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B Cells Expression in Follicular and Marginal Zone TLR Stimulation

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B Cells Expression in Follicular and Marginal Zone TLR Stimulation TLR Stimulation Modifies BLyS Receptor Expression in Follicular and Marginal Zone B Cells This information is current as Laura S. Treml, Gianluca Carlesso, Kristen L. Hoek, Jason of October 2, 2021. E. Stadanlick, Taku Kambayashi, Richard J. Bram, Michael P. Cancro and Wasif N. Khan J Immunol 2007; 178:7531-7539; ; doi: 10.4049/jimmunol.178.12.7531 http://www.jimmunol.org/content/178/12/7531 Downloaded from References This article cites 57 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/178/12/7531.full#ref-list-1 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 • Fast Publication! 4 weeks from acceptance to publication by guest on October 2, 2021 *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 © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TLR Stimulation Modifies BLyS Receptor Expression in Follicular and Marginal Zone B Cells1 Laura S. Treml,2* Gianluca Carlesso,2† Kristen L. Hoek,† Jason E. Stadanlick,* Taku Kambayashi,* Richard J. Bram,‡ Michael P. Cancro,3* and Wasif N. Khan3† Through their differential interactions with B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), the three BLyS family receptors play central roles in B cell survival and differentiation. Recent evidence indicates BLyS receptor levels shift following BCR ligation, suggesting that activation cues can alter overall BLyS receptor profiles and thus ligand sensitivity. In this study, we show that TLR stimuli also alter BLyS receptor expression, but in contrast to BCR ligation, TLR9 and TLR4 signals, preferentially increase transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI) expression. Although both of these TLRs act through MyD88-dependent mechanisms to increase TACI expression, they differ in terms of their downstream mediators and the B cell subset affected. Surprisingly, only TLR4 relies on c-Rel and p50 to augment TACI expres- Downloaded from sion, whereas TLR9 does not. Furthermore, although all follicular and marginal zone B cells up-regulate TACI in response to TLR9 stimulation, only marginal zone B cells and a subset of follicular B cells respond to TLR4. Finally, we find that both BLyS and APRIL enhance viability among quiescent and BCR-stimulated B cells. However, although BLyS enhances viability among TLR stimulated B cells, APRIL does not, suggesting that TACI but not BLyS receptor 3 may share survival promoting pathways with TLRs. The Journal of Immunology, 2007, 178: 7531–7539. he B lymphocyte stimulator (BLyS)4 and its receptors (4, 17–19). Among the three known BLyS receptors, BLyS recep- http://www.jimmunol.org/ profoundly influence primary B cell homeostasis and se- tor 3 (BR3) interacts solely with BLyS and plays a dominant role T lection (reviewed in Refs. 1–3). The prompt increases in in maintaining normal follicular (FO) and marginal zone (MZ) B B cell numbers following BLyS administration (4–6), as well as cell numbers (8, 9, 11, 20, 21). The other two receptors, trans- the B cell deficiencies observed in BLyS knockouts (7), BLyS membrane activator calcium modulator and cyclophilin ligand in- receptor mutants (8–12), and BLyS blockade experiments (7), teractor (TACI) and B cell maturation Ag (BCMA), can bind both confirm a critical role for BLyS in maintaining naive B cells. Fur- BLyS and a proliferation-inducing ligand (APRIL), and affinity thermore, BLyS has been implicated in several humoral autoim- measurements suggest that APRIL may be their physiologically mune disorders and animal models of autoimmunity (13–16), con- relevant ligand. Mice lacking TACI have elevated B cell numbers by guest on October 2, 2021 firming its function in specificity-based selection. We and others (22, 23), suggesting a potential negative regulatory role for this have shown that mature B cells continuously compete for BLyS to receptor, whereas BCMA appears to be involved in the control of survive (10), and that BLyS levels determine the proportion of plasmacytes, rather than mature resting B cells (24). In addition, cells that successfully complete transitional B cell differentiation TACI knockout mice display defective T cell-independent type II responses, further suggesting that TACI and BCMA may be in- *Department of Pathology and Laboratory Medicine, University of Pennsylvania volved in regulating the behavior of activated B cells. School of Medicine, Philadelphia, PA 19104; †Department of Microbiology and Im- We recently showed that BCR stimulation increases BLyS bind- munology, Vanderbilt University School of Medicine, Nashville, TN 37232; and ‡De- ing capacity in FO and transitional B cells, through the selective partment