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In Murine Resting B Cells Dynamics of MHC Class II-Activating Signals Dynamics of MHC Class II-Activating Signals in Murine Resting B Cells Toufic O. Nashar and James R. Drake This information is current as J Immunol 2006; 176:827-838; ; of September 26, 2021. doi: 10.4049/jimmunol.176.2.827 http://www.jimmunol.org/content/176/2/827 Downloaded from References This article cites 43 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/176/2/827.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 26, 2021 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dynamics of MHC Class II-Activating Signals in Murine Resting B Cells1 Toufic O. Nashar2 and James R. Drake3 MHC class II (MHC II) proteins are competent signaling molecules on APC. However, little is known about the mechanisms that control generation of their activating signals. Previous reports highlighted a number of factors that could affect the nature and outcome of MHC II signals, including the inability of MHC II ligation on resting vs activated murine B cells to induce mobilization of Ca2؉. In the present study, we report that ligation of MHC II on resting murine B cells reproducibly induces mobilization of ,intracellular Ca2؉ using both mAbs and cognate T cells as ligands. Mobilization of Ca2؉ was independent of MHC II haplotype isotype, or mouse genetic background. MHC II-mediated mobilization of Ca2؉ is completely inhibited by inhibitors of src-like kinases and syk, and MHC II ligation increases overall tyrosine phosphorylation level. Moreover, MHC II ligation results in specific up-regulation of CD86. However, induction of these responses is dependent on the type of anti-MHC II Ab used, suggesting Downloaded from that epitope specificity and/or the nature of ligation is important. Moreover, we demonstrate that MHC II-derived signals are strictly regulated by the order and timing of BCR and CD40 signals, suggesting coordination of these signals preserves the integrity of early B cell priming events. Thus, the mode and the context of MHC II ligation influence generation of MHC II-derived activating signals in resting B cells. Based on these results, a new model that highlights the role of MHC II-activating signals in regulation of Ag presentation by B cells is proposed. The Journal of Immunology, 2006, 176: 827–838. http://www.jimmunol.org/ n addition to their classical function in Ag presentation of such as the uptake and processing of Ag may influence the context protein-derived peptide fragments, MHC class II (MHC II)4 in which MHC II is found in the plasma membrane and, as a result, I molecules are competent signaling molecules on Ag present- dictates the functional outcome of MHC II-mediated signals in B ing cells. In human and mouse B cells, ligation of MHC II by Abs cells. Consistent with the latter, we previously showed that target- or the TCR generates downstream signals that could affect activa- ing of Ag to the BCR generates MHC II-peptide complexes that tion status and survival of B cells (1, 2). The nature of the signals upon ligation by Ab or the TCR induce B cell activation and sur- generated following MHC II ligation by Abs or the TCR has been vival. In contrast, ligation of MHC II complexes generated by fluid examined in a variety of cells. MHC II transduces signals includ- phase uptake of the Ag induces B cell death in culture (2). There- ing the production of cAMP (3, 4), leads to tyrosine kinase acti- fore, induction of MHC II signals involves a complex mechanism by guest on September 26, 2021 vation, inositol lipid hydrolysis and mobilization of Ca2ϩ (5–8), that is influenced by a number of factors that ultimately dictate B and induces increase in ERK 1/2, AP-1, and NF-␬B activities (9– cell function. 