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<p>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 <i>β</i>-cell function in T1D.</p>

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PD-1/PD-L1 pathway and the U-Curve paradigm: implications for type 1 diabetes immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Jiahui Chen,
  • Hanbin Zhang,
  • Peng Yu,
  • Linghua Fu,
  • Pingping Yang

摘要

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.