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4662.Full.Pdf TLR4 Promotes B Cell Maturation: Independence and Cooperation with B Lymphocyte-Activating Factor This information is current as Elize A. Hayashi, Alessandra Granato, Luciana S. Paiva, of September 29, 2021. Álvaro L. Bertho, Maria Bellio and Alberto Nobrega J Immunol 2010; 184:4662-4672; Prepublished online 31 March 2010; doi: 10.4049/jimmunol.0903253 http://www.jimmunol.org/content/184/9/4662 Downloaded from References This article cites 48 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/184/9/4662.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 September 29, 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TLR4 Promotes B Cell Maturation: Independence and Cooperation with B Lymphocyte-Activating Factor Elize A. Hayashi,* Alessandra Granato,* Luciana S. Paiva,*,† A´ lvaro L. Bertho,‡ Maria Bellio,* and Alberto Nobrega* We have previously shown that TLR4 triggering promotes the generation of CD23+CD93+ transitional T2-like cells in vitro from mouse B cell precursors, suggesting a possible role for this receptor in B cell maturation. In this study, we perform an extensive study of cell surface markers and functional properties of B cells matured in vitro with LPS, comparatively with the well-known B cell maturation factor B lymphocyte-activating factor (BAFF). LPS increased generation of CD23+ transitional B cells in a TLR4-dependent way, upregulating IgD and CD21 and downregulating CD93, without inducing cell proliferation, in a manner essentially equivalent to BAFF. For both BAFF and LPS, functional maturation of the IgM+CD23+CD93+ cells was confirmed by their higher proliferative response to anti-CD40 plus IL-4 compared with IgM+CD23negCD93+ cells. BAFF-R-Fc–mediated Downloaded from neutralization experiments showed that TLR4-induced B cell maturation was independent of BAFF. Distinct from BAFF, mat- uration by LPS relied on the activation of canonical NF-kB pathway, and the two factors together had complementary effects, leading to higher numbers of IgM+CD23+CD93+ cells with their simultaneous addition. Importantly, BCR cross-linking abrogated the generation of CD23+ B cells by LPS or BAFF, indicating that signals mimicking central tolerance act on both systems. Addition of cyclosporin A reverted BCR-mediated inhibition, both for BAFF and LPS, suggesting similar regulation of signaling pathways by calcineurin. Finally, LPS-injected mice showed a rapid increase of mature B cells in the bone marrow, suggesting that http://www.jimmunol.org/ TLR4 signaling may effectively stimulate B cell maturation in vivo, acting as an accessory stimulus in B cell development, complementary to the BAFF physiological pathway. The Journal of Immunology, 2010, 184: 4662–4672. n mice, as well as in humans, B lymphocytes are generated taining self-tolerance, signaling outcome in B lymphocytes upon in the bone marrow (BM) throughout postnatal life from pre- BCR ligation changes dramatically according to their developmental I cursors derived from hematopoietic stem cells (1). Newly state: whereas mature B lymphocytes tend to proliferate and secrete formed immature B lymphocytes must pass through intermediary Ab, immature and transitional B cells are highly susceptible to stages named “transitional” before reaching mature state (2–5). negative selection by receptor editing or apoptosis (2, 8, 9). by guest on September 29, 2021 Many groups have resolved the transitional B cell subsets in the BM In addition to Ag-specific interaction, contact with cytokines and cell and spleen using different cell markers, and a standard classification surface ligands on stromal cells has also been shown to play critical roles has not been clearly defined yet (2–4, 6). Transitional B lymphocytes in B cell development and differentiation (1, 9). These accessory signals still express significant levels of CD93, which is absent in mature can cooperate positively or negatively with BCR-delivered signals, and B cells, and high levels of IgM. They are typically divided into T1 the balance among them seems to guide the fate of B lymphocytes and T2, the second one bearing more mature characteristics, such as throughout their maturation, regulating survival, differentiation, and theexpressionofCD23andCD21andhigherIgD.Passagefrom proliferation. A critical factor for B cell development is B