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Cell Differentiation to Plasma Cells B and MHC Class II Gene Expression ZBTB32 Is an Early Repressor of the CIITA and MHC Class II Gene Expression during B Cell Differentiation to Plasma Cells This information is current as Hye Suk Yoon, Christopher D. Scharer, Parimal Majumder, of September 27, 2021. Carl W. Davis, Royce Butler, Wendy Zinzow-Kramer, Ioanna Skountzou, Dimitrios G. Koutsonanos, Rafi Ahmed and Jeremy M. Boss J Immunol published online 30 July 2012 http://www.jimmunol.org/content/early/2012/07/29/jimmun Downloaded from ol.1103371 Supplementary http://www.jimmunol.org/content/suppl/2012/07/30/jimmunol.110337 Material 1.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 27, 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 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 30, 2012, doi:10.4049/jimmunol.1103371 The Journal of Immunology ZBTB32 Is an Early Repressor of the CIITA and MHC Class II Gene Expression during B Cell Differentiation to Plasma Cells Hye Suk Yoon,*,1 Christopher D. Scharer,*,1 Parimal Majumder,* Carl W. Davis,† Royce Butler,* Wendy Zinzow-Kramer,* Ioanna Skountzou,* Dimitrios G. Koutsonanos,* Rafi Ahmed,*,† and Jeremy M. Boss*,† CIITA and MHC class II expression is silenced during the differentiation of B cells to plasma cells. When B cell differentiation is carried out ex vivo, CIITA silencing occurs rapidly, but the factors contributing to this event are not known. ZBTB32, also known as repressor of GATA3, was identified as an early repressor of CIITA in an ex vivo plasma cell differentiation model. ZBTB32 activity occurred at a time when B lymphocyte-induced maturation protein-1 (Blimp-1), the regulator of plasma cell fate and suppressor Downloaded from of CIITA, was minimally induced. Ectopic expression of ZBTB32 suppressed CIITA and I-A gene expression in B cells. Short hairpin RNA depletion of ZBTB32 in a plasma cell line resulted in re-expression of CIITA and I-A. Compared with conditional Blimp-1 knockout and wild-type B cells, B cells from ZBTB32/ROG-knockout mice displayed delayed kinetics in silencing CIITA during ex vivo plasma cell differentiation. ZBTB32 was found to bind to the CIITA gene, suggesting that ZBTB32 directly regulates CIITA. Lastly, ZBTB32 and Blimp-1 coimmunoprecipitated, suggesting that the two repressors may ultimately function together to silence CIITA expression. These results introduce ZBTB32 as a novel regulator of MHC-II gene expression and http://www.jimmunol.org/ a potential regulatory partner of Blimp-1 in repressing gene expression. The Journal of Immunology, 2012, 189: 000–000. o initiate and regulate the adaptive and humoral immune mature into Ab-secreting plasma cells (10). As B cells transition to responses, MHC class II (MHC-II) genes encode hetero- plasma cells, the expression of CIITA is silenced, resulting in the T dimeric proteins that present antigenic peptides to CD4 subsequent loss of MHC-II expression (11, 12). T lymphocytes (1, 2). MHC-II genes are transcriptionally regu- Plasma cell differentiation requires extensive epigenetic re- lated by CIITA. CIITA is expressed in a limited number of cell programming and morphological changes that allow these cells to types, including dendritic cells, macrophages, and B lymphocytes secrete high levels of serum Abs (13, 14). This process represents by guest on September 27, 2021 (3, 4). CIITA functions as a transcriptional coactivator, connecting a critical event in the development and control of the humoral the DNA-binding transcription factors at MHC-II promoters with immune response. The B lymphocyte-induced maturation protein- chromatin-modifying complexes and the RNA polymerase ma- 1 (Blimp-1) encoded by the Pdrm1 gene is an important regulator chinery (5–7). Depending on the species, the expression of CIITA of this transition. Ectopic expression of Blimp-1 in some B cell is controlled by three or four tissue-specific promoters, with lines induces plasma cell differentiation (15, 16) and the silencing promoter III (pIII) principally used by B cells (8, 9). Following of CIITA and MHC-II gene expression (17). Moreover, B cells immune stimulation, activated B lymphocytes differentiate or carrying a B cell-specific, conditional knockout allele of Blimp-1 fail to form plasma cells, leading to a decrease of serum Ig levels, even though B cell development to this point was normal (18, 19). *Department of Microbiology and Immunology, Emory University School of Med- icine, Atlanta, GA 30322; and †Emory Vaccine Center, Emory University School of Biochemically, Blimp-1 functions as a transcriptional repressor