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B Cell–Intrinsic Mtorc1 Promotes Germinal Center–Defining B Cell−Intrinsic mTORC1 Promotes Germinal Center−Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell This information is current as Generation in Humoral Immunity of September 26, 2021. Ariel L. Raybuck, Sung Hoon Cho, Jingxin Li, Meredith C. Rogers, Keunwook Lee, Christopher L. Williams, Mark Shlomchik, James W. Thomas, Jin Chen, John V. Williams and Mark R. Boothby Downloaded from J Immunol published online 12 March 2018 http://www.jimmunol.org/content/early/2018/03/11/jimmun ol.1701321 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/03/11/jimmunol.170132 Material 1.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • 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 © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 12, 2018, doi:10.4049/jimmunol.1701321 The Journal of Immunology B Cell–Intrinsic mTORC1 Promotes Germinal Center–Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity Ariel L. Raybuck,* Sung Hoon Cho,* Jingxin Li,* Meredith C. Rogers,†,‡,1 Keunwook Lee,*,2 Christopher L. Williams,*,3 Mark Shlomchik,‡ James W. Thomas,x Jin Chen,x,{,‖,# John V. Williams,†,‡,1 and Mark R. Boothby*,{,‖ B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence Downloaded from signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell–intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid–sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6—a key transcriptional regulator of the germinal center (GC) fate—in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching http://www.jimmunol.org/ required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell–intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collec- tively, these data establish that mTORC1 governs critical B cell–intrinsic mechanisms essential for establishment of GC differ- entiation and effective Ab production. The Journal of Immunology, 2018, 200: 000–000. cell receptor–initiated signals in mature lymphocytes are i.e., Ab class-switch recombination and the point mutations that vital for Ag-activated B cell proliferation and clonal diversify and heighten affinity in the memory and Ab repertoires by guest on September 26, 2021 B expansion (1, 2). After several days and divisions, these (3, 4, 8–10). B cell activation and costimulation in the GCs and signals can also yield functionally important class-switch recom- extrafollicular milieux occur in the context of a variegated inter- bination as well as somatic hypermutation (SHM) coupled to the stitial environment (11–13). How sensors of environmental cues iterative selection of B cells with higher affinity Ag-specific BCR influence B lymphocyte–intrinsic mechanisms of differentiation in germinal center (GC) reactions (3–6). Humoral immunity then and function that determine Ab response properties through so- stems from the differentiation of B lymphocytes into Ab-secreting matic mutation is incompletely understood. plasmablasts and plasma cells (1, 4, 7). Activation-induced de- Ag-specific BCR-derived signals (2, 14) are modulated by aminase (AID), which is most highly induced in GCs, is essential CD19 along with a menu of additional B cell surface recep- for both classes of genome revision crucial in humoral immunity, tors (namely, CD40; IL-4R and IL-21R; TLR4 and 7) whose *Department of Pathology, Microbiology, and Immunology, Vanderbilt University This work was supported by National Institutes of Health Grants AI113292 and Medical Center, Nashville, TN 37232; †Division of Infectious Diseases, Department HL106812 (to M.R.B.) and AI085062 (to J.V.W.) for the experiments. Additional of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 27232; support was provided by National Institutes of Health Grant T32 HL069765 ‡Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, (to C.L.W.), Korean Ministry of Science Grant NRF-2014M3A9D5A01073841 PA 15261; xDivision of Rheumatology and Immunology, Department of Medicine, (to K.L.), and National Institutes of Health Shared Instrumentation Grant Vanderbilt University Medical Center, Nashville, TN 27232; {Medical and Research 1S10OD018015, as well as scholarships through Cancer Center Support Grant Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, CA068485 and Diabetes Research Center Grant DK0205930 to help defray costs Nashville, TN 37212; ‖Program in Cancer Biology, Vanderbilt University School of the Vanderbilt Cores. of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232; and #De- Address correspondence and reprint requests to Dr. Mark R. Boothby, Department of partment of Cell and Developmental Biology, Vanderbilt University School of Med- Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, icine, Vanderbilt University Medical Center, Nashville, TN 37232 A-5301 M. C. N., 1161 21st Avenue South, Nashville, TN 37232. E-mail address: 1Current address: Children’s Hospital and Department of Pediatrics, University of [email protected] Pittsburgh Medical Center, Pittsburgh, PA. The online version of this article contains supplemental material. 2Current address: Department of Biomedical Science, Hallym University, Chuncheon, Abbreviations used in this article: 7-AAD, 7-aminoactinomycin D; AID, activation- Korea. induced deaminase; ASC, Ab-secreting cell; 2DG, 2-deoxyglucose; DZ, dark zone; 3Current address: Institute for Cellular Therapeutics, University of Louisville, Louisville, FSC, forward-scattered (light) channel; GC, germinal center; GLT, germ line tran- KY. script; HA, hemagglutinin; hu, human; IgHa, Ig CH allotype-disparate; IRF, IFN response factor; LZ, light zone; mTOR, mechanistic target of rapamycin; mTORC1, ORCIDs: 0000-0002-6463-4032 (S.H.C.); 0000-0003-1798-6294 (M.C.R.); 0000- mTOR complex 1; SHM, somatic hypermutation; SSC, side-scattered (light) channel; 0002-2098-6458 (J.W.T.); 0000-0002-5557-2079 (J.C.); 0000-0001-8377- T , T follicular helper; WT, wild type. 5175 (J.V.W.). FH Received for publication September 18, 2017. Accepted for publication February 14, Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 2018. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701321 2 B CELL–INTRINSIC mTORC1 PROMOTES BCL6, IRF4, SHM, AND AFFINITY engagement and activity are crucial for the acquisition of a GC unanswered questions as to which functions of mTORC1 are in- B cell program (15–19). In the GC reaction, activated B cells trinsic to B lineage cells in vivo. Notable among these are: 1) what receive cognate help from T cells that specialize into a T follic- molecular defects of mTORC1-deficient B cells could explain a ular helper (TFH) phenotype (3, 4). This reaction can involve GC impact, 2) whether lower Aicda gene expression is accom- iterative rounds of proliferation and AID-dependent somatic mu- panied by defects of SHM, 3) if affinity maturation is altered, and tation in the dark zone (DZ), followed by restimulation and se- 4) to what extent the mTORC1 function within B cells influences lection in a TFH-enriched light zone (LZ) (5, 20–22). Diversification their capacity to generate memory. of the BCR on lymphoblasts by somatic mutation is one, but not the To investigate B cell–intrinsic actions of mTORC1, we used only, factor promoting high-affinity Ab (8, 23). The GC ultimately multiple Cre-driven approaches to cause loss-of-function after generates Ag-specific memory cells, plasmablasts, and long-lived establishment of normal B cell populations. In vivo and in vitro plasma cells that constitutively secrete Ab (3, 4). The B lineage also analyses with these systems revealed requirements for mTORC1 generates plasma cells and some memory through extrafollicular in promoting progression to GC and memory stages of the B responses, either TLR driven or aided by T cells
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