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Core Binding Factor Β Is Required for Group 2 Innate Lymphoid Cell Activation

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Core Binding Factor Β Is Required for Group 2 Innate Lymphoid Cell Activation Cutting Edge: Core Binding Factor β Is Required for Group 2 Innate Lymphoid Cell Activation This information is current as Xiaofei Shen, Mingwei Liang, Xiangyu Chen, Muhammad of September 24, 2021. Asghar Pasha, Shanti S. D'Souza, Kelsi Hidde, Jennifer Howard, Dil Afroz Sultana, Ivan Ting Hin Fung, Longyun Ye, Jiexue Pan, Gang Liu, James R. Drake, Lisa A. Drake, Jinfang Zhu, Avinash Bhandoola and Qi Yang J Immunol 2019; 202:1669-1673; Prepublished online 6 Downloaded from February 2019; doi: 10.4049/jimmunol.1800852 http://www.jimmunol.org/content/202/6/1669 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2019/02/05/jimmunol.180085 Material 2.DCSupplemental References This article cites 20 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/202/6/1669.full#ref-list-1 Why The JI? Submit online. by guest on September 24, 2021 • 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 *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 © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Cutting Edge: Core Binding Factor b Is Required for Group 2 Innate Lymphoid Cell Activation Xiaofei Shen,*,1 Mingwei Liang,*,1 Xiangyu Chen,*,1 Muhammad Asghar Pasha,† Shanti S. D’Souza,* Kelsi Hidde,* Jennifer Howard,* Dil Afroz Sultana,* Ivan Ting Hin Fung,* Longyun Ye,* Jiexue Pan,* Gangx Liu,* James R. Drake,* Lisa A. Drake,* Jinfang Zhu,‡ Avinash Bhandoola, and Qi Yang* Group 2 innate lymphoid cells (ILC2) are tissue-resident, IL-5 and IL-13 as well as other effector molecules such as long-lived innate effector cells implicated in allergy and VEGFA (1, 2). Activated ILC2 are potent inducers of airway asthma. Upon activation, mature ILC2 rapidly secrete hyperresponsiveness (AHR) and are implicated in allergic asthma and asthma exacerbation. The molecular pathways large amounts of type-2 cytokines and other effector mol- Downloaded from ecules. The molecular pathways that drive ILC2 activa- that drive ILC2 activation, however, are not well understood. b b tion are not well understood. In this study, we report Core binding factor (CBF ) is a non-DNA–binding sub- that the transcriptional controller core binding factor unit that binds with the RUNX proteins to form different CBF transcriptional complexes. CBFs are critical for early lymphocyte b (CBFb) is required for ILC2 activation. Deletion or development. CBFb is required for the generation of thymic inhibition of CBFb did not impair the maintenance of T cell progenitors, bone marrow B cell precursors, and early http://www.jimmunol.org/ ILC2 at homeostasis but abolished ILC2 activation innate lymphoid progenitors (3–7). CBFs are dispensable for during allergic airway inflammation. Treatment with b the maintenance of mature T cells, but they control several CBF inhibitors prevented ILC2-mediated airway aspects of T cell differentiation. CBFs are known to repress hyperresponsiveness in a mouse model of acute Alternaria CD4+ Th2 differentiation (8–10). Deletion of CBFb or allergen inhalation. CBFb promoted expression of key RUNX proteins in T cells derepressed GATA3 and IL-4 ex- ILC2 genes at both transcriptional and translational pression in CD4+ T cells, resulting in elevated IgE and air- levels. CBF transcriptional complex directly bound way eosinophil inflammation in mice (8–10). Whether CBFs to Il13 and Vegfa promoters and enhancers, and con- play a similar role in repressing the function of innate type-2 by guest on September 24, 2021 trolled gene transcription. CBFb further promoted ri- cytokine–producing cells, such as ILC2, remains unknown. bosome biogenesis and enhanced gene translation in The current study was undertaken to examine the role of b activated ILC2. Together, these data establish an essen- CBF in the activation and function of mature ILC2. To b our surprise, contrary to its suppressive role in Th2 cell dif- tial role for CBF in ILC2 activation. The Journal of b Immunology, 2019, 202: 1669–1673. ferentiation, our data indicate that CBF promotes ILC2 activation. Deletion or inhibition of CBFb abrogated ILC2 activation during allergic airway inflammation and prevented roup 2 innate lymphoid cells (ILC2) are long-lived ILC2-mediated AHR. The requirement of CBFb in ILC2 innate effector cells residing at mucosal barriers such function was cell intrinsic and involved both transcriptional G as lung and gut. Mature ILC2 functionally and and posttranscriptional gene regulatory mechanisms. These transcriptionally mirror Th2 cells, but ILC2 lack clonal Ag data establish a critical role for CBFb in ILC2 activation and receptors and can