PD-1 suppresses germinal center reaction and affinity maturation of antibodies 2877

Description Autoantibodies are fundamental hallmark of autoimmune diseases. Aberrant antibody production in PD-1-knockout mice has implicated PD-1 in the regulation of antibody production. We have previously reported that PD-1 stimulation using agonist antibody could suppress antibody production in immunized mice and prevent autoantibody production in lupus models. To understand the mechanism by which PD-1 stimulation downregulates antibody production, we analyzed the target cells that are responsible for this effect. Although PD-1 expression could be found in CD4+ T cells and B cells, the PD-1 agonist downregulated antibody response by targeting CD4+ T cells, but the direct effect on B cells was dispensable. This result was consistent with the inhibition of Tfh cells and germinal center B cells by PD-1 agonist treatment in vivo. The lack of germinal center formation impaired affinity maturation as shown by the reduction of high-affinity antibodies and the mutation frequency in the immunoglobulin gene. In conclusion, PD-1 negatively regulates antibody production by targeting Tfh cells and by preventing germinal center formation. The inhibition of Tfh cells and Tph cells by PD-1 agonist antibodies might provide a novel strategy for the treatment of autoimmune diseases through the reduction of autoantibody titers and their affinity to target molecules. Funding Sources Supported by Meiji Seika Pharma Co., Ltd.