B Cell-Activating Factor Belonging to the TNF Family (BAFF)-R Is the Principal BAFF Receptor Facilitating BAFF Costimulation of Circulating T and B Cells This information is current as of September 23, 2021. Lai Guan Ng, Andrew P. R. Sutherland, Rebecca Newton, Fang Qian, Teresa G. Cachero, Martin L. Scott, Jeffrey S. Thompson, Julie Wheway, Tatyana Chtanova, Joanna Groom, Ian J. Sutton, Cynthia Xin, Stuart G. Tangye, Susan L. Kalled, Fabienne Mackay and Charles R. Mackay Downloaded from J Immunol 2004; 173:807-817; ; doi: 10.4049/jimmunol.173.2.807 http://www.jimmunol.org/content/173/2/807 http://www.jimmunol.org/ References This article cites 51 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/173/2/807.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology B Cell-Activating Factor Belonging to the TNF Family (BAFF)-R Is the Principal BAFF Receptor Facilitating BAFF Costimulation of Circulating T and B Cells1 Lai Guan Ng,2* Andrew P. R. Sutherland,2*† Rebecca Newton,* Fang Qian,§ Teresa G. Cachero,§ Martin L. Scott,§ Jeffrey S. Thompson,§ Julie Wheway,* Tatyana Chtanova,*† Joanna Groom,* Ian J. Sutton,* Cynthia Xin,*† Stuart G. Tangye,‡ Susan L. Kalled,§ Fabienne Mackay,*† and Charles R. Mackay3*† BAFF (B cell-activating factor belonging to the TNF family) is a cell survival and maturation factor for B cells, and overproduction of BAFF is associated with systemic autoimmune disease. BAFF binds to three receptors, BAFF-R, transmembrane activator and Downloaded from calcium modulator and cyclophilin ligand interactor (TACI), and B cell maturation Ag (BCMA). Using specific mAbs, BAFF-R was found to be the predominant BAFF receptor expressed on peripheral B cells, in both humans and mice, and antagonist mAbs to BAFF-R blocked BAFF-mediated costimulation of anti-␮ responses. The other BAFF receptors showed a much more restricted expression pattern, suggestive of specialized roles. BCMA was expressed by germinal center B cells, while TACI was expressed predominantly by splenic transitional type 2 and marginal zone B cells, as well as activated B cells, but was notably absent from germinal center B cells. BAFF was also an effective costimulator for T cells, and this costimulation occurs entirely through http://www.jimmunol.org/ BAFF-R. BAFF-R, but not TACI or BCMA, was expressed on activated/memory subsets of T cells, and T cells from BAFF-R mutant A/WySnJ mice failed to respond to BAFF costimulation. Thus, BAFF-R is important not only for splenic B cell maturation, but is the major mediator of BAFF-dependent costimulatory responses in peripheral B and T cells. The Journal of Immunology, 2004, 173: 807–817. he B cell-activating factor from the TNF family (BAFF)4 and salivary glands of Sjo¨gren’s syndrome patients (7). These el- (also known as BLyS, TALL-1, zTNF-4, THANK, evated levels of BAFF in blood and tissues in human autoimmune TNFSF 13b), is emerging as an important regulator of B patients likely affect peripheral B cell survival as well as B cell T by guest on September 23, 2021 cell and T cell responses. BAFF was originally identified as a maturation and activation in the spleen, similar to effects of BAFF factor responsible for B cell survival and maturation (reviewed in in BAFF transgenic mice. Although high levels of BAFF have Refs. 1–3). BAFF was subsequently associated with autoimmune been associated mostly with autoimmune diseases, BAFF is likely disease, because transgenic mice overproducing BAFF produce important for normal immune responses to microbial challenge, by autoantibodies and develop diseases akin to human systemic lupus priming or enhancing T and B cell activity to facilitate clearance erythematosus and Sjo¨gren’s syndrome (4–8). In humans, high (11). The baff gene, located in humans on chromosome 13, has levels of BAFF are detectable in the blood of a proportion of been identified as a likely determinant for susceptibility to Ascaris patients with autoimmune rheumatic diseases, particularly sys- infection (12). temic lupus erythematosus and Sjo¨gren’s syndrome (7, 9, 10), and BAFF binds to several receptors. These include transmembrane BAFF is present at high levels in rheumatoid synovial fluid (9), activator and calcium modulator and cyclophilin ligand interactor (TACI), BAFF-R (BR3), and B cell maturation Ag (BCMA) (13– 17). Another TNF family member termed a