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Jimmunol.1200623.Full.Pdf Transcription Factor Zinc Finger and BTB Domain 1 Is Essential for Lymphocyte Development This information is current as Divya Punwani, Karen Simon, Youngnim Choi, Amalia of September 28, 2021. Dutra, Diana Gonzalez-Espinosa, Evgenia Pak, Martin Naradikian, Chang-Hwa Song, Jenny Zhang, David M. Bodine and Jennifer M. Puck J Immunol published online 29 June 2012 http://www.jimmunol.org/content/early/2012/06/29/jimmun Downloaded from ol.1200623 Supplementary http://www.jimmunol.org/content/suppl/2012/06/29/jimmunol.120062 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 by guest on September 28, 2021 • 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 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published June 29, 2012, doi:10.4049/jimmunol.1200623 The Journal of Immunology Transcription Factor Zinc Finger and BTB Domain 1 Is Essential for Lymphocyte Development Divya Punwani,*,1 Karen Simon,†,1 Youngnim Choi,‡ Amalia Dutra,† Diana Gonzalez-Espinosa,* Evgenia Pak,† Martin Naradikian,*,x Chang-Hwa Song,*,{ Jenny Zhang,* David M. Bodine,† and Jennifer M. Puck* Absent T lymphocytes were unexpectedly found in homozygotes of a transgenic mouse from an unrelated project. T cell develop- ment did not progress beyond double-negative stage 1 thymocytes, resulting in a hypocellular, vestigial thymus. B cells were present, but NK cell number and B cell isotype switching were reduced. Transplantation of wild-type hematopoietic cells corrected the defect, which was traced to a deletion involving five contiguous genes at the transgene insertion site on chromosome 12C3. Com- plementation using bacterial artificial chromosome transgenesis implicated zinc finger BTB-POZ domain protein 1 (Zbtb1) in the immunodeficiency, confirming its role in T cell development and suggesting involvement in B and NK cell differentiation. Targeted Downloaded from disruption of Zbtb1 recapitulated the T2B+NK2 SCID phenotype of the original transgenic animal. Knockouts for Zbtb1 had expanded populations of bone marrow hematopoietic stem cells and also multipotent and early lymphoid lineages, suggesting a differentiation bottleneck for common lymphoid progenitors. Expression of mRNA encoding Zbtb1, a predicted transcription repressor, was greatest in hematopoietic stem cells, thymocytes, and pre-B cells, highlighting its essential role in lymphoid devel- opment. The Journal of Immunology, 2012, 189: 000–000. http://www.jimmunol.org/ evelopment of lymphocytes from hematopoietic stem DN1–DN4, after which they undergo TCR rearrangement and cells (HSCs) is incompletely understood. Current models become CD4+CD8+ double-positive (DP) cells (5). DP cells un- D suggest that T, B, and NK cell precursors are predomi- dergo selection, with surviving self-tolerant CD8+ or CD4+ single- nantly derived from common lymphoid progenitors (CLPs) in bone positive, naive T cells emerging from the thymus to populate marrow (BM) (1). CLPs can differentiate into all-lymphoid pro- peripheral lymphoid organs. The zinc finger BTB-POZ (Zbtb) genitors (ALPs), which retain full lymphoid differentiation po- transcription factor 7 (Zbtb7/Th-POK/cKrox) is crucial for tential, forming both T cell progenitors that seed the thymus and switching a fraction of DP cells from the default CD8+ pathway B cell-biased lymphoid progenitors that become B cells (2). to form CD4+ cells (6, 7). Identification of additional signaling by guest on September 28, 2021 Notch-1 signals are required to redirect common lymphoid pro- factors at developmental branch points is required to understand genitors from the default B lineage to the T lineage (3, 4). After lymphoid lineage commitment and differentiation in both mice migration to the thymus, T lineage precursors proceed through and humans. distinct CD42CD82 (double-negative, or DN) thymic stages, Human SCID syndromes, defined by profound defects in both cellular and humoral immunity, comprise experiments of nature that have revealed many nonredundant, critical functions in human *Department of Pediatrics, University of California San Francisco, San Francisco, CA 91413; †National Human Genome Research Institute, National Institutes of lymphoid developmental pathways. Human SCID is caused by Health, Bethesda, MD 20892; ‡Department of Oromaxillofacial Infection and Immu- defects in a wide variety of genes encoding proteins necessary and nity, School of Dentistry, Seoul National University, Seoul 110-744, South Korea; x { specific for lymphocyte differentiation, proliferation, and activation University of Pennsylvania, Philadelphia, Pennsylvania, PA 19104; and Department of Microbiology, College of Medicine, Chungnam National University, Daejeon 301- (8–11). About two-thirds of SCID patients lack T cells but have 2 2 747, South Korea B cells that fail to make specific Abs (T B+ phenotype); T B+ 1D.P. and K.S. contributed equally to this work and are listed in alphabetical order. SCID can be caused by defects in the X-linked common g-chain Received for publication February 23, 2012. Accepted for publication May 31, 2012. receptor for IL-2, -7, -9, -15, and -21; the IL-7 receptor a-chain; This work was supported in part by National Institutes of Health Grant R01 intracellular cytokine signal transducers JAK3 or STAT5; protein AI078248 (to J.M.P.) and by the Division of Intramural Research, National Human tyrosine phosphatase receptor CD45; or components of the CD3 Genome Research Institute, National Institutes of Health. receptor. Patients with these forms of SCID are in contrast to those D.P., K.S., Y.C., M.N., C.-H.S., J.Z., D.G.-E., E.P., and A.D. designed and performed with T2B2 SCID, whose defects may lie in mediators of T and BCR experiments, prepared figures, and analyzed data; D.M.B. codesigned experiments and provided essential tools and guidance; and J.M.P. designed and supervised the gene rearrangement, including RAG1, RAG2, and Artemis, or in research, performed experiments, and wrote the article with D.P. and K.S. adenosine deaminase or purine nucleoside phosphorylase, which Address correspondence are reprint requests to Dr. Jennifer M. Puck, Department of normally remove purine intermediates that are toxic to lymphocytes. Pediatrics, University of California San Francisco, Box 0519, 513 Parnassus Avenue, Up to 10% of humans with SCID have other rare, or as yet un- HSE 301A, San Francisco, CA 94143-0519. E-mail address: [email protected] identified, genetic defects. The online version of this article contains supplemental material. In contrast to humans, the most studied mouse models for SCID Abbreviations used in this article: ALP, all-lymphoid progenitor; BAC, bacterial have the T2B2 phenotype, including the scid mouse deficient in artificial chromosome; BM, bone marrow; BMT, bone marrow transplantation; CLP, common lymphoid progenitor; DN, double-negative; DP, double-positive; the DNA-dependent kinase DNA-PKc, and Rag1/Rag2-deficient eGFP, enhanced GFP; ES, embryonic stem; FISH, fluorescence in situ hybridization; mice, all of which fail to complete V(D)J rearrangement of Ab and HDAC, histone deacetylase; HSC, hematopoietic stem cell; IRES, internal ribosome entry site; MPP, multipotent progenitor; MSCV, murine stem cell virus; tg, trans- TCR genes during B and T cell development (12–17). These and genic; Zbtb, zinc finger BTB-POZ. the the athymic nude mouse lacking transcription factor Foxn1 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1200623 2 Zbtb1 IS ESSENTIAL FOR LYMPHOCYTE DEVELOPMENT (18, 19) have greatly facilitated basic studies of lymphoid cell BM transplantation maturation after the commitment to the T and B lineages has been Donor BM cell suspensions were harvested by flushing femurs and tibias made, but they have not permitted dissection of prethymic lym- with PBS and straining. HSCs were enriched by depletion with biotinylated phoid development. Moreover, lymphocyte phenotypes are dis- Abs (BD Biosciences) to lineage markers CD3, CD4, CD8, B220, Gr-1, and cordant between mice and humans with disruption of most human Ter-119, followed by addition of streptavidin microbeads and purification SCID genes, limiting the utility of mouse knockouts for illumi- using a MACS column (Miltenyi Biotec, Auburn, CA). Two million cells were injected by tail vein into nine gray irradiated recipients. Lineage nating mechanisms for human T lineage commitment or to serve engraftment was determined in blood and tissues after 4 mo. Experiments as faithful models for optimizing human SCID therapies. For were performed in duplicate. example, while humans with gc and JAK3 defects have T2B+ NK2 SCID, mice with targeted disruption of these genes have Bacterial artificial chromosome isolation, cytogenetics, and T cells, but lack B cells (T+B2NK2) (20). mapping 2 2 AT B+NK SCID phenotype was unexpectedly observed in Metaphases from Con A-stimulated splenocytes from heterozygous trans- homozygotes of one of five mouse
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