lymphocyte immature to transitional and then to mature stages is marked by activating factor (BAFF, also known as BLyS or TALL-1) (10), a cyto- clonal selection, in which only a small fraction of the daily generated kine belonging to the TNF superfamily. Interaction of BAFF with immature B cells can survive and complete differentiation (7). BAFF-R provide constitutive signals necessary for B cell survival, es- Interaction with self-Ags through the BCR is a crucial checkpoint in pecially at the T2 stage, and is required for normal B cell maturation (10, B cell maturation. As part of an important mechanism for main- 11). The enforced expression of BAFF in transgenic mice results in a lupus-like autoimmune disease (12). Interestingly, MyD88 has been shown to be necessary for the outbreak of lupus-like autoimmune dis- *Department of Immunology, Institute of Microbiology, Federal University of Rio de ease in BAFF transgenic mice, denoting a dependence on signals from Janeiro; †Department of Immunobiology, Institute of Biology, Fluminense Federal University; and ‡Flow Cytometry Core Lab, Laboratory of Immunoparasitology, TLRs, besides the central role of BAFF signaling in this model (13). Oswaldo Cruz Institute-Fiocruz, Rio de Janeiro, Brazil TLR4, TLR2, and TLR9 agonists such as LPS, bacterial lipoproteins, Received for publication October 5, 2009. Accepted for publication February 19, and CpG-DNA are largely known as potent B cell mitogens, inducing 2010. a T-independent polyclonal activation and Ig secretion (14–16), but an This work was supported by grants from the Conselho Nacional de Pesquisas (Bra- increasing amount of data has evidenced that TLR-derived signals play zil), Fundac¸a˜o de Amparo a` Pesquisa do Estado do Rio de Janeiro, Comissao de a much more fine-tuned role in B cell activation. TLR engagement Aperfeic¸oamento de Pessoal de Nival Superior, and Financiadora de Estudos e Pro- jetos. seems to provide important costimulatory signals for optimal Ag- Address correspondence and reprint requests to Dr. Alberto Nobrega, Department of specific B cell response (17, 18). Activation of autoreactive B cells Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de against chromatin and RNA-associated self-Ags in murine models for Janeiro 21941-590, Brazil. E-mail address: [email protected] systemic autoimmune diseases has also been shown to depend on BCR- Abbreviations used in this paper: BAFF, B lymphocyte-activating factor; BM, bone TLR9 and BCR-TLR7 sequential engagements, respectively (19, 20). marrow; CsA, cyclosporin A; PI, propidium iodide. It remains unclear, however, whether the BCR and TLR collaboration Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 observed in mature B cells is also valid for immature B lymphocytes www.jimmunol.org/cgi/doi/10.4049/jimmunol.0903253 The Journal of Immunology 4663 and whether signals from TLRs could influence B cell developmental washed, and resuspended in MACS buffer, according to the manufacturer’s specifications. Cells were applied into an LD depletion column (Miltenyi events other than cell activation. It has recently been suggested that neg immature antichromatin autoreactive B cells could also be activated by Biotec), and the effluent cells were collected as the BM IgM fraction and washed in complete OptiMEM medium. IgMneg fraction was incubated for CpG-DNA (21). However, total IgM secretion and proliferation in 20 min on ice with anti-B220 or anti-CD19 MicroBeads (Miltenyi Biotec) immature B subset were still much lower than in mature subset, even and processed as described above. Cells were applied into MS-positive sort though TLR9 is highly expressed in early immature stage. Likewise, column, and after washing, retained cells were collected. Viable cells were immature B cells poorly proliferate upon LPS stimulation (4, 5), al- scored by trypan blue dye using a hemacytometer, and the purity of cell preparations was verified by flow cytometry. Usually, IgM+ cells corre- though they express considerable levels of TLR4 (22). In contrast, it has sponded to ,1% of B lineage cells after depletion, and B220+ cells corre- been shown that TLR4 and TLR2 agonists rapidly reach BM in sponded to .95% of recovered cells after positive selection. a context of infection, inhibiting lymphoid precursor proliferation (23). Cell staining,
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