Abstract The PD-1/PD-L1 pathway is a pivotal regulator of peripheral immune tolerance and a key modulator of pancreatic islet immunity. Paradoxically, both inhibition and overexpression of PD-1/PD-L1 have been associated with either protection or exacerbation of type 1 diabetes (T1D), complicating the development of targeted therapies. Here, we integrate preclinical and clinical evidence to propose the “PD-1/PD-L1 U-Curve Equilibrium Hypothesis,” which posits that immune outcomes are determined by the stoichiometric balance between PD-1 and PD-L1 at the cellular interface. At the nadir of this curve, balanced PD-1/PD-L1 engagement maintains tolerance, whereas deviations toward either extreme-excessive ligand or receptor expression, or disruption by soluble isoforms and checkpoint inhibitors-lead to dysregulated and potentially stimulatory signaling. We review evidence from animal models, immune checkpoint inhibitor–induced diabetes, and emerging PD-1/PD-L1–modulating therapies that illustrate the explanatory and predictive power of this framework. Finally, we outline translational priorities, including biomarker development, spatial and single-cell profiling, precision immune endotyping, and the design of localized PD-1/PD-L1 agonists to restore islet tolerance without systemic immunosuppression. The U-curve hypothesis provides a unified model that reconciles previously conflicting findings and guides the rational design of context-specific PD-1/PD-L1–based immunotherapies aimed at preserving β -cell function in T1D.
Chen et al. (Mon,) studied this question.