rapidly respond to the epithelial alarmin function. The positive regulation of ILC2 function by CBFb IL-33 in the absence of Ag stimulus (1). Upon activation, is in contrast with the suppressive role of CBFb in CD4+ Th2 mature ILC2 quickly secrete large amounts of type-2 cytokines cell differentiation (8, 9). Our data thus indicate that adaptive *Department of Immunology and Microbial Diseases, Albany Medical College, Albany, Programs of the National Cancer Institute, the Center for Cancer Research (to A.B.), NY 12208; †Division of Allergy, Asthma and Immunology, Department of Medicine, and the National Institute of Allergy and Infectious Disease (to J.Z.) Albany Medical Center, Albany, NY 12203; ‡Molecular and Cellular Immunoregulation The microarray data presented in this article have been submitted to the Gene Expression Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, x Omnibus (https://www.ncbi.nlm.nih.gov/geo) under accession number GSE116062. National Institutes of Health, Bethesda, MD 20892; and Laboratory of Genome In- tegrity, Center for Cancer Research, National Cancer Institute, National Institutes of Address correspondence and reprint requests to Dr. Qi Yang or Dr. Avinash Bhandoola, Health, Bethesda, MD 20892 Department of Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, MC-151, Albany, NY 12208 (Q.Y.) or Center for Cancer Research, 1X.S., M.L., and X.C. contributed equally to this work. National Cancer Institute, Building 37, Room 1108, Bethesda, MD 20892 (A.B.). ORCIDs: 0000-0002-5206-1353 (M.L.); 0000-0002-3560-9284 (X.C.); 0000-0001- E-mail addresses: [email protected] (Q.Y.) or [email protected] (A.B.) 5542-4511 (S.S.D.); 0000-0001-6773-0743 (I.T.H.F.); 0000-0001-7125-9608 (J.P.); The online version of this article contains supplemental material. 0000-0002-4888-1439 (G.L.); 0000-0002-8365-0986 (Q.Y.). Abbreviations used in this article: AHR, airway hyperresponsiveness; CBFb, core bind- Received for publication June 20, 2018. Accepted for publication January 20, 2019. ing factor b; CHIP, chromatin immunoprecipitation; gRNA, guide RNA; ILC2, group This work was supported by National Institutes of Health (NIH) Grants 2 innate lymphoid cell; 4-OHT, 4-hydroxytamoxifen; qPCR, quantitative PCR. R01HL137813, R01AG057782, and K22AI116728 (to Q.Y.), the Alexandrine and Alexander L. Sinsheimer Scholar Award (to Q.Y.), and NIH Intramural Research Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800852 1670 CUTTING EDGE: A CRITICAL ROLE OF CBFb IN ILC2 ACTIVATION and innate type-2 immune responses are controlled by divergent (Sigma-Aldrich) was added to primary lung ILC2 culture at day 6. Cells were molecular mechanisms. Such divergence in molecular control cultured for nine more days in the presence of 4-OHT. Cytokine production of YFP+ cells was examined by intracellular staining and flow cytometry analysis. might help explain the extreme heterogeneity and complexity In some experiments, YFP+ cells were sorted after 5 d of culture with 4-OHT of human diseases and necessitates consideration of personalized and cultured for another 4 d in the presence of 4-OHT. Growth rate of YFP+ medicine based on the specific immune responses involved. cells were measured as the inverse of doubling time. In vitro Th2 differen- tiation was performed as described (12). Materials and Methods Flow cytometry analysis Mice Abs were purchased from eBioscience, BioLegend, or MD Biosciences. Flow f/f tm2.1Ddg CreERt2 tm1.1(cre/ERT2)Blh/ZhuJ CBFb (Cbfb /J, line 028550), Id2 (B6.129S(Cg)-Id2 cytometric analysis was performed on FACSCanto (BD Biosciences). Flow yfp tm1(EYFP)Cos line 016222), and Rosa26R (B6.129 3 1-Gt(ROSA)26Sor /J, line cytometry cell sorting was performed on a FACSAria II (BD Biosciences). 006148) mice were obtained from The Jackson Laboratory (11). CBFbf/f Id2CreERt2 Rosa26Ryfp and control Id2CreERt2 Rosa26Ryfp mice were bred at the Albany Medical Examination of gene transcription and translation College Animal Research Facility. BALB/c mice were purchased from Taconic Biosciences. mRNA was extracted by Qiagen RNeasy kits. Gene expression was exam- For deletion of CBFb in ILC2, five doses of 5 mg of tamoxifen were ined by quantitative PCR (qPCR). Microarray analysis was performed at administrated i.p. every other day. Twenty-eight days after the first tamoxifen Boston University Microarray and Sequencing Resource (accession number treatment, mice were administrated with a single dose of IL-33 (400 ng; GSE116062, https://www.ncbi.nlm.nih.gov/geo). Gene enrichment analyses BioLegend) i.p. BALB/c mice received a single dose of intranasal adminis- were provided by Boston University Clinical and Translational Science tration of Alternaria extracts (100 mg; Greer) as described (2).
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