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The BAFF Receptor TACI Controls IL-10 Production by Regulatory B Cells and CLL B Cells

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The BAFF Receptor TACI Controls IL-10 Production by Regulatory B Cells and CLL B Cells Leukemia (2016) 30, 163–172 © 2016 Macmillan Publishers Limited All rights reserved 0887-6924/16 www.nature.com/leu ORIGINAL ARTICLE The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells D Saulep-Easton1, FB Vincent1, PS Quah1,AWei2,3, SB Ting2,3, CM Croce4,CTam5 and F Mackay1 Interleukin (IL)-10-producing B cells (B10 cells) have emerged as important regulatory elements with immunosuppressive roles. Chronic lymphocytic leukemia (CLL) B cells also secrete IL-10 and share features of B10 cells, suggesting a possible contribution of CLL B cells to immunosuppression in CLL patients. Factors controlling the emergence of B10 cells are not known. B-cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) is critical for B-cell maturation and survival, and is implicated in the development and progression of CLL. We sought to investigate the role of BAFF in the emergence of IL-10-producing regulatory B cells in healthy donors and CLL patients. Here, we report that BAFF signaling promotes IL-10 production by CLL B cells in a mouse model of CLL and in CLL patients. Moreover, BAFF-mediated IL-10 production by normal and CLL B cells is mediated via its receptor transmembrane activator and cyclophilin ligand interactor. Our work uncovered a major targetable pathway important for the generation of regulatory B cells that is detrimental to immunity in CLL. Leukemia (2016) 30, 163–172; doi:10.1038/leu.2015.174 INTRODUCTION niches.15 Incidence of hypogammaglobulinemia increases with Chronic lymphocytic leukemia (CLL) is the most common leukemia advanced disease as the consequence of the extensive breakdown of adults in the developed world.1 It is characterized by the of many immune functions, and has been associated with 16 accumulation of monoclonal neoplastic CD5+CD23+CD19+ B cells increased infectious complications. (CLL B cells) over time, in the peripheral blood and secondary Interleukin (IL)-10 is also a well-known immunosuppressor 17 lymphoid organs including the spleen.2 CLL B cells share (reviewed in Couper et al. ) and numerous studies have phenotypic features with several normal B-cell subsets including implicated IL-10-secreting B (B10) cells as strong immunosuppres- marginal zone B cells, B1 B cells3 and memory B cells.4 sive drivers facilitating the progression of malignancy (reviewed in 18 19 Characteristics such as unmutated immunoglobulin (Ig) variable Mauri and Bosma and Balkwill et al. ). Indeed, the frequency of 5 (ref. 6) 5 fi μ heavy chain (IGVH) genes, and ZAP70 and CD38 proteins, B10 cells was signi cantly increased in E TCL1-Tg mice and 20 are broadly associated with a poor prognosis. As is common in correlated with TCL1 expression. Moreover, the proportion of many hematological malignancies, systemic immunosuppression B10 B cells increased in EμTCL1-Tg mice treated with specific Toll- is associated with a more aggressive disease course.7 like receptor (TLR) ligands.20 However, factors facilitating IL-10 Expression of T-cell leukemia gene 1 (TCL1) has been described production by this subset of B cells remain unknown. as a molecular marker of aggressive disease and poor outcome in B-cell-activating factor of the tumor necrosis factor (TNF) family patients with CLL.8 Transgenic (Tg) mice overexpressing TCL1 (BAFF) is an indispensable survival factor necessary for the under the B-cell-specific μ enhancer (EμTCL1-Tg) develop a maturation and maintenance of B2 B cells (reviewed in Vincent disease similar to progressive CLL. EμTCL1-Tg mice display et al. 21). BAFF mediates class switching, anti-apoptotic activity and cumulative expansion of circulating CD5+CD19+ B cells beginning maintenance of long-lived plasma cells residing in the bone at 3–4 months of age with consequent splenomegaly, hepatome- marrow, via three cognate receptors, namely transmembrane galy and lymphadenopathy, as seen in patients with progressive activator and cyclophilin ligand interactor (TACI), BAFF receptor CLL.9 In addition, the EμTCL1-Tg mice display T-cell dysregulation, (BAFF-R) and B-cell maturation antigen (BCMA), respectively resulting in decreased T-cell activation, increased regulatory T-cell (reviewed in Mackay and Schneider22). A paralogue of BAFF, a (Treg) numbers and attenuated effector function.10 Increased proliferation-inducing ligand (APRIL) also mediates survival effects Treg numbers in EμTCL1-Tg mice11 and in CLL patients12,13 via cognate receptors, TACI and BCMA.22 Both BAFF and APRIL are contribute to active immunosuppression, which facilitates disease implicated in the development and maintenance of leukemic B progression. cells, including CLL (reviewed in Vincent et al.21). Autocrine Multiple immunosuppressive mechanisms have been described production of BAFF in CLL patients is a key driver of tumor