title: BAFF regulates activation of self-reactive T cells through B-cell dependent mechanisms and mediates protection in NOD mice.
abstract: Targeting the BAFF/APRIL system has shown to be effective in preventing T-cell dependent autoimmune disease in the NOD mouse, a spontaneous model of type 1 diabetes. In this study we generated BAFF-deficient NOD mice to examine how BAFF availability would influence T-cell responses in vivo and the development of spontaneous diabetes. BAFF-deficient NOD mice which lack mature B cells, were protected from diabetes and showed delayed rejection of an allogeneic islet graft. Diabetes protection correlated with a failure to expand pathogenic IGRP-reactive CD8(+) T cells, which were maintained in the periphery at correspondingly low levels. Adoptive transfer of IGRP-reactive CD8(+) T cells with B cells into BAFF-deficient NOD mice enhanced IGRP-reactive CD8(+) T-cell expansion. Furthermore, when provoked with cyclophosphamide, or transferred to a secondary lymphopenic host, the latent pool of self-reactive T cells resident in BAFF-deficient NOD mice could elicit beta cell destruction. We conclude that lack of BAFF prevents the procurement of B-cell-dependent help necessary for the emergence of destructive diabetes. Indeed, treatment of NOD mice with the BAFF-blocking compound, BR3-Fc, resulted in a delayed onset and reduced incidence of diabetes.
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Centre of Immunology and Inflammation, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Eliana
authors.initials: E
authors.lastname: Mariño
authors.forename: Stacey N
authors.initials: SN
authors.lastname: Walters
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Villanueva
authors.forename: James L
authors.initials: JL
authors.lastname: Richards
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005952:Glucose-6-Phosphatase / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D016381:Islets of Langerhans Transplantation / Q000379:methods; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D053264:B-Cell Activating Factor; C505720:Tnfsf13b protein, mouse; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse
keywords: BAFF; Diabetes; Islet allograft; NOD mice; Self-reactive T cells