The Cyclin-Dependent Kinase 8 (CDK8) Inhibitor DCA Promotes a Tolerogenic Chemical Immunophenotype in CD4⁺ T Cells via a Novel CDK8-GATA3-FOXP3 Pathway

REFERENCES

• Zigmond E, Varol C, Farache J, Elmaliah E, Satpathy AT, Friedlander G, Mack M, Shpigel N, Boneca IG, Murphy KM, Shakhar G, Halpern Z, Jung S. 2012. Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37:1076–1090. https://doi.org/10.1016/j.immuni.2012.08.026.
   PubMed Web of Science ®Google Scholar
• Zigmond E, Jung S. 2013. Intestinal macrophages: well educated exceptions from the rule. Trends Immunol 34:162–168. https://doi.org/10.1016/j.it.2013.02.001.
   PubMed Web of Science ®Google Scholar
• Josefowicz SZ, Lu L-F, Rudensky AY. 2012. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564. https://doi.org/10.1146/annurev.immunol.25.022106.141623.
   PubMed Web of Science ®Google Scholar
• Cretney E, Kallies A, Nutt SL. 2013. Differentiation and function of Foxp3(+) effector regulatory T cells. Trends Immunol 34:74–80. https://doi.org/10.1016/j.it.2012.11.002.
   PubMed Web of Science ®Google Scholar
• O’Shea JJ, Paul WE. 2010. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327:1098–1102. https://doi.org/10.1126/science.1178334.
   PubMed Web of Science ®Google Scholar
• Batlle E, Massagué J. 2019. Transforming growth factor-β signaling in immunity and cancer. Immunity 50:924–940. https://doi.org/10.1016/j.immuni.2019.03.024.
   PubMed Web of Science ®Google Scholar
• Khor B, Gagnon JD, Goel G, Roche MI, Conway KL, Tran K, Aldrich LN, Sundberg TB, Paterson AM, Mordecai S, Dombkowski D, Schirmer M, Tan PH, Bhan AK, Roychoudhuri R, Restifo NP, O’Shea JJ, Medoff BD, Shamji AF, Schreiber SL, Sharpe AH, Shaw SY, Xavier RJ. 2015. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. Elife 4:e05920. https://doi.org/10.7554/eLife.05920.
   Google Scholar
• Sundberg TB, Choi HG, Song J-H, Russell CN, Hussain MM, Graham DB, Khor B, Gagnon J, O’Connell DJ, Narayan K, Dancik V, Perez JR, Reinecker H-C, Gray NS, Schreiber SL, Xavier RJ, Shamji AF. 2014. Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells. Proc Natl Acad Sci U S A 111:12468–12473. https://doi.org/10.1073/pnas.1412308111.
   PubMed Web of Science ®Google Scholar
• Aoki S, Watanabe Y, Tanabe D, Arai M, Suna H, Miyamoto K, Tsujibo H, Tsujikawa K, Yamamoto H, Kobayashi M. 2007. Structure-activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids. Bioorg Med Chem 15:6758–6762. https://doi.org/10.1016/j.bmc.2007.08.017.
   PubMed Web of Science ®Google Scholar
• Cee VJ, Chen DY-K, Lee MR, Nicolaou KC. 2009. Cortistatin A is a high-affinity ligand of protein kinases ROCK, CDK8, and CDK11. Angew Chem Int Ed Engl 48:8952–8957. https://doi.org/10.1002/anie.200904778.
   PubMed Web of Science ®Google Scholar
• Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A, Poss ZC, Da Silva DH, Caruso BT, Arefolov A, Fadeyi O, Christie AL, Du K, Banka D, Schneider EV, Jestel A, Zou G, Si C, Ebmeier CC, Bronson RT, Krivtsov AV, Myers AG, Kohl NE, Kung AL, Armstrong SA, Lemieux ME, Taatjes DJ, Shair MD. 2015. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 526:273–276. https://doi.org/10.1038/nature14904.
