This study systematically reveals the critical roles of PD-1 and PD-L1 in regulating memory B cell generation and antibody responses, showing that their deficiency leads to reduced memory B cells, defective antibody secretion, and decreased BCR repertoire diversity. The study also demonstrates that PD-1 signaling promotes B cell differentiation via the c-Myc pathway, offering new molecular insights into the mechanisms underlying infections and autoimmune complications associated with anti-PD-1/PD-L1 immunotherapy.
Literature Overview
This article, "Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling," published in the journal Immunity, reviews and summarizes the physiological functions of PD-1 and its ligand PD-L1 in B cell immune responses. By analyzing individuals with genetic deficiencies in PD-1 or PD-L1 and corresponding gene knockout mouse models, the study reveals the central role of PD-1 signaling in memory B cell development, antibody diversity, class switching, and long-term humoral immunity. These findings provide a potential mechanistic explanation for infections and autoimmune diseases observed following anti-PD-1/PD-L1 immunotherapy.Background Knowledge
PD-1 (Programmed Cell Death Protein 1) is a key immune checkpoint receptor broadly expressed on activated T cells, B cells, NK cells, and certain myeloid cell populations. Its ligand, PD-L1, is expressed on various immune and non-immune cells, delivering inhibitory signals upon binding to PD-1 to maintain immune tolerance and limit excessive immune responses. PD-1/PD-L1 blocking antibodies are widely used in cancer immunotherapy, but their side effects include increased susceptibility to infections and autoimmune disorders, suggesting a critical physiological role for this pathway in maintaining humoral immune homeostasis. While previous studies have shown PD-1 regulation of IL-21 secretion in Tfh cells, its intrinsic role in B cells remains unclear. This study systematically analyzes the cell-autonomous functions of PD-1 in B cells and its overall contribution to humoral immunity using both human and mouse models, filling an important gap in the field.
Research Methods and Experiments
The study included two Turkish siblings fully deficient in PD-1 and two Moroccan siblings lacking PD-L1, along with healthy controls, and applied flow cytometry, PhIP-Seq, scRNASeq, and bulk RNASeq analyses. Additionally, mouse models including Pdcd1−/−, Cd274−/−Pdcd1lg2−/−, and B cell-specific Pdcd1fl/fl mb1-Cre mice were generated to assess B cell development, memory B cell counts, antibody production, and BCR diversity. In vitro experiments involved treating B cells from healthy donors with anti-PD-1 or PD-L1 blocking agents to evaluate changes in proliferation and antibody secretion. Gene regulatory network analysis further revealed significant downregulation of c-Myc and NF-κB pathways in PD-1-deficient B cells, which were validated for their role in B cell differentiation.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to systematically define the autonomous and non-autonomous regulatory roles of the PD-1:PD-L1 axis in memory B cell development and antibody diversity using human genetic deficiency models. It provides a molecular basis for infections and autoimmune complications following PD-1/PD-L1 blockade therapy. Future studies should explore PD-1 expression and function at distinct B cell developmental stages, evaluate the long-term effects of blocking therapy on vaccine responses and infection susceptibility, and develop targeted interventions to preserve humoral immune homeostasis.
Conclusion
This study systematically elucidates the dual mechanisms by which PD-1 and PD-L1 regulate memory B cell development and humoral immunity through human genetic deficiencies and mouse models. PD-1 deficiency impairs both B cell-intrinsic c-Myc-driven transcriptional programs and T cell-derived IL-21 secretion, ultimately leading to reduced memory B cells, defective antibody production, and diminished BCR diversity. These findings offer novel mechanistic insights into the infections and autoimmune complications associated with PD-1/PD-L1 blockade therapy and highlight the importance of monitoring humoral immunity in treated patients. The study further reinforces the essential role of PD-1 signaling in maintaining normal humoral immune responses, suggesting that its deficiency may affect immune homeostasis via both B cell-autonomous and -extrinsic mechanisms. Future studies should focus on the functional roles of PD-1 in distinct B cell subsets and its potential regulatory impact on vaccine responses and infection defense.
