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Endothelial Plasmalemma Vesicle–Associated Protein Regulates the Homeostasis of Splenic Immature B Cells and B-1 B Cells

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Endothelial Plasmalemma Vesicle–Associated Protein Regulates the Homeostasis of Splenic Immature B Cells and B-1 B Cells Endothelial Plasmalemma Vesicle−Associated Protein Regulates the Homeostasis of Splenic Immature B Cells and B-1 B Cells This information is current as Raul Elgueta, Dan Tse, Sophie J. Deharvengt, Marcus R. of September 26, 2021. Luciano, Catherine Carriere, Randolph J. Noelle and Radu V. Stan J Immunol 2016; 197:3970-3981; Prepublished online 14 October 2016; doi: 10.4049/jimmunol.1501859 Downloaded from http://www.jimmunol.org/content/197/10/3970 Supplementary http://www.jimmunol.org/content/suppl/2016/10/13/jimmunol.150185 Material 9.DCSupplemental http://www.jimmunol.org/ References This article cites 64 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/197/10/3970.full#ref-list-1 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Endothelial Plasmalemma Vesicle–Associated Protein Regulates the Homeostasis of Splenic Immature B Cells and B-1 B Cells Raul Elgueta,*,† Dan Tse,‡,1 Sophie J. Deharvengt,‡ Marcus R. Luciano,‡ Catherine Carriere,x,{,1 Randolph J. Noelle,*,{ and Radu V. Stan*,‡,‖ Plasmalemma vesicle-associated protein (Plvap) is an endothelial protein with roles in endothelial diaphragm formation and main- tenance of basal vascular permeability. At the same time, Plvap has roles in immunity by facilitating leukocyte diapedesis at in- flammatory sites and controlling peripheral lymph node morphogenesis and the entry of soluble Ags into lymph node conduits. Based on its postulated role in diapedesis, we have investigated the role of Plvap in hematopoiesis and show that deletion of Plvap + lo results in a dramatic decrease of IgM IgD B cells in both the spleen and the peritoneal cavity. Tissue-specific deletion of Plvap Downloaded from demonstrates that the defect is B cell extrinsic, because B cell and pan-hematopoietic Plvap deletion has no effect on IgM+IgDlo B cell numbers. Endothelial-specific deletion of Plvap in the embryo or at adult stage recapitulates the full Plvap knockout phenotype, whereas endothelial-specific reconstitution of Plvap under the Chd5 promoter rescues the IgM+IgDlo B cell phenotype. Taken together, these results show that Plvap expression in endothelial cells is important in the maintenance of IgM+ B cells in the spleen and peritoneal cavity. The Journal of Immunology, 2016, 197: 3970–3981. http://www.jimmunol.org/ he innate immune response is the host’s first and most favored as the first cells to sample Ags in the blood and gut. rapid response to infection with a pathogen, whereas the Moreover, MZ and B-1 B cells are well characterized as having a T adaptive immune response involves a complex process low activation threshold and their BCRs recognize a wide range of including activation, expansion, and differentiation of pathogen- microbial Ags (4). Both B cell subsets significantly contribute to specific B and T cells. The development of adaptive immunity levels of serum IgM and the production of natural Abs. Natural requires several days to weeks to generate a long-standing effector Abs in many cases can be specific to pathogen-encoded molecules and memory immune response (1, 2). A key transition from innate and be critical in the rapid neutralization of both viruses and to adaptive immunity is mediated by the marginal zone (MZ) B bacteria (5). and B-1 cells because they produce the first set of low-affinity Abs MZ B cells arise from bone marrow precursors through tran- by guest on September 26, 2021 against the pathogen (3). MZ B and B-1 cells are localized in the sitional B cells, which colonize the periarteriolar lymphoid sheath marginal sinus and peritoneal cavity, respectively, where they are (5). The differentiation of transitional B cells to MZ B cells is driven by a weak BCR activity through a dependent pathway Bruton’s tyrosine kinase (6–8). This and the interaction of NOTCH *Department of Microbiology and Immunology, Geisel School of Medicine at Dart- expressed on transitional B cells with the ligand, D-like 1, on † mouth, Lebanon, NH 03756; Department of Immune Regulation and Intervention, endothelial cells induce the differentiation to MZ B cells (9). The Medical Research Council Centre for Transplantation, King’s College London, Guy’s Hospital, London, SE1 9RT, United Kingdom; ‡Department of Pathology, Geisel homing of MZ B cells is dependent on circulating sphingosine-1- School of Medicine at Dartmouth, Lebanon, NH 03756; xDepartment of Medicine, { phosphate (S1P) binding to S1P1 and S1P3 receptors expressed in Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; Norris Cotton Can- the endothelial cells of blood vessels of MZ (10, 11). After mi- cer Center, Geisel School of Medicine at Dartmouth and Dartmouth-Hitchcock Med- ical Center, Lebanon, NH 03756; and ‖Department of Biochemistry and Cell Biology, gration, MZ B cells are retained by the interaction of aLb2 and Geisel School of Medicine at Dartmouth, Lebanon, NH 03756 a4b1 with ICAM1 and VCAM1, respectively (12). 