   PubMed Web of Science ®Google Scholar
• Shi J, Manolikakes G, Yeh C-H, Guerrero CA, Shenvi RA, Shigehisa H, Baran PS. 2011. Scalable synthesis of cortistatin A and related structures. J Am Chem Soc 133:8014–8027. https://doi.org/10.1021/ja202103e.
   PubMed Web of Science ®Google Scholar
• Chen M, Li J, Liang J, Thompson ZS, Kathrein K, Broude EV, Roninson IB. 2019. Systemic toxicity reported for CDK8/19 inhibitors CCT251921 and MSC2530818 is not due to target inhibition. Cells 8:1413. https://doi.org/10.3390/cells8111413.
   PubMed Web of Science ®Google Scholar
• Conaway RC, Conaway JW. 2011. Function and regulation of the Mediator complex. Curr Opin Genet Dev 21:225–230. https://doi.org/10.1016/j.gde.2011.01.013.
   PubMed Web of Science ®Google Scholar
• Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CAS, Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC. 2004. A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology. Mol Cell 14:685–691. https://doi.org/10.1016/j.molcel.2004.05.006.
   PubMed Web of Science ®Google Scholar
• Malumbres M. 2014. Cyclin-dependent kinases. Genome Biol 15:122. https://doi.org/10.1186/gb4184.
   PubMed Web of Science ®Google Scholar
• Galbraith MD, Andrysik Z, Pandey A, Hoh M, Bonner EA, Hill AA, Sullivan KD, Espinosa JM. 2017. CDK8 kinase activity promotes glycolysis. Cell Rep 21:1495–1506. https://doi.org/10.1016/j.celrep.2017.10.058.
   PubMed Web of Science ®Google Scholar
• Fant CB, Taatjes DJ. 2019. Regulatory functions of the Mediator kinases CDK8 and CDK19. Transcription 10:76–90. https://doi.org/10.1080/21541264.2018.1556915.
   PubMed Web of Science ®Google Scholar
• Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, Dölken L, Strobl B, Müller M, Taatjes DJ, Kovarik P. 2013. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity 38:250–262. https://doi.org/10.1016/j.immuni.2012.10.017.
   PubMed Web of Science ®Google Scholar
• Johannessen L, Sundberg TB, O’Connell DJ, Kolde R, Berstler J, Billings KJ, Khor B, Seashore-Ludlow B, Fassl A, Russell CN, Latorre IJ, Jiang B, Graham DB, Perez JR, Sicinski P, Phillips AJ, Schreiber SL, Gray NS, Shamji AF, Xavier RJ. 2017. Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells. Nat Chem Biol 13:1102–1108. https://doi.org/10.1038/nchembio.2458.
   PubMed Web of Science ®Google Scholar
• Akamatsu M, Mikami N, Ohkura N, Kawakami R, Kitagawa Y, Sugimoto A, Hirota K, Nakamura N, Ujihara S, Kurosaki T, Hamaguchi H, Harada H, Xia G, Morita Y, Aramori I, Narumiya S, Sakaguchi S. 2019. Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19. Sci Immunol 4:eaaw2707. https://doi.org/10.1126/sciimmunol.aaw2707.
   Google Scholar
• Fryer CJ, White JB, Jones KA. 2004. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 16:509–520. https://doi.org/10.1016/j.molcel.2004.10.014.
   PubMed Web of Science ®Google Scholar
• Witalisz-Siepracka A, Gotthardt D, Prchal-Murphy M, Didara Z, Menzl I, Prinz D, Edlinger L, Putz EM, Sexl V. 2018. NK cell-specific CDK8 deletion enhances antitumor responses. Cancer Immunol Res 6:458–466. https://doi.org/10.1158/2326-6066.CIR-17-0183.
