PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigens

SUMMARY Adaptive B cell immunity to environmental antigens must be regulated by multiple CD4 T cell dependent tolerance mechanisms. Using integrated single cell strategies, we demonstrate that acute PD-1 blockade induces extensive and selective local anti-inflammatory IgG1 plasma cell (PC) differentiation. Expansion of pre-existing IgG1 germinal center (GC) B cell and enhanced GC programming without memory B cell involvement reveals an isotype-specific GC checkpoint that blocks steady-state IgG1 antibody maturation. While there was no adjuvant impact on immunization, acute PD-1 checkpoint blockade exaggerates anti-commensal IgG1 antibody production, alters microbiome composition and exerts its action in a CD4 T cell dependent manner. These findings reveal a PD-1 controlled adaptive B cell tolerance checkpoint that selectively constrains maturation of pre-existing anti-inflammatory antibodies to prevent over-reaction to steady-state foreign antigens. In Brief PD-1 controls an adaptive B cell tolerance checkpoint in steady-state germinal centers to inhibit the maturation and production of IgG1 antibody with pre-existing foreign specificities. Highlights – Acute PD-1 blockade induces extensive IgG1 PC differentiation at homeostasis – PD-1 blockade releases an IgG1 GC B cell checkpoint that drives expansion and PC formation – No adjuvant effect on foreign antigen but expansion of pre-existing IgG1 specificities to non-self – PD-1 exerts CD4 T cell dependent tolerance in the GC to restrict IgG1 maturation to non-self Graphical Abstract