-CD28 (2 mg/ml; BioLegend) Abs together with recombinant human IL-2 (10 ng/ml; R&D Systems), the cellular memory and transcriptional patterns primarily through recombinant mouse IL-12 (5 ng/ml; R&D Systems) and BM-derived a mechanism of silencing genes (20, 21). Several studies indicate an dendritic cells at a ratio of 1:16. Cultured T cells were restimulated with important role of Ezh2 and H3K27me3 in multiple lineages of ef- anti-CD3 Ab (1 mg/ml; BioLegend) 5 h before intracellular staining. fector T cells (22–25). Genome-wide mapping analysis revealed that Retroviral construction and T cell infection repressive H3K27me3 marked genes associated with differentiation and maintenance of effector and memory T cells (26, 27). Recently, The MigR1 retroviral vector system was described previously (35, 37). MigR1 vector was provided by Warren Pear (University of Pennsylvania), we demonstrated new and essential roles of Ezh2 in regulating in- and MigR1 vector encoding T-bet or STAT4 was provided by Steve Reiner flammatory T cell responses in mice after allogeneic BMT (28). (Columbia University, New York, NY) and Takashi Usui (Kyoto Univer- Loss of Ezh2 led to impaired production of alloreactive T cells that sity, Kyoto, Japan). MigR1 virus was produced as described (38). For + induce damage to epithelial organs (28). However, whether Ezh2 retroviral infection, CD4 T cells were prestimulated with anti-CD3 and mediates pathogenic Th1 responses in AA and the mechanism of anti-CD28 Abs for 24 h, and then the retrovirus supernatant was added in the presence of 8 mg/ml polybrene (Sigma). Cells were spinoculated at Ezh2 action in regulating Th1 cells remain unknown. 3000 rpm, 32˚C for 3 h. The same retroviral infection procedure was re- Mouse models of human AA have been established successfully peated 24 h later. (4, 29). Transfer of parent lymph node (LN) cells into hap- Western blot analysis loidentical daughter recipients caused BM hypoplasia and blood pancytopenia, typical features of clinical AA. These AA mouse Western blot was performed as described (28). Cell lysates were examined models have proved to be a unique approach studying patho- with routine Western blotting. The blots were incubated with anti-Ezh2 (612667; BD Biosciences), Stat4 (sc-486; Santa Cruz Biotechnology), physiology of immune cell-mediated BMF (4, 6, 30, 31). In this T-bet (sc-21749; Santa Cruz Biotechnology), GATA-3 (558686; BD Bio- report, we exploited the functional impact of Ezh2 on Th1 cell sciences), or actin (ab3280; Abcam) Abs, and subsequently incubated with responses in vitro and in vivo. Using genetic approaches and a HRP-conjugated anti-rabbit or mouse IgG (Vector Laboratories) in TBS mouse model of human BMF, we identified a novel and critical containing 5% nonfat dry milk and 0.05% Tween 20. The final reaction was developed with a chemiluminescent system (Pierce). role of Ezh2 in regulating Th1 cells mediating AA.
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