   PubMed Web of Science ®Google Scholar
• Putz EM, Gotthardt D, Hoermann G, Csiszar A, Wirth S, Berger A, Straka E, Rigler D, Wallner B, Jamieson AM, Pickl WF, Zebedin-Brandl EM, Müller M, Decker T, Sexl V. 2013. CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep 4:437–444. https://doi.org/10.1016/j.celrep.2013.07.012.
   PubMed Web of Science ®Google Scholar
• Guo Z, Wang G, Lv Y, Wan YY, Zheng J. 2019. Inhibition of Cdk8/Cdk19 activity promotes Treg cell differentiation and suppresses autoimmune diseases. Front Immunol 10:01988. https://doi.org/10.3389/fimmu.2019.01988.
   PubMed Web of Science ®Google Scholar
• Martinez-Fabregas J, Wang L, Pohler E, Cozzani A, Wilmes S, Kazemian M, Mitra S, Moraga I. 2020. CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci. Cell Rep 33:108545. https://doi.org/10.1016/j.celrep.2020.108545.
   PubMed Web of Science ®Google Scholar
• Coombes JL, Siddiqui KRR, Arancibia-Cárcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F. 2007. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204:1757–1764. https://doi.org/10.1084/jem.20070590.
   PubMed Web of Science ®Google Scholar
• Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. 2007. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260. https://doi.org/10.1126/science.1145697.
   PubMed Web of Science ®Google Scholar
• Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y. 2007. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204:1775–1785. https://doi.org/10.1084/jem.20070602.
   PubMed Web of Science ®Google Scholar
• Haxhinasto S, Mathis D, Benoist C. 2008. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med 205:565–574. https://doi.org/10.1084/jem.20071477.
   PubMed Web of Science ®Google Scholar
• Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N, Chambon P, Belkaid Y, Mathis D, Benoist C. 2008. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. Immunity 29:758–770. https://doi.org/10.1016/j.immuni.2008.09.018.
   PubMed Web of Science ®Google Scholar
• Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O’Connor E, Shokat KM, Fisher AG, Merkenschlager M. 2008. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 105:7797–7802. https://doi.org/10.1073/pnas.0800928105.
   PubMed Web of Science ®Google Scholar
• Hall JA, Cannons JL, Grainger JR, Santos Dos LM, Hand TW, Naik S, Wohlfert EA, Chou DB, Oldenhove G, Robinson M, Grigg ME, Kastenmayer R, Schwartzberg PL, Belkaid Y. 2011. Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity 34:435–447. https://doi.org/10.1016/j.immuni.2011.03.003.
   PubMed Web of Science ®Google Scholar
• Herman AE, Freeman GJ, Mathis D, Benoist C. 2004. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 199:1479–1489. https://doi.org/10.1084/jem.20040179.
   PubMed Web of Science ®Google Scholar
• Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. 2004. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199:1467–1477. https://doi.org/10.1084/jem.20040180.
   PubMed Web of Science ®Google Scholar
• Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL. 1993. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol 5:1461–1471. https://doi.org/10.1093/intimm/5.11.1461.
   PubMed Web of Science ®Google Scholar
• Valatas V, He J, Rivollier A, Kolios G, Kitamura K, Kelsall BL. 2013. Host-dependent control of early regulatory and effector T-cell differentiation underlies the genetic susceptibility of RAG2-deficient mouse strains to transfer colitis. Mucosal Immunol 6:601–611. https://doi.org/10.1038/mi.2012.102.
   PubMed Web of Science ®Google Scholar
• Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. 2013. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–573. https://doi.org/10.1126/science.1241165.
   PubMed Web of Science ®Google Scholar
• Kovarik P, Mangold M, Ramsauer K, Heidari H, Steinborn R, Zotter A, Levy DE, Müller M, Decker T. 2001. Specificity of signaling by STAT1 depends on SH2 and C-terminal domains that regulate Ser727 phosphorylation, differentially affecting specific target gene expression. EMBO J 20:91–100. https://doi.org/10.1093/emboj/20.1.91.
