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A major complication of hemophilia A therapy is the development of alloantibodies (inhibitors) that neutralize intravenously administered coagulation factor VIII (FVIII). Immune tolerance induction therapy (ITI) by repetitive FVIII injection can eradicate inhibitors, and thereby reduce morbidity and treatment costs. However, ITI success is difficult to predict and the underlying immunological mechanisms are unknown. Here, we demonstrated that immune tolerance against FVIII under nonhemophilic conditions was maintained by programmed death (PD) ligand 1 (PD-L1)-expressing regulatory T cells (Treg) that ligated PD-1 on FVIII-specific B cells, causing them to undergo apoptosis. FVIII-deficient mice injected with FVIII lacked such Treg and developed inhibitors. Using an ITI mouse model, we found that repetitive FVIII injection induced FVIII-specific PD-L1 + Tregs and re-engaged removal of inhibitor-forming B cells. We demonstrated the existence of FVIII-specific Tregs also in humans and showed that such Tregs upregulated PD-L1 after successful ITI.Simultaneously, FVIII-specific B cells upregulated PD-1 and became killable by Tregs. In summary, we showed that PD-1-mediated B cell tolerance against FVIII operated in healthy individuals and in hemophilia A patients without inhibitors, and that ITI re-engaged this mechanism. These findings may impact monitoring of ITI success and treatment of hemophilia A patients.

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