in CLL, including indoleamine 2,3-dioxygenase production,12 persistence.23 Early reports suggested a role for BAFF in inducing disruption of effector T-cell synapses14 and evasion of perforin- the emergence of B10 cells in the context of autoimmunity.24 To mediated CD4+ T-cell killing by cellular sequestration in stromal date, the role of the BAFF system in CLL has primarily been 1Department of Immunology, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), Melbourne, Victoria, Australia; 2Department of Haematology, The Alfred Hospital, Melbourne, Victoria, Australia; 3Australian Centre for Blood Diseases, Division of Blood Cancers, Department of Medicine, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), Melbourne, Victoria, Australia; 4Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA and 5Department of Haematology, Peter MacCallum Cancer Centre, St. Andrews’s Place, East Melbourne, Victoria, Australia. Correspondence: Professor F Mackay, Department of Immunology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University AMREP, 89 Commercial Road, Melbourne, VIC 3004, Australia. E-mail: [email protected] Received 8 October 2014; revised 28 April 2015; accepted 16 June 2015; accepted article preview online 3 July 2015; advance online publication, 31 July 2015 TACI and IL-10 in CLL D Saulep-Easton et al 164 studied in the context of tumor survival, yet a role for this factor in Cell cultures active immunosuppression has not been investigated. RPMI and Dulbecco’s modified Eagle’s medium media (Invitrogen) were Here, we report that BAFF stimulation enhanced IL-10 produc- used for all mouse and human cultures, respectively. Media were tion by leukemic B cells in CLL patients and EμTCL1-Tg mice. supplemented with 10% fetal calf serum, L-glutamine, 2ME, HEPES and Furthermore, splenic B cells from TACI-deficient (TACI− / −) mice penicillin/streptomycin; all from Invitrogen. Stimulatory factors were used were unable to secrete IL-10 following TLR stimulation, and TACI− / − at the following concentrations: lipopolysaccharide (LPS), 30 ug/ml; mouse BAFF recombinant protein, 50 ng/ml; human BAFF recombinant protein, mice had undetectable basal serum concentrations of IL-10. These fi 50 ng/ml; mouse APRIL recombinant protein, 50 ng/ml; human APRIL ndings indicate that TACI signaling is important for IL-10 protein, 50 ng/ml; all from R&D Systems (Minneapolis, MN, USA). CpG B production by normal and leukemic B cells. This work expands ODN 1826, 1 μM; CpG B ODN 2006, 1 μM; all purchased from Invivogen our understanding of the BAFF system and highlights the dual (San Diego, CA, USA). CpG stimulations were conducted from 5 to 48 h. In functions of BAFF in supporting CLL B-cell survival and promoting vitro neutralization of protein ligands BAFF and IL-10 was achieved with B10 cells activity and immunosuppression in CLL. purified anti-human BAFF (AF124), anti-mouse BAFF (AF2106), anti-human IL-10 (AF-217-NA) and anti-mouse IL-10 (AF-417-NA) all from R&D Systems and used at 50 μg/ml. In vitro neutralization of BAFF-Rs TACI, BAFF-R and MATERIALS AND METHODS BCMA was achieved with purified anti-mouse TACI (AF1041), anti-mouse BAFF-R (AF1357), anti-mouse BCMA (AF593) and anti-human TACI (AF174), Patients anti-human BAFF-R (AF1162) and anti-human BCMA (AF193) all from R&D Patients were recruited from the Alfred Hospital and the Peter MacCallum Systems and used at 1 μg/ml. Cells were cultured in 96-, 48- or 24-wells cell Cancer Centre. All patients were over 18 years of age and were diagnosed culture plates (BD). with progressive CLL in accordance with the National Cancer Institute (NCI) Working Group criteria for diagnosis and staging. All samples were taken from patients with advanced disease who had not yet received treatment Suppression assay and would require treatment in the near future, according to the NCI In vitro suppression assays were carried out in RPMI supplemented with clinical guidelines.2 The Australasian Leukaemia and Lymphoma Group 10% fetal calf serum in 96-well V-bottom plates (Costar, Corning, NY, USA). 4 + - fl (ALLG) Tissue Bank provided cryosamples of CLL lymphocytes. The In all, 2.5 × 10 autologous CD4 CD25 responder T cells were uorescence- μ Australian Red Cross Blood Service collected and provided age-matched activated cell-sorted (FACS) from spleens of WT or E TCL1-Tg mice and stained with AlexaFluor cytotracker proliferation dye (eBioscience). FACS- healthy donor (HD) whole blood samples. All patients involved in this + + + study provided written informed consent. Patients undergoing therapy for sorted CD4 CD25 CD39 Tregs were cultured with IL-10 for 12 h, then CLL or other pathologies were excluded from this study. This study was FACS-sorted and co-cultured as ratios of 1:8, 1:4 and 1:2 relative to fi responder cells. Stimulation was carried out with CD3/CD28 beads approved by the ALLG scienti c and management committees, and the fi fi ethics review boards of The Alfred Hospital and Monash University.
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