PD-L1 promotes T cell help to B cells 2238

Abstract Description Germinal center (GC) responses generate humoral immunity through coordinated interactions between B cells and T follicular helper (TFH) and T follicular regulatory (TFR) cells. Despite high expression of PD-1 by TFH and TFR cells, the function of its ligand PD-L1 in the GC remains unknown. Here, we show that PD-L1 tunes T-B collaboration in the GC to promote humoral immunity. Integrated analyses of human and mouse secondary lymphoid organs revealed that follicular dendritic cells (FDCs) express PD-L1 and this expression is increased in autoantibody disease. FDC specific deletion of PD-L1 decreases GC formation and prevents loss of B cell tolerance. Autoreactive B cells also express increased PD-L1 and B cell specific deletion of PD-L1 similarly hinders GC responses. Intravital multiphoton microscopy demonstrated that FDC PD-L1 controls TFH and GC B cells by promoting stable T-B contacts. Single cell analyses of TFH cells revealed that PD-1 expression is highly correlated with Sostdc1 expression, which has been shown to promote TFR formation. Mechanistically, PD-L1 limits TFH production of Sostdc1, thereby suppressing TFR differentiation and enabling the GC response. These findings uncover an immunogenic non-cell autonomous role of PD-L1 that is orthogonal to its well-established role in suppression of cell mediated immunity. We propose a model in which levels of PD-L1 on FDCs and bystander B cells tune the GC response by manipulating the follicular T cell compartment. Funding Sources Supported by grants from NIH (R01AI130307, R01AR074105, T32GM007753, T32GM144273, T32AI007529, and F30AI160909). Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)