Impaired development of memory B cells and antibody responses in humans and mice 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. [Display omitted] •Impaired B cell memory in PD-1- and PD-L1-deficient humans and mice deficient in PD-1 signaling•PD-1 deficiency but not PD-L1 deficiency disrupts Tfh cell phenotype and function•Human PD-1-PD-L1 axis promotes antibody responses in a B cell-intrinsic manner•B cell-specific deletion of PD-1 triggers striking phenotypic alterations in mice Ogishi, Kitaoka, et al. examine humans deficient in PD-1 and PD-L1 as well as associated mouse models and find that PD-1 and PD-L1 promote B cell memory and antibody responses through both T cell-dependent and B cell-intrinsic mechanisms. Their findings provide insight into the mechanisms underlying the infectious and autoimmune complications associated with anti-PD-1-PD-L1 immunotherapy.