11). The outcome of MHC II-mediated signals includes increased In the present study, we examine in nontransformed (primary) B expression of costimulatory molecules, such as CD86 (12), in- cells a number of factors that could influence the context in which creased cell-cell adhesion through up-regulation of LFA-1 (13), ligation of MHC II generates intracellular Ca2ϩ signals. MHC II- induction of B cell differentiation (4), and cell death (1, 2, 14). derived signaling is examined following ligation by different types However, a number of factors could influence the magnitude, of mAbs and by cognate T cells. Mobilization of Ca2ϩ was ex- nature, and functional outcomes of MHC class II-mediated signals. amined in cells from mice of different haplotypes and in both rest- These include B cell activation status (15, 16), species differences ing and activated B cells. We report for the first time that ligation (8, 15), B cell transformation (8), MHC II haplotype or isotype (4, of MHC II on the surface of resting unstimulated murine B cells 9, 17), and signals generated from other cell surface receptors, reproducibly induces mobilization of intracellular Ca2ϩ. This is including the BCR (18) or CD40 (19). Additionally, other factors found to be independent of the MHC II haplotype or isotype. Fur- thermore, MHC II ligation induces an increase in overall cellular tyrosine phosphorylation levels, and inhibition of src-like kinases ϩ Albany Medical College, Center for Immunology and Microbial Disease, Albany, NY and syk inhibits the MHC II-induced Ca2 response. Ligation of 12208 MHC II also increases specific expression of the activation marker Received for publication May 18, 2005. Accepted for publication November 2, 2005. CD86. These results demonstrate that like resting human B cells The costs of publication of this article were defrayed in part by the payment of page (8, 20), MHC II on the surface of resting mouse B cells is a com- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. petent signaling molecule for induction of activating signals. How- ever, consistent with other studies, some mAbs were not able to 1 This work is supported by National Institutes of Health Grant A1-46405 (to J.R.D.). induce mobilization of Ca2ϩ or increase expression of CD86, sug- 2 Address reprint requests to Dr. Toufic O. Nashar, Albany Medical College, Center for Immunology and Microbial Disease, 47 New Scotland Avenue, MC-151, Albany, gesting that binding to specific epitopes and/or the nature of MHC NY 12208-3479. E-mail address: [email protected] II ligation is important. In analyzing the level of MHC II signaling, ϩ 3 Address correspondence to Dr. James R. Drake, Albany Medical College, Center for we found that MHC II-derived Ca2 signaling and surface expres- Immunology and Microbial Disease, 47 New Scotland Avenue, MC-151, Albany, NY sion of MHC II are negatively regulated by prior simultaneous 12208-3479. E-mail address: [email protected] signals via the BCR and CD40. However, prior signaling via either 4 Abbreviations used in this paper: MHC II, MHC class II; HEL, hen egg lysozyme; BCR or CD40 alone did not negatively regulate MHC II-derived IC, isotype control; SA, streptavidin; PTK, protein tyrosine kinase; PKC, protein ϩ kinase C; DC, dendritic cell. Ca2 signaling. Furthermore, prior BCR signaling followed by Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 828 REGULATION OF MHC II-ACTIVATING SIGNALS simultaneous signaling via MHC II and CD40, a procedure that ␮g/ml of each of the anti-MHC II mAbs in the absence of SA or another mimics engagement of T cells following B cell priming by Ag, did secondary reagent. not affect MHC II-derived Ca2ϩ signaling. These results indicate that the three signals are well coordinated in Ag-specific B cells to ϩ B cell video imaging of Ca2 during B and T cell cognate preserve the integrity of early B cell priming events and to promote interactions appropriate B-T cell interactions. Pure splenic B cells were isolated as described above. Cells were incubated ␮ with and without a final concentration of 300 M HEL46–61 peptide for Materials and Methods 3.5 h at 37°C. Cells were gently washed and labeled with Fluo-3/AM (2 Mice ␮g/ml) as described above. The T cell hybridoma H4Ly 50.5 (a gift from ␮a k Dr. W. Wade, Dartmouth Medical School, Lebanon, NH) that recognizes BCR transgenic mice (MD4.B10.BR, , H-2 ) expressing hen egg ly- k sozyme (HEL)-specific BCR that have been bred onto the B10 background HEL46–61 peptide bound to IA was used. Both B and T cells were resus- 2ϩ ϫ 5 over 15 generations were used with their nontransgene littermates from 8 pended in Ca buffer. T cells (2 10 ) were allowed to adhere for 15 min d k on glass coverslips pretreated with 1 ␮g/ml poly-L-lysine. Measurement of to 14 wk of age. BALB/cJ (H-2 ) and CBA/J (H-2 ) mice were used at 8 2ϩ wk of age.
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