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Expression in B Cells Receptor-Induced Regulation of B7-2

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Expression in B Cells Receptor-Induced Regulation of B7-2 The Journal of Immunology ␤ B Cell Receptor- and 2-Adrenergic Receptor-Induced Regulation of B7-2 (CD86) Expression in B Cells1 Adam P. Kohm,2* Afsaneh Mozaffarian,3* and Virginia M. Sanders4*† The costimulatory molecule B7-2 (CD86) is expressed on the surface of APCs, including B cells. Considering the importance of B7-2 in regulating both T and B cell function, it may be important to understand the regulatory mechanisms governing its ␤ expression. We report in this study that stimulation of the B cell receptor (BCR) and/or a neurotransmitter receptor, the 2- ␤ ␤ adrenergic receptor ( 2AR), may cooperate to regulate B cell-associated B7-2 expression in vitro and in vivo. 2AR stimulation further enhanced the level of BCR-induced B7-2 expression in B cells potentially via protein tyrosine kinase-, protein kinase A-, ␤ protein kinase C-, and mitogen-activated protein kinase-dependent mechanisms. Importantly, BCR and/or 2AR stimulation, but not histone hyperacetylation and DNA hypomethylation alone, increased B cell-associated B7-2 expression by increasing B7-2 mRNA stability, NF-␬B nuclear binding, and NF-␬B-dependent gene transcription. Thus, this study provides additional insight ␤ into the signaling intermediates and molecular mechanisms by which stimulation of the BCR and 2AR may regulate B cell- associated B7-2 expression. The Journal of Immunology, 2002, 168: 6314–6322. he growing B7 family of costimulatory molecules criti- tion increased the level of B7-2 mRNA and protein expression in cally influences the T cell-dependent Ab response. The the B cell with peak expression at 12 and 24 h, respectively (5–9). T level of B7 expression on APCs regulates the level of T Therefore, cellular activation appears to be one mechanism by cell-dependent Ab production by the B cell, cytokine production which the level of B7-2 protein expression is up-regulated on the by the T cell, and germinal center formation (reviewed in Refs. 1 B cell surface. and 2). For example, concurrent immunization of mice with T Additional stimuli may also enhance the level of B7-2 expres- cell-dependent Ags and anti-B7-2 (CD86) Ab, to block the B7-2/ sion on B cells, such as the stimulation of cytokine receptors (10, CD28 interaction, inhibited both the level of Ag-specific Ab pro- 11), complement receptors (12), MHC class II (13), and CD40 duced by the B cell and the level of germinal center formation in (14–17). Interestingly, while the initial BCR-induced level of B7-2 vivo (3). Also, costimulatory molecule expression may influence expression is CD40 independent, extended expression for 48–72 h ϩ CD4 T cell differentiation since B7-1 (CD80) or B7-2 expression may be CD40 dependent (18). Thus, signals generated following on APCs may favor the formation of either a Th1 or Th2 cell- CD40 stimulation may synergize with BCR-induced signals to mediated Ab response, respectively (4). Thus, the level of B cell- maintain B7-2 expression on the B cell surface for longer periods associated B7-2 expression may exert a variety of influences on of time. In light of the importance of B7-2 stimulation in regulating both T and B cell function. B cell and T cell function, it is not surprising that mechanisms exist In light of the influence of B7-2 expression on immune cell to augment the level of B cell-associated B7-2 expression during function, it may be important to understand the mechanisms reg- the course of an immune response. However, in addition to im- ulating the expression of this and other costimulatory molecules. mune cell-derived stimuli, signals originating outside the immune Presently, the exact regulatory mechanisms that govern B7-2 ex- system may also regulate the level of B cell-associated B7-2 pression on a B cell are unknown. While B7-2 is expressed at very expression. low levels on resting B cells (5), a number of early studies ob- The sympathetic neurotransmitter norepinephrine (NE) is re- 5 served that B cell receptor (BCR) - or LPS-induced B cell activa- leased from peripheral nerves during the course of a T cell-depen- ␤ ␤ dent Ab response in vivo to bind 2-adrenergic receptors ( 2ARs) *Departments of Cell Biology, Neurobiology, and Anatomy, and †Microbiology and expressed by B cells and Th1 cells, but not Th2 cells (reviewed in ␤ Immunology, Loyola University Stritch School of Medicine, Maywood, IL 60153 Refs. 19 and 20). Stimulation of the B cell-associated 2AR in Received for publication September 27, 2001. Accepted for publication April vivo has been reported to influence the level of Ab production (21, 19, 2002. 