   PubMed Web of Science ®Google Scholar
• Shen Y, Schlessinger K, Zhu X, Meffre E, Quimby F, Levy DE, Darnell JE. 2004. Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation. Mol Cell Biol 24:407–419. https://doi.org/10.1128/MCB.24.1.407-419.2004.
   PubMed Web of Science ®Google Scholar
• Varinou L, Ramsauer K, Karaghiosoff M, Kolbe T, Pfeffer K, Müller M, Decker T. 2003. Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity. Immunity 19:793–802. https://doi.org/10.1016/S1074-7613(03)00322-4.
   PubMed Web of Science ®Google Scholar
• Wen Z, Zhong Z, Darnell JE. 1995. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241–250. https://doi.org/10.1016/0092-8674(95)90311-9.
   PubMed Web of Science ®Google Scholar
• Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy TL, Murphy KM. 2002. T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nat Immunol 3:549–557. https://doi.org/10.1038/ni794.
   PubMed Web of Science ®Google Scholar
• Lighvani AA, Frucht DM, Jankovic D, Yamane H, Aliberti J, Hissong BD, Nguyen BV, Gadina M, Sher A, Paul WE, O’Shea JJ. 2001. T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci U S A 98:15137–15142. https://doi.org/10.1073/pnas.261570598.
   PubMed Web of Science ®Google Scholar
• Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C. 2007. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363. https://doi.org/10.1074/jbc.C600321200.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Josefowicz SZ, Kas A, Chu T-T, Gavin MA, Rudensky AY. 2007. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445:936–940. https://doi.org/10.1038/nature05563.
   PubMed Web of Science ®Google Scholar
• Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, Levine SS, Fraenkel E, Boehmer von H, Young RA. 2007. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445:931–935. https://doi.org/10.1038/nature05478.
   PubMed Web of Science ®Google Scholar
• Fu W, Ergun A, Lu T, Hill JA, Haxhinasto S, Fassett MS, Gazit R, Adoro S, Glimcher L, Chan S, Kastner P, Rossi D, Collins JJ, Mathis D, Benoist C. 2012. A multiply redundant genetic switch “locks in” the transcriptional signature of regulatory T cells. Nat Immunol 13:972–980. https://doi.org/10.1038/ni.2420.
   PubMed Web of Science ®Google Scholar
• Hori S, Nomura T, Sakaguchi S. 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061. https://doi.org/10.1126/science.1079490.
   PubMed Web of Science ®Google Scholar
• Zheng W, Flavell RA. 1997. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587–596. https://doi.org/10.1016/S0092-8674(00)80240-8.
   PubMed Web of Science ®Google Scholar
• Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, Hall JA, Yagi R, Naik S, Bhairavabhotla R, Paul WE, Bosselut R, Wei G, Zhao K, Oukka M, Zhu J, Belkaid Y. 2011. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J Clin Invest 121:4503–4515. https://doi.org/10.1172/JCI57456.
   PubMed Web of Science ®Google Scholar
• Wei G, Abraham BJ, Yagi R, Jothi R, Cui K, Sharma S, Narlikar L, Northrup DL, Tang Q, Paul WE, Zhu J, Zhao K. 2011. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity 35:299–311. https://doi.org/10.1016/j.immuni.2011.08.007.
   PubMed Web of Science ®Google Scholar
• Rudra D, deRoos P, Chaudhry A, Niec RE, Arvey A, Samstein RM, Leslie C, Shaffer SA, Goodlett DR, Rudensky AY. 2012. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 13:1010–1019. https://doi.org/10.1038/ni.2402.
   PubMed Web of Science ®Google Scholar
• Fang TC, Yashiro-Ohtani Y, Del Bianco C, Knoblock DM, Blacklow SC, Pear WS. 2007. Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27:100–110. https://doi.org/10.1016/j.immuni.2007.04.018.
