Impaired Development of Memory B Cells and Antibody Responses in Humans Deficient in PD-1 Signaling

T follicular helper (Tfh) cells abundantly express the immunoreceptor programmed cell death protein 1 (PD-1), and the impact of PD-1 deficiency on antibody (Ab)-mediated immunity in mice is associated with compromised Tfh cell functions. Here, we revisited the role of the PD-1-PD-L1 axis on Ab-mediated immunity. Individuals with inherited PD-1 or PD-L1 deficiency had fewer memory B cells and impaired Ab responses, similar to Pdcd1-/- and Cd274-/-Pdcd1lg2-/- mice. PD-1, PD-L1, or both could be detected on the surface of human naive B cells following in vitro activation. PD-1– or PD-L1–deficient B cells had reduced expression of the transcriptional regulator c-Myc and c-Myc–target genes in vivo, and PD-1 deficiency or neutralization of PD-1 or PD-L1–impeded c-Myc expression and Ab production in human B cells isolated in vitro. Furthermore, B cell–specific deletion of Pdcd1 prevented the physiological accumulation of memory B cells in mice. Thus, PD-1 shapes optimal B cell memory and Ab-mediated immunity through B cell–intrinsic and B cell–extrinsic mechanisms, suggesting that B cell dysregulation contributes to infectious and autoimmune complications following anti–PD-1-PD-L1 immunotherapy.