of Medicine, Atlanta, GA 30322 gene activity (18, 20). However, Blimp-1 is only part of this cell 1H.S.Y. and C.D.S. contributed equally to this work. fate decision. A complex network of activators and repressors Received for publication November 23, 2011. Accepted for publication June 29, controls B cell fate and development. For example, whereas B cell 2012. lymphoma-6 (BCL6) maintains the B cell program and represses This work was supported by National Institutes of Health Grants R56AI3400 and Blimp-1 expression, Blimp-1 represses the B cell program by si- R01AI34000 (to J.M.B.), HHSN266 200700006C (to I.S. and D.G.K.), and R01A1030048 and U19A1091493 (to R.A.). lencing BCL6, Pax5, and SpiB, critical modulators of B cell fate (20, 21). Blimp-1 also serves to induce the plasma cell program by The microarray data presented in this article have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus database (http:// contributing to the regulation of XBP-1 and syndecan-1 (22). www.ncbi.nlm.nih.gov/gds) under accession number GSE17999. Although this seems complete, additional data indicate that other Address correspondence and reprint requests to Dr. Jeremy M. Boss, Emory Univer- factors may act independently of Blimp-1 to initiate this differ- sity, 1510 Clifton Road, Room 3001, Atlanta, GA 30322. E-mail address: jmboss@emory. entiation program (23). With respect to CIITA silencing in plasma edu cells, Blimp-1 was found to bind directly to sequences upstream of The online version of this article contains supplemental material. three tissue-specific promoters of the CIITA gene (promoters I, III, Abbreviations used in this article: BCL6, B cell lymphoma-6; Blimp-1, B lymphocyte-induced maturation protein-1; ChIP, chromatin immunoprecipitation; and IV), suggesting that it directly repressed CIITA expression HDAC, histone deacetylase; LCMV, lymphocytic choriomeningitis virus; MHC-II, (17, 24, 25). The molecular mechanism(s) by which Blimp-1 MHC class II; pIII, promoter III; ROG, repressor of GATA3; shRNA, short hairpin mediates repression is still not well defined. Blimp-1 was found RNA. to interact with histone deacetylase (HDAC)-1 and HDAC-2 in Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 repressing the c-Myc gene during plasma cell differentiation (26). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1103371 2 ZBTB32 REPRESSES CIITA EXPRESSION During dendritic cell maturation, Blimp-1 bound CIITA promoter I Primary murine splenic B cells were purified from 5- to 8-wk-old and recruited G9a and HDAC2, resulting in the acquisition of C57BL/6 mice, using magnetic separation columns (MACS; Miltenyi repressive histone marks (25). In other systems, Blimp-1 formed Biotec), as previously described (35). Ex vivo differentiation of B cells to plasma-like cells (35) was performed by incubating murine primary a complex with histone methyltransferases G9a (27) and PRMT5 splenic B cells for the indicated time in the above culture medium sup- (28), suggesting a role in modulating the remodeling of chro- plemented with LPS (20 mg/ml; Sigma-Aldrich), IL-2 (20 ng/ml; Sigma- matin. However, the participating factors and the mechanism of Aldrich), and IL-5 (5 ng/ml; Sigma-Aldrich). In addition, each 24 h the m Blimp-1 repression at CIITA pIII in plasma cells are largely un- culture medium was supplemented with LPS (10 g/ml), IL-2 (10 ng/ml), and IL-5 (2.5 ng/ml) for the duration of the time course. The Burkitt’s known. lymphoma B cell line Raji was grown in RPMI 1640 medium supple- ZBTB32 encodes a transcriptional repressor and member of the mented with 5% FBS (HyClone Laboratories) and 5% bovine calf serum zinc finger, broad complex, tram track, bric-a-brac (BTB) family (HyClone Laboratories). The plasmacytoma cell line H929 was cultured in of proteins (29). ZBTB32, which is also known as repressor of RPMI 1640 medium with 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, GATA3 (ROG), PLZF-like zinc finger protein (PLZP), testis zinc 4.5 g/L glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, and 0.05 mM 2-ME. HEK293 and HEK293FT cells were cultured in DMEM with 10% finger protein (TZFP), and Fanconi anemia zinc finger (FAZF), heat-inactivated FBS. was identified in multiple screens involving either immune cell tumorigenesis or development (30–32). In T cells, ZBTB32 ac- Primary plasmablast purification tivity inhibits the development of Th2 cells by interfering with the To obtain primary plasmablasts from the spleen, BALB/c mice (six per activity of GATA3, a factor required for Th2 development and experiment) were infected by i.p.
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