The PD-1 Regulatory Axis Inhibits T Cell–Independent B Cell Memory Generation and Reactivation

Abstract

The inability of T cell–independent type 2 (TI-2) Ags to induce recall responses is a poorly understood facet of humoral immunity, yet critically important for improving vaccines. Using normal and VHB1–8 transgenic mice, we demonstrate that B cell–intrinsic PD-1 expression negatively regulates TI-2 memory B cell (Bmem) generation and reactivation in part through interacting with PDL1 and PDL2 on non–Ag-specific cells. We also identified a significant role for PDL2 expression on Bmems in inhibiting reactivation and Ab production, thereby revealing a novel self-regulatory mechanism exists for TI-2 Bmems. This regulation impacts responses to clinically relevant vaccines, because PD-1 deficiency was associated with significantly increased Ab boosting to the pneumococcal vaccine after both vaccination and infection. Notably, we found a B cell–activating adjuvant enabled even greater boosting of protective pneumococcal polysaccharide-specific IgG responses when PD-1 inhibition was relieved. This work highlights unique self-regulation by TI-2 Bmems and reveals new opportunities for significantly improving TI-2 Ag-based vaccine responses. Key Points B cell–intrinsic PD-1 expression inhibits TI-2 Bmem formation and reactivation. PDL2 expressed by TI-2 Bmem contributes to self-suppression of reactivation. Adjuvant enables robust IgG boosting to PPS in the context of PD-1 deficiency.