B Cell Maturation Antigen, the Receptor for a Proliferation-Inducing Ligand and B Cell-Activating Factor of the TNF Family, Induces Antigen Presentation in B Cells This information is current as of September 27, 2021. Min Yang, Hidenori Hase, Diana Legarda-Addison, Leena Varughese, Brian Seed and Adrian T. Ting J Immunol 2005; 175:2814-2824; ; doi: 10.4049/jimmunol.175.5.2814 http://www.jimmunol.org/content/175/5/2814 Downloaded from References This article cites 54 articles, 36 of which you can access for free at: http://www.jimmunol.org/content/175/5/2814.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 27, 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology B Cell Maturation Antigen, the Receptor for a Proliferation-Inducing Ligand and B Cell-Activating Factor of the TNF Family, Induces Antigen Presentation in B Cells1 Min Yang,* Hidenori Hase,* Diana Legarda-Addison,* Leena Varughese,* Brian Seed,† and Adrian T. Ting2* B cell maturation Ag (BCMA), a member of the TNFR superfamily expressed on B cells, binds to a proliferation-inducing ligand (APRIL) and B cell-activating factor of the TNF family (BAFF) but the specific B cell responses regulated by BCMA remain unclear. This study demonstrates that ligation of A20 B cells transfected with BCMA induces the expression of CD40, CD80/B7-1, CD86/B7-2, MHC class II, and CD54/ICAM-1, which subsequently enhances the presentation of OVA peptide Ag to DO11.10 T cells. BCMA expression in murine splenic B cells can be induced with IL-4 and IL-6, allowing subsequent treatment with APRIL Downloaded from or agonist anti-BCMA to similarly induce Ag presentation. A comparative analysis of hybrid receptors of TNFR2 fused to the cytoplasmic domains of APRIL/BAFF receptors found that only BCMA, but not transmembrane activator and calcium-modulator and cyclophilin ligand interactor or BAFF-R, is capable of activating Ag presentation. Although all three receptors can trigger NF-␬B signaling, only BCMA activates the JNK pathway conferring on BCMA the specific ability to activate this Ag presentation response. The Journal of Immunology, 2005, 175: 2814–2824. http://www.jimmunol.org/ embers of the TNF and TNFR superfamilies are crit- the development of lupus in these animals (9, 10). These obser- ical for the development and response of the immune vations in animal models have led to the suggestion that elevated system (1). Two recent additions to the TNF super- BAFF levels may play a role in human autoimmune disorders. M 3 family, B cell-activating factor (BAFF), also known as BLYS, Consistent with this hypothesis, patients with SLE were reported TALL-1, zTNF4, or THANK, and a proliferation-inducing ligand to have elevated levels of BAFF when compared with normal (APRIL), also known as TALL-2 or TRDL-1, have been shown to individuals (11, 12). have a role in regulating B cells (2). BAFF was initially cloned by In contrast to the well-characterized physiological role of BAFF, sequence homology to the TNF family and was shown to stimulate that of APRIL remains less clear. APRIL is the closest relative of B cell growth and Ig production in vitro (3, 4). BAFF was subse- BAFF in the TNF family, sharing 33% sequence identity, and was by guest on September 27, 2021 quently shown to be required for maintaining the survival of pe- initially reported to stimulate the proliferation of tumor cells (13). ripheral B cell as baffϪ/Ϫ mice lack follicular and marginal zone B Subsequent in vitro experiments demonstrated that APRIL could cells (5, 6). The B cell developmental blockade in the BAFF-de- also stimulate proliferation, Ig secretion, and class switching in B ficient animals appears to be in the T1 to T2 transition step during cells (14, 15). Two groups recently generated aprilϪ/Ϫ mice with the maturation of B cells and as a result, these animals have im- slightly different observations. One group reported that these mice paired humoral responses to both T cell-dependent and T cell- did not have any overt immune defects (16), whereas a second independent Ags. In contrast, transgenic overexpression of BAFF group observed defects in isotype class switching to IgA (17). The in mice resulted in elevated number of B cells and these animals reason for the discrepancy between the two reports is unclear at subsequently developed a systemic lupus erythematosus (SLE)- this point. Thus in contrast to