   PubMed Web of Science ®Google Scholar
• Mota C, Nunes-Silva V, Pires AR, Matoso P, Victorino RMM, Sousa AE, Caramalho I. 2014. Delta-like 1-mediated Notch signaling enhances the in vitro conversion of human memory CD4 T cells into FOXP3-expressing regulatory T cells. J Immunol 193:5854–5862. https://doi.org/10.4049/jimmunol.1400198.
   PubMed Web of Science ®Google Scholar
• Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, Xia J, Tan TG, Sefik E, Yajnik V, Sharpe AH, Quintana FJ, Mathis D, Benoist C, Hafler DA, Kuchroo VK. 2014. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569–581. https://doi.org/10.1016/j.immuni.2014.02.012.
   PubMed Web of Science ®Google Scholar
• Yevshin I, Sharipov R, Kolmykov S, Kondrakhin Y, Kolpakov F. 2019. GTRD: a database on gene transcription regulation—2019 update. Nucleic Acids Res 47:D100–D105. https://doi.org/10.1093/nar/gky1128.
   PubMed Web of Science ®Google Scholar
• Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. 2005. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550. https://doi.org/10.1073/pnas.0506580102.
   PubMed Web of Science ®Google Scholar
• Mootha VK, Lindgren CM, Eriksson K-F, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. 2003. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273. https://doi.org/10.1038/ng1180.
   PubMed Web of Science ®Google Scholar
• Kitagawa M. 2016. Notch signalling in the nucleus: roles of Mastermind-like (MAML) transcriptional coactivators. J Biochem 159:287–294. https://doi.org/10.1093/jb/mvv123.
   PubMed Web of Science ®Google Scholar
• Wang Y, Su MA, Wan YY. 2011. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35:337–348. https://doi.org/10.1016/j.immuni.2011.08.012.
   PubMed Web of Science ®Google Scholar
• Mantel P-Y, Kuipers H, Boyman O, Rhyner C, Ouaked N, Rückert B, Karagiannidis C, Lambrecht BN, Hendriks RW, Crameri R, Akdis CA, Blaser K, Schmidt-Weber CB. 2007. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol 5:e329. https://doi.org/10.1371/journal.pbio.0050329.
   PubMed Web of Science ®Google Scholar
• Wei J, Duramad O, Perng OA, Reiner SL, Liu Y-J, Qin FX-F. 2007. Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 104:18169–18174. https://doi.org/10.1073/pnas.0703642104.
   PubMed Web of Science ®Google Scholar
• Hadjur S, Bruno L, Hertweck A, Cobb BS, Taylor B, Fisher AG, Merkenschlager M. 2009. IL4 blockade of inducible regulatory T cell differentiation: the role of Th2 cells, Gata3 and PU.1. Immunol Lett 122:37–43. https://doi.org/10.1016/j.imlet.2008.11.001.
   PubMed Web of Science ®Google Scholar
• Ouyang W, Ranganath SH, Weindel K, Bhattacharya D, Murphy TL, Sha WC, Murphy KM. 1998. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 9:745–755. https://doi.org/10.1016/s1074-7613(00)80671-8.
   PubMed Web of Science ®Google Scholar
• Yagi R, Junttila IS, Wei G, Urban JF, Jr, Zhao K, Paul WE, Zhu J. 2010. The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-γ. Immunity 32:507–517. https://doi.org/10.1016/j.immuni.2010.04.004.
   PubMed Web of Science ®Google Scholar
• van Hamburg JP, de Bruijn MJW, de Almeida CR, van Zwam M, van Meurs M, de Haas E, Boon L, Samsom JN, Hendriks RW. 2008. Enforced expression of GATA3 allows differentiation of IL-17-producing cells, but constrains Th17-mediated pathology. Eur J Immunol 38:2573–2586. https://doi.org/10.1002/eji.200737840.
   PubMed Web of Science ®Google Scholar
• Fiorentino DF, Bond MW, Mosmann TR. 1989. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170:2081–2095. https://doi.org/10.1084/jem.170.6.2081.
