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BAFF Upregulates CD28/B7 and CD40/CD154 Expression and Promotes Mouse T and B Cell Interaction in Vitro Via BAFF Receptor

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BAFF Upregulates CD28/B7 and CD40/CD154 Expression and Promotes Mouse T and B Cell Interaction in Vitro Via BAFF Receptor Acta Pharmacologica Sinica (2016) 37: 1101–1109 © 2016 CPS and SIMM All rights reserved 1671-4083/16 www.nature.com/aps Original Article BAFF upregulates CD28/B7 and CD40/CD154 expression and promotes mouse T and B cell interaction in vitro via BAFF receptor Feng ZHANG#, Shan-shan SONG#, Jin-ling SHU, Ying LI, Yu-jing WU, Qing-tong WANG, Jing-yu CHEN, Yan CHANG, Hua-xun WU, Ling-ling ZHANG*, Wei WEI* Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Hefei 230032, China Aim: B cell-activating factor belonging to the TNF family (BAFF) is a member of TNF family and required for peripheral B cell survival and homeostasis. BAFF has been shown to promote the proliferation of T and B cells. In this study we examined whether and how BAFF mediated the interaction between mouse T and B cells in vitro. Methods: BAFF-stimulated B or T cells were co-cultured with T or B cells. The interactions between T and B cells were analyzed by measuring the expression of co-stimulatory molecules (CD28/CD80 or CD40/CD154), the proliferation and secretion of T and B cells and other factors. Two siRNAs against the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and BAFF receptor (BAFF-R) were used to identify the receptors responsible for the actions of BAFF. Results: BAFF-stimulated B cells significantly promoted the proliferation and activity of co-cultured T cells, and increased the percentages of CD4+CD28+ and CD4+CD154+ T cells. Similarly, BAFF-stimulated T cells significantly promoted the proliferation and activity of co-cultured B cells, and increased CD19+CD80+ and CD19+CD40+ B cell subpopulations. BAFF-R siRNA-silenced B cells showed significantly lower expression of CD40 and CD80 than the control B cells. When the BAFF-R siRNA-silenced B cells were stimulated with BAFF, then co-cultured with T cells, the expression of CD28 and CD154 on T cells was not increased. TACI siRNA- silenced B cells exhibited higher expression of CD40 and CD80 than the control B cells. When the TACI siRNA-silenced B cells were stimulated with BAFF, then co-cultured with T cells, the expression of CD28 and CD154 on T cells was significantly increased. Conclusion: BAFF upregulates CD28/B7 and CD40/CD154 expression, and promotes the interactions between T and B cells in a BAFF- R-dependent manner. Keywords: T cells; B cells; T and B cell interaction; co-stimulatory molecules; BAFF; BAFF receptors; TACI Acta Pharmacologica Sinica (2016) 37: 1101–1109; doi: 10.1038/aps.2016.15; published online 16 May 2016 Introduction B7 (CD80, CD86) and CD40/CD154 (CD40 ligand)[2, 3]. The B lymphocytes play an important role as antigen-presenting CD28/B7 interaction is mainly involved in the activation and cells (APCs) that facilitate the activation of T cells[1]. The inter- proliferation of T lymphocytes, whereas the CD40/CD40L action between T and B lymphocytes is required for antigen interaction is mainly involved in B lymphocyte activation and responses and antibody production. Two signal systems proliferation. Electron microscopy has shown that T and B mediate this interaction. The first signal system involves lymphocytes are spatially close to each other, which not only type II major histocompatibility complex (MHC II), antigen facilitates the interactions of surface molecules on cells (eg, peptide and T cell receptors (TCRs). The second signal sys- TCR-MHC, CD28/B7, CD40/CD40L, and other adhesive mol- tem involves co-stimulatory molecules, including CD28/ ecules) but also promotes the efficient secretion of cytokines[4]. The proliferation of B lymphocytes is modulated by the cyto- # These two authors contributed equally. kines secreted from T lymphocytes, whereas the activation of * To whom correspondence should be addressed. T lymphocytes relies on the antigen-presenting function of B E-mail [email protected] (Ling-ling ZHANG); [5] [email protected] (Wei WEI) lymphocytes . Received 2015-11-25 Accepted 2016-02-06 B cell-activating factor belonging to the TNF family (BAFF) Acta Pharmacologica Sinica www.nature.com/aps 1102 Zhang F et al is required for peripheral B cell survival and homeosta- and Platinum SYBR Green were purchased from Invitrogen sis[6]. Our previous results have shown that the proliferation Co (Beijing, China). Enzyme-linked immunosorbent assay of T and B lymphocytes is enhanced by stimulation with (ELISA) kits for IL-2, IL-17, IgM, and IgG were purchased BAFF. BAFF promoted the production of CD4+CD154+ and from Research & Development (R&D, USA). Anti-CD28, anti- CD4+CD69+ T lymphocytes and CD19+CD21+, CD19+CD23+, CD154, anti-CD80, and anti-CD40 antibodies were purchased and CD19+/IgD+ B lymphocytes[7]. BAFF plays a