BAFF, APRIL appears to have a role like autoimmune disorder (7–9). Furthermore, increased BAFF in the immune system that can be largely compensated by other ϫ levels were observed in the NZW BF1 mouse model of SLE as cytokines. In addition to effects in the immune system, there is a the disease progresses and antagonist soluble BAFF-R inhibited growing body of evidence that BAFF and APRIL are likely to be involved in lymphoid malignancies by conferring antiapoptotic signals to tumor cells (18–22). BAFF and APRIL can be produced *Immunobiology Center, Mount Sinai School of Medicine, New York, NY 10029; and †Department of Molecular Biology, Massachusetts General Hospital, Boston, MA by the tumor cells and thus can act in an autocrine manner, or they 02114 can be produced by accessory cells to act in a paracrine manner. Received for publication February 3, 2005. Accepted for publication June 10, 2005. Both BAFF and APRIL can bind to multiple receptors of the The costs of publication of this article were defrayed in part by the payment of page TNFR superfamily expressed on B cells. BAFF binds to BCMA, charges. This article must therefore be hereby marked advertisement in accordance transmembrane activator and calcium-modulator and cyclophilin with 18 U.S.C. Section 1734 solely to indicate this fact. ligand interactor (TACI), and BAFF-R, whereas APRIL binds only 1 This study was supported in part by an Extended Fellowship (to M.Y.) and by a to BCMA and TACI (2). The prosurvival effects of BAFF on B research grant (to A.T.T.) from the Systemic Lupus Erythematosus Foundation. cells is most likely mediated by BAFF-R in that the A/WySnJ 2 Address correspondence and reprint requests to Dr. Adrian T. Ting, Immunobiology mouse strain that has a loss-of-function mutation in BAFF-R lacks Center, Mount Sinai School of Medicine, Box 1630, One Gustave L. Levy Place, New Ϫ Ϫ York, NY 10029. E-mail address: [email protected] peripheral B cells, a phenotype that is most similar to baff / mice Ϫ/Ϫ 3 Abbreviations used in this paper: BAFF, B cell-activating factor of the TNF family; (23, 24). On the contrary, taci mice have elevated B cell num- BCMA, B cell maturation Ag; TACI, transmembrane activator and calcium-modu- bers (25, 26), and older taciϪ/Ϫ mice subsequently develop auto- lator and cyclophilin ligand interactor; SLE, systemic lupus erythematosus; APRIL, a proliferation-inducing ligand; HA, hemagglutinin; I-␬BSR, I-␬B super-repressor; immunity (27), suggesting that TACI may play a negative regula- IRES, internal ribosome entry site; JNKK, JNK kinase; MKK, MAPK kinase. tory role in B cells. To date, the function of BCMA has remained Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 2815 the most enigmatic of the three receptors. BCMA was initially mated sequencing (PE Applied Biosystems). All receptors were cloned into cloned as a translocation product from a human T cell lymphoma a previously described Moloney murine leukemia virus-based retroviral and its expression profile was shown to correlate with the matu- vector upstream of an internal ribosome entry site (IRES)-puromycin re- sistance cassette (34). The dominant negative JNK kinase (JNKK)2 or ration of B cells, with the highest level observed in plasma cell MAPK kinase (MKK)7 (JNKK2/MKK7) is a lysine to methionine substi- lines (28). Although both BAFF and APRIL can bind to BCMA, tution at residue 149 of human JNKK2, which has been previously de- APRIL binds with much higher affinity (29, 30) suggesting per- scribed to behave in a dominant negative manner (35). Mutagenesis was haps that the APRIL-BCMA interaction may be more physiolog- performed using the Quikchange site-directed mutagenesis kit (Stratagene) and verified by sequencing. The I-␬B super-repressor (I-␬BSR) with the ically relevant. However, the functional consequences of BCMA serine to alanine substitutions at residues 32 and 36 of I-␬B␣ was sub- ligation on B cells have remained unclear and the generation of cloned from a previously described plasmid pEAK8-I␬B␣ double negative Ϫ Ϫ bcma / mice has not provided further clues to this question. Ini- (36). The JNKK2 (K149M) mutant, I-␬BSR, and the GST irrelevant con- tial examination of the BCMA-deficient mice revealed no discern- trol were cloned into the retroviral vector upstream of an IRES-GFP cas- ible phenotype (5, 31) but a more recent analysis indicated that sette.