Blockade of BAFF Receptor BR3 on T Cells Enhances Their Activation and Cytotoxicity

The BAFF receptor BR3 plays key roles in B-cell activation, maturation, and survival whereas the function of BR3 on T lymphocytes is less well characterized. Previous reports have demonstrated that BR3 costimulates human T-cell activation in vitro in the presence of high nonphysiological levels of plate-bound BAFF. Here, relying on the soluble and membrane-bound BAFF expressed by T cells themselves, we investigated the function of BR3 on activated primary CD4 and CD8 T lymphocytes using a BR3-specific neutralization antibody and shRNA gene down-modulation. Interestingly, the anti-BR3 blocking antibody resulted in significant augmentation of CD25 and IFN-γ expression by both subsets, as did shRNA-mediated down-modulation of BR3. In addition, granzyme B expression was substantially elevated in anti-BR3-treated and BR3-silenced T cells. Anti-BR3 blockade increased the expression of CD25 on cytolytic CRTAM T cells. Importantly, anti-BR3 significantly enhanced redirected killing of P-815 cells by both CD4 and CD8 cytotoxic T cells [cytotoxic T lymphocytes (CTLs)]. Furthermore, anti-BR3-augmented CD4 T-cell-mediated killing of class II melanoma cell line A375 and cervical cancer cell line HeLa in vitro, increasing the level of granzyme B activity as measured by PARP-1 cleavage and active caspase 3. Together, our data indicate that BR3 neutralization increases the activation and cytolytic function of CD4 and CD8 cytotoxic T lymphocytes. Our findings provide a novel strategy for ex vivo T-cell activation applicable to T-cell immunotherapy platforms such as TIL or CAR-T cell therapeutics.