PD-L1 expression in germinal centers promotes humoral immunity by restricting T follicular regulatory cell differentiation

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 is unclear. Here, we show an immunogenic role for PD-L1 via tuning T-B collaboration to promote humoral immunity. Integrated analyses of secondary lymphoid organs (SLOs) revealed that B cell zone reticular cells (BRCs), including follicular dendritic cells (FDCs), expressed PD-L1. BRC expression of PD-L1 facilitated GC formation and enabled loss of B cell tolerance in autoantibody disease. Mechanistically, BRC-specific deletion of PD-L1 enhanced TFH cell production of Sostdc1 and TFR cell differentiation, destabilizing T-B contacts in the GC. Patient-derived tumor biopsies indicated that a tumor-infiltrating TFH SOSTDC1 signature inversely correlated with immunotherapy responsiveness. These findings reveal a non-canonical immunogenic role for PD-L1 in the GC and suggest that augmenting B cell responses could improve the efficacy of PD-L1 blockade.