BAFF regulates activation of self-reactive T cells through B-cell dependent mechanisms and mediates protection in NOD mice
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 which mice 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 full T cell activation and 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||Marino E.M, Walters S.N, Villanueva J.E, Richards J.L, Mackay C.R and Grey S.T.|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12089|