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Junb and GATA3 Transcription Factors Cytokine Expression Through Regulating CARMA1 Controls Th2 Cell-Specific

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CARMA1 Controls Th2 Cell-Specific Cytokine Expression through Regulating JunB and GATA3 Transcription Factors This information is current as Marzenna Blonska, Donghyun Joo, Patrick A. of September 27, 2021. Zweidler-McKay, Qingyu Zhao and Xin Lin J Immunol published online 27 February 2012 http://www.jimmunol.org/content/early/2012/02/26/jimmun ol.1102943 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/02/27/jimmunol.110294 Material 3.DC1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 27, 2012, doi:10.4049/jimmunol.1102943 The Journal of Immunology CARMA1 Controls Th2 Cell-Specific Cytokine Expression through Regulating JunB and GATA3 Transcription Factors Marzenna Blonska,* Donghyun Joo,*,† Patrick A. Zweidler-McKay,‡ Qingyu Zhao,*,1 and Xin Lin*,† The scaffold protein CARMA1 is required for the TCR-induced lymphocyte activation. In this study, we show that CARMA1 also plays an essential role in T cell differentiation. We have found that the adoptive transfer of bone marrow cells expressing constitutively active CARMA1 results in lung inflammation, eosinophilia, and elevated levels of IL-4, IL-5, and IL-10 in recipient mice. In contrast, CARMA1-deficient T cells are defective in TCR-induced expression of Th2 cytokines, suggesting that CARMA1 preferentially directs Th2 differentiation. The impaired cytokine production is due to reduced expression of JunB and GATA3 transcription factors. CARMA1 deficiency affects JunB stability resulting in its enhanced ubiquitination and degradation. In contrast, TCR-dependent induction of GATA3 is suppressed at the transcriptional level. We also found that supplementation with Downloaded from IL-4 partially restored GATA3 expression in CARMA1-deficient CD4+ splenocytes and subsequently production of GATA3- dependent cytokines IL-5 and IL-13. Therefore, our work provides the mechanism by which CARMA1 regulates Th2 cell differ- entiation. The Journal of Immunology, 2012, 188: 000–000. D4+ T cells, also known as Th cells, play a central role diseases, whereas overproduction of Th2 cytokines causes allergic in immune protection by directing responses to various inflammation (1). http://www.jimmunol.org/ C infectious agents. Inappropriate regulation of the Th Previous studies have established the central and indispensible response results in chronic inflammation, autoimmune diseases, role of the NF-kB transcription factor in TCR-induced prolifera- and/or allergies (1). Therefore, activation, differentiation, and ex- tion of CD4+ T cells (11). In resting cells, NF-kB is sequestered in pansion of Th cells are tightly regulated by specific transcription an inactive state by the cytoplasmic inhibitory proteins IkB. Upon factors and cytokine network. Stimulation of the TCR leads to stimulation, the IkB kinase (IKK) complex, composed of IKKa a rapid activation of transcription factors, such as NF-kB, AP-1, and IKKb kinases and regulatory subunit NEMO, phosphorylates and NF-AT, that initiates IL-2 production and is required for cell IkB inhibitors, tagging them for ubiquitination and degradation. proliferation and expansion (2). Activated Th cells further dif- Released NF-kB is translocated to the nucleus and initiates tran- ferentiate into one of the four major effector populations, Th1, scription of its target genes (12). To date, several signaling mol- by guest on September 27, 2021 Th2, and Th17, and inducible regulatory T cells (1). Each Th ecules have been shown to transduce signals from TCR to the IKK lineage preferentially expresses distinct transcription factors and complex (13, 14). One of the critical molecules is CARMA1 (also cytokines. T-bet is upregulated in Th1 cells and controls IFN-g known as CARD11), a scaffold protein exclusively expressed in production (3); in contrast, GATA3, c-Maf, and JunB are ex- lymphoid and myeloid tissues (14, 15). Loss of CARMA1 impairs pressed at high levels in Th2 cells and induce IL-4, IL-5, and IL- AgR-induced IKK activation, NF-kB translocation, IL-2 pro- 13 (4–8). Th17 is a novel subset of effector cells that require duction, and proliferation of T cells (16–18). Ligation of TCR RORa and RORgt for its differentiation and produce IL-17 (9, and CD28 coreceptor results in activation of protein kinase Cu 10). Both, Th1 and Th17 have been associated with autoimmune (PKCu) (19) and phosphorylation of CARMA1 in the linker re- gion between the coiled-coil and PDZ domains (20, 21). This critical modification destabilizes an inhibitory conformation of *Department of Molecular and Cellular Oncology, University of Texas MD Anderson CARMA1 and uncovers the protein interaction sites (21). Acti- Cancer Center, Houston, TX 77030; †Cancer Biology Program, Graduate School of vated CARMA1 recruits its downstream signaling components, ‡ Biomedical Sciences, University of Texas, Houston, TX 77030; and Division of Bcl10, MALT1, and IKK, leading to activation of the IKK com- Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX 77030. plex and subsequently NF-kB (22, 23). Our previous study also 1Currentaddress:IntensiveCareUnit,Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China demonstrates that the CARMA1–Bcl10 complex is indispensible Received for publication October 12, 2011. Accepted for publication January 22, for recruitment and assembly of the MAPK module that phos- 2012. phorylates JNK2 (24, 25). JNK2 is known to regulate the ex- This work was supported by National Institutes of Health Grants GM065899 and pression level of AP-1 family members c-Jun and JunB by targeting AI050848 (to X.L.). M.B. is a Special Fellow of the Leukemia and Lymphoma them for ubiquitination and degradation (26–28). CARMA1- Society. dependent JNK2 phosphorylation is required for stabilization and Address correspondence and reprint requests to Dr. Xin Lin, Department of Mo- accumulation of c-Jun in activated cells (24). lecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 108, Houston, TX 77030. E-mail address: xllin@ In this study, we demonstrate that stable expression of consti- mdanderson.org tutively active CARMA1 increases the basal levels of c-Jun and The online version of this article contains supplemental material. JunB in vitro, suggesting its role in cell proliferation. However, Abbreviations used in this article: BAL, bronchoalveolar lavage; ChIP, chromatin upregulation of CARMA1 in vivo results in Th2 cell-mediated immunoprecipitation; IKK, IkB kinase; ph, phospho; PKC, protein kinase C; PKCu, inflammation. Mice expressing constitutively active CARMA1 protein kinase C u; WT, wild-type. have elevated IL-4, IL-5, and IL-10 and spontaneously develop Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 pulmonary inflammation and eosinophilia. We found that CARMA1 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102943 2 CARMA1 REGULATES Th2 CYTOKINE EXPRESSION regulates JunB and GATA3 expression, which are crucial for the CD4+ T cell isolation and activation initiation and propagation of Th2 polarization. CARMA1-deficient + + CD4 T cells were isolated from mouse spleens and peripheral lymph CD4 T cells have severely impaired production of IL-4 because of nodes using magnetic beads (StemCell Technologies). The cells were the reduced JunB level and defective GATA3 induction. We also purified by negative selection with a panel of biotinylated Abs directed found that CARMA1-deficient CD4+ splenocytes could induce against CD8, CD11b, CD19, CD45R/B220, CD49b, TER119 (StemCell GATA3 in the presence of exogenous IL-4, and the supplementa- Technologies), and CD25 (eBioscence). After 3 h of resting, the cells were activated with plate-bound anti-CD3ε (2 mg/ml) and anti-CD28 (1 mg/ml) tion with IL-4 partially restored production of GATA3-dependent (both from BD Biosciences). For Th2 polarization, 10 mg/ml anti–IFN-g cytokines IL-5 and IL-13. (XMG1.2) and 10 ng/ml murine IL-4 (PeproTech) were added. Because CARMA1-deficient T cells are defective in IL-2 production, every cell Materials and Methods culture was supplemented with rIL-2 (30 U/ml). Reagents and plasmids ELISA 63/73 202 Abs specific for phospho (ph)–c-Jun (Ser ), c-Jun, ph-ERK1/2 (Thr / Cytokines were measured in cell culture supernatants and mouse plasma by 204 32/36 183 185 Tyr ), ph-IkBa (Ser ), ph-JNK (Thr /Tyr ), JNK2, and CARMA1 sandwich ELISA. IL-4, IL-5, IL-10, IL-13, and IFN-g Ready-SET-GO kits were purchased from Cell Signaling Technology. Abs specific for JunB, were purchased from eBioscience, and IL-2 OptEIA kit was obtained from JunD, GATA3, T-bet, c-Maf, NFAT, IkBa, Myc, laminB, Ub (P4D1), and BD Biosciences. Results
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    xO PANEL DNA GENE LIST ~1700 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes (at 400 -500x average coverage on tumor) Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11
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    Open Full Page

    Published OnlineFirst July 25, 2019; DOI: 10.1158/2159-8290.CD-19-0138 RESEARCH ARTICLE Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis Florian Halbritter1,2, Matthias Farlik1,3, Raphaela Schwentner2, Gunhild Jug2, Nikolaus Fortelny1, Thomas Schnöller2, Hanja Pisa2, Linda C. Schuster1, Andrea Reinprecht4, Thomas Czech4, Johannes Gojo5, Wolfgang Holter2,5,6, Milen Minkov2,7, Wolfgang M. Bauer3, Ingrid Simonitsch-Klupp8, Christoph Bock1,9,10,11, and Caroline Hutter2,5,6 ABSTRACT Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory dis- eases, which makes it an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including puta- tive LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analyzed biopsies using IHC, and we defined an epigenomic and gene- regulatory basis of the different LCH-cell subsets by chromatin-accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions. SIGNIFICANCE: This study sketches a molecular portrait of LCH lesions by combining single-cell tran- scriptomics with epigenome profiling. We uncovered extensive cellular heterogeneity, explained in part by an intrinsic developmental hierarchy of LCH cells.