vital role in from Biosynthesis Co (Beijing, China). Transwell inserts (0.4 the development of autoimmune disorders. High serum levels μm) were from Corning Co, Ltd (USA). TACI-Ig was a kind of BAFF have been clinically demonstrated in RA patients[8]. gift from Dr WX WANG (Rongchang Pharmaceutical Research There are currently three identified receptors of BAFF: B cell Institute, Beijing, China). The anti-mouse BAFF antibody maturation antigen (BCMA), transmembrane activator and (AF2106) was from R&D, and the BLyS (310-13) was from calcium modulator and cyclophilin ligand interactor (TACI), PeproTech Co, Ltd (USA). and BAFF receptor (BAFF-R)[9]. TACI is expressed in both B lymphocytes and activated T lymphocytes. TACI has emerged Mice as an unusual TNF receptor-like molecule with a sophisti - DBA/1 mice (male, 18±2 g) were obtained from the Shanghai cated mode of action. However, the functions of TACI have Institute of Materia Medica, Chinese Academy of Sciences not been fully elucidated. TACI–/– mice have revealed two (production license No: SCXK [HU] 2008-0016). All mice were functions of this receptor: upregulation of T cell-independent maintained in a specific-pathogen-free animal facility at Anhui immune responses and downregulation of B cell activation Medical University. All experiments were approved by the and expansion[10]. BAFF-R is highly expressed in resting B Ethics Review Committee for Animal Experimentation of the cells and is also detectable in resting CD4+ T cells. BAFF-R is Institute of Clinical Pharmacology at Anhui Medical Univer- crucial for the survival of mature B cells and homeostasis in sity. the peripheral lymphoid organs. BAFF/BAFF-R signals medi- ate PI3K/Akt/mTOR signaling, which is involved in antibody B cell magnetic separation production by B lymphocytes from collagen-induced arthritis B cells were isolated from mouse spleens by positive selec- rats[8]. BAFF/BAFF-R signaling also induces the expression of tion using magnetic cell separation (MACS). For this purpose, CD21 and CD23 on the B cell surface, promoting the survival a single cell suspension from mouse spleen (approximately of the mature B cell. FO and MZ cells will die in the absence 1×108 cells) in 500 µL of MACS buffer was incubated with of either BAFF-R or BAFF[11]. By contrast, BCMA appears to PE-anti-CD19 for 20 min, followed by incubation with anti- be a B cell-specific BAFF receptor. BAFF’s function in B cell PE beads for an additional 20 min. The cell suspension was proliferation and activation is mediated through these three loaded onto an LS column (Miltenyi Biotec, German). After receptors[12, 13]. washing with degassed buffer three times, labeled B cells were These findings raise some questions. Is BAFF involved in collected. the interaction between T and B lymphocytes? If so, does BAFF mediate these interactions by regulating the expression Proliferation assays[14] of co-stimulatory molecules, such as CD28/B7 and CD40/ T and B lymphocyte proliferation was analyzed using [3H]TdR CD154? Which receptor is the main receptor through which intake (Institute of the Atomic Energy, Beijing, China). The BAFF mediates the interaction between T and B lymphocytes? murine thymus and spleen were removed under sterile condi- The answers to these questions are still unclear. The current tions. T or B lymphocyte suspensions (200 μL) in DMEM sup- study aimed to investigate the mechanisms by which BAFF plemented with 10% fetal calf serum were seeded in 96-well mediates the interaction between T and B lymphocytes in mice culture plates and stimulated by BAFF (1 μg/mL). Cells were and to determine whether TACI or BAFF-R plays a significant plated in triplicates and cultured for 48 h. Six hours before the role. The results of this study showed that BAFF upregulated end of the culture period, 20 µL of [3H]TdR was added to each the co-stimulatory molecules CD28/B7 and CD40/CD154 well. Radioactivity was measured using the LS6500 liquid and promoted the interactions between T and B lympho- scintillation counter (Beckman Co, USA). The results were cytes. TACI-Ig and anti-BAFF antibody inhibited the interac- described as the average of counts per minute measured in tions between T and B lymphocytes by neutralizing BAFF triplicate. and repressing the expression of co-stimulatory molecules. BAFF-R rather than TACI was the receptor through which Secretion assays BAFF promotes the interaction of T and B lymphocytes. T or B cell suspensions (500 μL) were seeded into 24-well cul- ture plates and stimulated by BAFF (1 μg/mL). After 48 h, T Materials and methods and B lymphocyte supernatants were collected and analyzed Reagents, antibodies and primers for IL-2 and IL-17 (from T lymphocyte culture supernatants) Anti-mouse PE-CD28, PE-CD154, PE-CD40, PE-CD80, FITC- or IgG and IgM (from B lymphocytes) by ELISA. CD19, and FITC-CD4 antibodies were purchased from eBiosci- ence, Inc (San Diego City, California, USA).
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