   PubMed Web of Science ®Google Scholar
• Feng Y, Arvey A, Chinen T, van der Veeken J, Gasteiger G, Rudensky AY. 2014. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158:749–763. https://doi.org/10.1016/j.cell.2014.07.031.
   PubMed Web of Science ®Google Scholar
• Li X, Liang Y, LeBlanc M, Benner C, Zheng Y. 2014. Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 158:734–748. https://doi.org/10.1016/j.cell.2014.07.030.
   PubMed Web of Science ®Google Scholar
• Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. 2016. Induced regulatory T cells: their development, stability, and applications. Trends Immunol 37:803–811. https://doi.org/10.1016/j.it.2016.08.012.
   PubMed Web of Science ®Google Scholar
• Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N, Huehn J, Fehling HJ, Sparwasser T, Nakai K, Sakaguchi S. 2012. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37:785–799. https://doi.org/10.1016/j.immuni.2012.09.010.
   PubMed Web of Science ®Google Scholar
• Menzl I, Witalisz-Siepracka A, Sexl V. 2019. CDK8—novel therapeutic opportunities. Pharmaceuticals 12:92–12. https://doi.org/10.3390/ph12020092.
   Web of Science ®Google Scholar
• Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, Freed E, Ligon AH, Vena N, Ogino S, Chheda MG, Tamayo P, Finn S, Shrestha Y, Boehm JS, Jain S, Bojarski E, Mermel C, Barretina J, Chan JA, Baselga J, Tabernero J, Root DE, Fuchs CS, Loda M, Shivdasani RA, Meyerson M, Hahn WC. 2008. CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature 455:547–551. https://doi.org/10.1038/nature07179.
   PubMed Web of Science ®Google Scholar
• Clarke PA, Ortiz-Ruiz M-J, TePoele R, Adeniji-Popoola O, Box G, Court W, Czasch S, Bawab El S, Esdar C, Ewan K, Gowan S, De Haven Brandon A, Hewitt P, Hobbs SM, Kaufmann W, Mallinger A, Raynaud F, Roe T, Rohdich F, Schiemann K, Simon S, Schneider R, Valenti M, Weigt S, Blagg J, Blaukat A, Dale TC, Eccles SA, Hecht S, Urbahns K, Workman P, Wienke D. 2016. Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. Elife 5:e20722. https://doi.org/10.7554/eLife.20722.
   PubMed Web of Science ®Google Scholar
• Shi J, Shigehisa H, Guerrero CA, Shenvi RA, Li C-C, Baran PS. 2009. Stereodivergent synthesis of 17-alpha and 17-beta-alpharyl steroids: application and biological evaluation of D-ring cortistatin analogues. Angew Chem Int Ed Engl 48:4328–4331. https://doi.org/10.1002/anie.200901116.
   PubMed Web of Science ®Google Scholar
• Cousins DJ, Lee TH, Staynov DZ. 2002. Cytokine coexpression during human Th1/Th2 cell differentiation: direct evidence for coordinated expression of Th2 cytokines. J Immunol 169:2498–2506. https://doi.org/10.4049/jimmunol.169.5.2498.
   PubMed Web of Science ®Google Scholar
• Roth TL, Puig-Saus C, Yu R, Shifrut E, Carnevale J, Li PJ, Hiatt J, Saco J, Krystofinski P, Li H, Tobin V, Nguyen DN, Lee MR, Putnam AL, Ferris AL, Chen JW, Schickel J-N, Pellerin L, Carmody D, Alkorta-Aranburu G, Del Gaudio D, Matsumoto H, Morell M, Mao Y, Cho M, Quadros RM, Gurumurthy CB, Smith B, Haugwitz M, Hughes SH, Weissman JS, Schumann K, Esensten JH, May AP, Ashworth A, Kupfer GM, Greeley SAW, Bacchetta R, Meffre E, Roncarolo M-G, Romberg N, Herold KC, Ribas A, Leonetti MD, Marson A. 2018. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature 559:405–409. https://doi.org/10.1038/s41586-018-0326-5.