1Current address: ImmuNext, Lebanon, NH. In contrast, B-1 cells are competently produced before birth and ORCIDs: 0000-0002-7083-2430 (R.E.); 0000-0003-0766-2464 (S.J.D.); 0000-0003- throughout the first couple weeks after birth. The precursors for B-1 2969-1725 (R.V.S.). cells have been discovered in the splanchnopleural region, yolk sac Received for publication August 20, 2015. Accepted for publication September 18, and intraembryonic hemogenic endothelium, and fetal liver, but 2016. they are absent from adult bone marrow (13–16). B-1 cells con- This work was supported by National Institutes of Health Grants GM120592, stantly circulate to and from the peritoneal space across the CA175592, CA172983, CA023108, and S10OD010330. omentum in a process that involves CXCL13, which is likely Address correspondence and reprint requests to Dr. Radu V. Stan or Prof. Randolph J. Noelle, Department of Biochemistry and Cell Biology, Geisel School of Medicine at produced by macrophages (17). Collectively, these findings show Dartmouth, One Medical Center Drive, Lebanon, NH 03756 (R.V.S.) or Department that B cell progenitor migration is highly regulated by molecules of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One expressed on endothelial cells. However, it is not known whether Medical Center Drive, Lebanon, NH 03756 (R.J.N.). E-mail addresses: radu.v. [email protected] (R.V.S.) or [email protected] (R.J.N.) molecules expressed on endothelial cells are involved in B cell The online version of this article contains supplemental material. differentiation and trafficking. Abbreviations used in this article: AF, Alexa Fluor; MZ, marginal zone; PLN, pe- Plasmalemma vesicle-associated protein (Plvap) is a vertebrate ripheral lymph node; Plvap, plasmalemma vesicle-associated protein; PP, Peyer’s gene (18, 19) whose product, Plvap, is a heparin-binding (20), patches; RT, room temperature; S1P, sphingosine-1-phosphate; T1, transitional 1; homodimeric, single-span type II membrane glycoprotein (21–23) T2, transitional 2; WT, wild type. critical for the formation of the stomatal diaphragms of caveolae, Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 transendothelial channels, and vesiculo-vacuolar organelles, as www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501859 The Journal of Immunology 3971 well as the diaphragms of fenestrae in both mice (24–27) and using Tie2/Tek-cretg/+ mice [JAX strain B6.Cg-Tg(Tek-cre)12Flv/J] (label PlvapECKO-Tie2, genotype PlvapL/L;Tek-cretg/+); 4) B cells in the embryo humans (28). Microscopic (19, 22) and genetic (26, 28, 29) lines KI/+ tm1(cre)Cgn of investigation led to the conclusion that Plvap is specifically using CD19-cre knock-in mice (JAX strain B6.Cg-Cd19 /J) (45) (label CD19CrexPlvapL/L, genotype PlvapL/L;CD19-creki/+); and 5) expressed in the endothelial cells of blood vessel capillaries and hematopoietic cells in the embryo using Vav1-cre+/2 transgenic mice (46), venules in select vascular beds and in the heart endocardium, and for deletion of Plvap in all the hematopoietic cell lineages, but not in is absent from lymphatic endothelial cells. This pattern of ex- endothelium (44, 46). For inducible deletion of Plvap in the endothelial tg/+ pression was fully supported by a large body of literature obtained cells of the adult mice, we used end-SCL-Cre-ERT transgenic mice to generate mice with the genotype PlvapL/L; end-SCL-CreERTtg/+(label with two endothelial-specific mAbs that bind Plvap, such as PlvapiECKO). Deletion of Plvap was achieved by dosing 4-wk-old mice MECA-32 (30, 31) in the mouse and PAL-E (32–34) in humans (both males and females) by gavage with seven doses of 4 mg of tamoxifen (reviewed in Refs. 35, 36). However, recently, Plvap expression spaced at 48 h. Experiments were carried out 2 wk after the last tamoxifen was also demonstrated in the sinus lymphatic endothelial cells of dose administration. Control animals for germline deletion were sex- and age-matched wild type (WT) or CMV-cretg/+ (labeled WT) and Plvap+/2 or peripheral lymph nodes (PLNs) while confirming its absence from 2 2 Plvap+/ ;CMV-cretg/+ (labeled Plvap+/ ) littermates.
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