proliferation-inducing *Arthritis and Asthma Research Program, The Garvan Institute of Medical Research, Sydney, †Cooperative Research Center for Asthma, Sydney, ‡Centenary Institute of ligand (APRIL) also binds to TACI and BCMA (14, 18). BAFF-R Cancer Medicine and Cell Biology, Newtown, New South Wales, Australia; and appears to be particularly important for the regulation of B cell §Department of Research, Biogen Idec Inc., Cambridge, MA 02142 survival and maturation in the spleen, because A/WySnJ mice ex- Received for publication March 15, 2004. Accepted for publication May 14, 2004. pressing a defective BAFF-R have disrupted B cell maturation, The costs of publication of this article were defrayed in part by the payment of page similar to that seen in BAFF-deficient mice (17, 19). The BCMA charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. receptor appears not to play a role in B cell maturation but is 1 This work was supported by the Wellcome Trust, the Cooperative Research Center involved in plasma cell survival (20). In TACI-deficient mice, for Asthma, and the National Heath and Medical Research Council of Australia. there are increased B cell numbers, marked splenomegaly, and 2 L.G.N. and A.S. contributed equally to this work. mice develop autoimmune disorders (21). Antigenic challenge in 3 Address correspondence and reprint requests to Dr. Charles R. Mackay, Arthritis these mice results in enhanced Ab production (21). Because an and Inflammation Research Program, The Garvan Institute of Medical Research, 384 agonistic mAb to TACI inhibited B cell proliferation, signaling Victoria Street, Sydney, New South Wales 2010, Australia. E-mail address: [email protected] through TACI may in fact serve to down-regulate B cell activity (21). 4 Abbreviations used in this paper: BAFF, B cell-activating factor belonging to the TNF family; BCMA, B cell maturation Ag; h., human; hIgG, human IgG; GC, ger- BAFF and possibly APRIL also act on T cells. In vitro studies minal center; m., mouse; MZ, marginal zone; RBL, rat basophilic leukemia; TACI, of human T cells showed that BAFF provided a complete costimu- transmembrane activator and calcium modulator and cyclophilin ligand interactor; T1, transitional type 1; T2, transitional type 2; WT, wild type; APRIL, a proliferation- latory signal together with anti-TCR stimulation (22, 23). In mice, inducing ligand. a TACI-Fc fusion protein blocked activation of T cells in vitro, and Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 808 BAFF-R IS THE PRINCIPAL BAFF RECEPTOR FOR B AND T CELLS inhibited T cell priming in vivo (24). Also, treatment with hIgG (Novartis Pharmaceuticals, East Hanover, NJ), h.BCMA-Fc, or anti- TACI-Fc substantially inhibited inflammation, as well as bone and mouse BAFF-R (m.BAFF-R) mAbs (29). For Ag-specific T cell assays, cartilage destruction, in a mouse model of rheumatoid arthritis splenic T cells from DO11.10 TCR transgenic mice were purified by mag- netic separation, and 5 ϫ 104 cells/well were cultured with 1 ϫ 105 cells/ (24). T cells from transgenic mice that overexpressed human well of mitomycin C-inactivated APC, together with OVA peptide in 96- APRIL showed greatly enhanced survival in vitro and in vivo (25). well U-bottom plates. BAFF costimulation of T cells was performed by In autoimmune patients, inappropriate costimulation of T and B adding 4 ␮g/ml soluble BAFF or denatured BAFF to wells. For inhibition cells by BAFF may be an important component of disease patho- assays, cells were cultured with anti-m.BAFF-R mAbs (2 ␮g/ml), h.B- CMA-Fc, or hIgG (2 ␮g/ml). genesis. The receptor for BAFF on T cells is largely unknown, For anti-CD3 T cell proliferation assay, human T cells were activated although one study reported TACI expression on a subset of acti- using plate-bound anti-human CD3 mAb (mAb TR66), and mouse T cells vated T cells using a polyclonal Ab (26). Expression of BCMA and were activated with anti-mouse-CD3 mAb 145-2C11 (BD Pharmingen). BAFF-R is thought to be restricted to B cells (16, 17, 27, 28). Anti-CD3 mAb and BAFF were coated onto plates overnight in PBS at 4°C either separately or in combination, followed by two PBS washes. A total The critical functions of BAFF for B and T cell biology are ϩ of 2 ϫ 106 PBMC (human) or CD3 (human or mouse) cells/ml were facilitated by the regulated expression of BAFF receptors.