   PubMed Web of Science ®Google Scholar
• Aksoy P, Aksoy BA, Czech E, Hammerbacher J. 2019. Viable and efficient electroporation-based genetic manipulation of unstimulated human T cells. biorxiv https://doi.org/10.1101/466243.
   Google Scholar
• Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich J-M, Jack RS, Wunderlich FT, Brüning JC, Muller W, Rudensky AY. 2011. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34:566–578. https://doi.org/10.1016/j.immuni.2011.03.018.
   PubMed Web of Science ®Google Scholar
• Collison LW, Vignali DAA. 2011. In vitro Treg suppression assays. Methods Mol Biol 707:21–37. https://doi.org/10.1007/978-1-61737-979-6_2.
   PubMedGoogle Scholar
• De Jong YP, Comiskey M, Kalled SL, Mizoguchi E, Flavell RA, Bhan AK, Terhorst C. 2000. Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration. Gastroenterology 119:715–723. https://doi.org/10.1053/gast.2000.16485.
   PubMed Web of Science ®Google Scholar
• Schneider CA, Rasband WS, Eliceiri KW. 2012. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675. https://doi.org/10.1038/nmeth.2089.
   PubMed Web of Science ®Google Scholar
• Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR. 2013. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21. https://doi.org/10.1093/bioinformatics/bts635.
   PubMed Web of Science ®Google Scholar
• Anders S, Pyl PT, Huber W. 2015. HTSeq–—a Python framework to work with high-throughput sequencing data. Bioinformatics 31:166–169. https://doi.org/10.1093/bioinformatics/btu638.
   PubMed Web of Science ®Google Scholar
• Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, 1000 Genome Project Data Processing Subgroup. 2009. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25:2078–2079. https://doi.org/10.1093/bioinformatics/btp352.
   PubMed Web of Science ®Google Scholar
• Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. 2015. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47. https://doi.org/10.1093/nar/gkv007.
   PubMed Web of Science ®Google Scholar
• Wickham H, Averick M, Bryan J, Chang W, McGowan L, François R, Grolemund G, Hayes A, Henry L, Hester J, Kuhn M, Pedersen T, Miller E, Bache S, Müller K, Ooms J, Robinson D, Seidel D, Spinu V, Takahashi K, Vaughan D, Wilke C, Woo K, Yutani H. 2019. Welcome to the Tidyverse. J Open Source Softw 4:1686. https://doi.org/10.21105/joss.01686.
   Google Scholar
• Durinck S, Moreau Y, Kasprzyk A, Davis S, De Moor B, Brazma A, Huber W. 2005. BioMart and Bioconductor: a powerful link between biological databases and microarray data analysis. Bioinformatics 21:3439–3440. https://doi.org/10.1093/bioinformatics/bti525.
   PubMed Web of Science ®Google Scholar
• McCarthy DJ, Chen Y, Smyth GK. 2012. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res 40:4288–4297. https://doi.org/10.1093/nar/gks042.
   PubMed Web of Science ®Google Scholar
• Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. 2015. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 1:417–425. https://doi.org/10.1016/j.cels.2015.12.004.
   PubMed Web of Science ®Google Scholar
• Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-Toh K, Lander ES, Kellis M. 2005. Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434:338–345. https://doi.org/10.1038/nature03441.
   PubMed Web of Science ®Google Scholar
• Seumois G, Chavez L, Gerasimova A, Lienhard M, Omran N, Kalinke L, Vedanayagam M, Ganesan APV, Chawla A, Djukanović R, Ansel KM, Peters B, Rao A, Vijayanand P. 2014. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility. Nat Immunol 15:777–788. https://doi.org/10.1038/ni.2937.
   PubMed Web of Science ®Google Scholar