of Pediatric and Adolescent Medicine, Mayo Clinic, Mayo Medical School, Rochester, MN 55905 up-regulation of BR3 message (25, 26). These findings suggest Received for publication November 27, 2006. Accepted for publication April 4, 2007. that B cell activation cues can alter the levels and mix of BLyS The costs of publication of this article were defrayed in part by the payment of page family receptors, modulating sensitivity to BLyS or APRIL and charges. This article must therefore be hereby marked advertisement in accordance dictating the outcomes of signals from these ligands. In this study, with 18 U.S.C. Section 1734 solely to indicate this fact. we have extended these analyses to B cell activation via TLRs. 1 This study is supported in part by Research Grants AI50213 and AI060729 (to Although phagocytes express the greatest repertoire of TLRs, sev- W.N.K.) and Grant AI54488 (to M.P.C.) from the U.S. Public Health Service. K.L.H. and L.S.T. are supported by Training Grants AI069770 and RR07063, respectively, eral are also expressed by B cells (27). Activation through these from the U.S. Public Health Service. innate receptors differs from that achieved via BCR signaling in 2 L.S.T. and G.C. contributed equally to this study. several ways. First, whereas BCRs are highly diverse and interact 3 Address correspondence and reprint requests to Dr. Michael P. Cancro, Department individually with a narrow range of epitopes, TLRs bind broadly of Pathology and Laboratory Medicine, 284 John Morgan Building, University of expressed, conserved molecular patterns on microbial pathogens Pennsylvania School of Medicine, 36th and Hamilton Walk, Philadelphia, PA 19104; E-mail address: [email protected] or Dr. Wasif N. Khan, Department of (28). Second, whereas BCR cross-linking requires concomitant T Microbiology and Immunology, Medical Center North A4207, Vanderbilt University cell help to afford optimal activation, TLR ligation per se can pro- School of Medicine, 1161 21st Avenue South, Nashville, TN 37232; E-mail address: [email protected] vide the signals required for proliferation and differentiation to Ab secretion (29). In fact, BCR and TLR signals may cooperate for 4 Abbreviations used in this paper: BLyS, B lymphocyte stimulator; FO, follicular; MZ, marginal zone; TACI, transmembrane activator calcium modulator and cyclo- maximal production of pathogen-specific IgM secretion (30). philin ligand interactor; APRIL, a proliferation-inducing ligand; BCMA, B cell mat- Finally, T cell-dependent, BCR-driven responses lead to ger- uration Ag; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-␤. minal center formation, affinity maturation, and memory cell Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 differentiation, whereas TLR-driven responses tend toward www.jimmunol.org 7532 TLR REGULATION OF TACI rapid Ab-forming cell differentiation with limited affinity mat- uration and memory (29). Accordingly, the stimulation of mu- rine B cells through either TLR9 or TLR4 yields a compara- tively brief increase in IgM secretion and B cell proliferation (31, 32). Most TLRs signal via the adaptor protein MyD88, and initiate the classical NF-␬B cascade (reviewed in Refs. 33, 34), although TLR3 and TLR4 can also signal through a MyD88- independent pathway (35). We have used CpG DNA and LPS to stimulate B cells through TLR9 and TLR4, respectively. Our results show that stimulation with either leads to altered BLyS binding capacity by strongly up-regulating TACI and increasing BR3, although to a lesser ex- tent. These effects are B cell intrinsic and MyD88-dependent but, surprisingly, they differ in their downstream transcriptional medi- ators. Finally, all FO and MZ B cells respond to CpG, whereas only MZ B cells and a subset of FO B cells respond to LPS. Furthermore, we find that APRIL, although not mitogenic, im- proved survival in both quiescent and BCR-stimulated B cells. These findings suggest that high TACI expression may be a hall- mark of TLR activation, and that signaling through this receptor Downloaded from influences survival in resting and activated B cells. Materials and Methods Mice C57BL/6J, A/J, and A/WySnJ mice were obtained from The Jackson http://www.jimmunol.org/ Laboratory. Spleens from MyD88 knockout mice originally generated by Akira and colleagues (36) were obtained from Dr. M. Schmidt and Dr. K. Alugupalli (University of Massachusetts Medical School, Worcester, MA) or from Dr. S. Joyce (Vanderbilt University, Nashville, TN). c-Rel knockout mice were originally generated and their use permitted by H.-C. Liou et al. (37) and provided by M. Boothby (Vanderbilt University, Nashville, TN). TACI-deficient mice have been previously described (38). TLR4-defi- cient mice have been previously described (39) and were provided by Dr.
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