22), cell proliferation (21), cell trafficking (23), and germinal cen- The costs of publication of this article were defrayed in part by the payment of page ␤ ter formation (21). In addition, 2AR stimulation also increases the charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. level of B7-2 expression on the B cell surface in vitro, but more ␤ 1 This work was supported in part by research funds from the National Institutes of importantly, concurrent stimulation of the BCR and 2AR syner- ␤ Health AI37326 and AI47420 (to V.M.S.). gistically increases the level of B7-2 expression (24). Thus, 2AR 2 Current address: Department of Microbiology and Immunology, Northwestern Uni- stimulation represents one mechanism by which signals from the versity School of Medicine, 303 East Superior Avenue, Chicago, IL 60611. nervous system may augment BCR-induced regulation of B cell 3 Current address: Corixa Corp., 733 99th Avenue SE, Bellevue, WA 98004. function and B7-2 expression. 4 Address correspondence and reprint requests to Dr. Virginia M. Sanders at the current address: Department of Molecular Virology, Immunology and Medical Ge- netics, Ohio State University, 2194 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210. E-mail address: [email protected] epinephrine; 6-OHDA, 6-hydroxydopamine hydrochloride; PDTC, 1-pyrrolidinecar- 5 ␤ ␤ Abbreviations used in this paper: BCR, B cell receptor; 2AR, 2-adrenergic re- bodithioic acid; PKA, protein kinase A; PKC, protein kinase C; PP, phosphatase; ceptor; Btk, Bruton’s tyrosine kinase; ERK, extracellular signal-regulated kinase; PTK, protein tyrosine kinase; RGG, rabbit ␥-globulin; TFIID, RNA polymerase II JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NE, nor- transcription factor; TNP, trinitrophenyl; UTR, untranslated region. Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 The Journal of Immunology 6315 We report in this study two mechanisms by which BCR and Reverse-transcription and real-time PCR ␤ 2AR stimulation may regulate B7-2 expression on the B cell sur- mRNA was isolated from B cells using the GlassMax RNA isolation spin face. While epigenetic DNA modifications alone did not influence columns (Life Technologies). Before RT-PCR, all RNA samples were the level of B7-2 mRNA expression, stimulation of the BCR treated with 1 ␮g DNase I (Life Technologies) per 1 ␮g mRNA. Reverse and/or ␤ AR increased both B7-2 mRNA stability and NF-␬B- transcription was performed on 2.5 ␮g DNase-treated RNA per sample 2 ␮ mediated gene transcription. In support of these findings, pretreat- using a common master mix (50 U murine leukemia virus, 2.5 M random hexamer, 20 U RNase inhibitor, 1 mM dNTPs, 5 mM MgCl ,10mM ␬ ␤ 2 ment of cells with a NF- B inhibitor blocked BCR- and/or 2AR- Tris-HCl, pH 8.3, and 50 mM KCl; PerkinElmer/Cetus, Norwalk, CT), and induced B7-2 protein and mRNA expression in B cells, suggesting the samples were incubated at 25°C for 10 min, 42°C for 15 min, 99°C for that NF-␬B plays a critical role in regulating B7-2 expression in 5 min, and 5°C for 5 min. In addition, 2.5 ␮g RNA from each sample was murine B cells. not reverse transcribed to ensure the effectiveness of the DNase treatment. A total of 1.25 ␮l cDNA and gene-specific primers were added to 25 ␮l SYBR Green PCR Master Mix (PerkinElmer/Cetus). Amplification reac- Materials and Methods tion was performed and analyzed on GeneAmp 5700 Sequence Detection Animals System (PerkinElmer/Cetus). Primers were as follows: murine B7-2, 5Ј- Ј Ј Lps-d Ϫ/Ϫ CGAGCACTATTTGGGCACAGAG-3 and 5 -TTTCCAGAACACACA Six-week-old female C.B-17/scid, BALB/c, C.C3H-Tlr4 (Toll4 ), CAACGGTC-3Ј; murine ␤-actin, 5Ј-ATGGATGACGATATCGCT-3Ј and and C57BL/6 mice were obtained from The Jackson Laboratory (Bar Har- 5Ј-ATGAGGTAGTCTGTCAGGT-3Ј. bor, ME) or Taconic Farms (Germantown, NY). All mice were provided autoclaved pellets and water ad libitum. Mice were permitted 2 wk to Histone hyperacetylation and DNA hypomethylation acclimate to their environment before being manipulated, and were used at 8 wk of age in all experiments. Mice were housed under a 12-h light/dark For histone hyperacetylation studies, resting B cells were exposed to in- cycle in microisolater cages contained within a laminar flow system, thus creasing concentrations of the histone deacetylase inhibitor butyrate (Sig- maintaining a pathogen-free environment, and all experimental manipula- ma-Aldrich) for9hat37°C and 6% CO2 in cRPMI. For DNA hypom- tions occurred ϳ4 h into the light cycle. ethylation studies, B cells were pretreated with the methyl transferase inhibitor 5-azacytidine (10 ␮M; Sigma-Aldrich) for 24 h at 37°C and 6% Reagents CO2 in cRPMI before butyrate exposure, as described above. Concentra- tions of butyrate and 5-azacytidine used have previously been shown to The following protein kinase and protein phosphatase (PP) inhibitors were induce significant histone hyperacetylation or DNA hypomethylation in a purchased from Biomol (Plymouth Meeting, PA): H-89, genistein, okadaic ␬ variety of cell types (26, 27).
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