Tissue expression of PD-L1 mediates peripheral T cell tolerance

TLDR

PD‑1, an inhibitory receptor on activated lymphocytes, regulates tolerance and autoimmunity, with its ligands PD‑L1 broadly expressed on hematopoietic and parenchymal cells and PD‑L2 restricted to macrophages and dendritic cells. The study aimed to determine whether PD‑L1 and PD‑L2 have synergistic or distinct roles in T‑cell activation and tolerance. To address this, the authors generated mice lacking both PD‑L1 and PD‑L2 and compared them to mice lacking either ligand, and performed bone‑marrow chimera experiments to assess tissue‑specific effects. PD‑L1 and PD‑L2 both suppress IL‑2 and IFN‑γ production, but PD‑L1 uniquely controls pancreatic self‑reactive T cells; expression only on antigen‑presenting cells fails to prevent early diabetes, whereas islet PD‑L1 protects against immunopathology and inhibits pathogenic CD4⁺ T‑cell‑mediated destruction, demonstrating that parenchymal PD‑L1 mediates tissue tolerance.

Abstract

Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells; and PD-L2, which is restricted to macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have synergistic or unique roles in regulating T cell activation and tolerance, we generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2(-/-) mice) and compared them to mice lacking either PD-L. PD-L1 and PD-L2 have overlapping functions in inhibiting interleukin-2 and interferon-gamma production during T cell activation. However, PD-L1 has a unique and critical role in controlling self-reactive T cells in the pancreas. Our studies with bone marrow chimeras demonstrate that PD-L1/PD-L2 expression only on antigen-presenting cells is insufficient to prevent the early onset diabetes that develops in PD-L1/PD-L2(-/-) non-obese diabetic mice. PD-L1 expression in islets protects against immunopathology after transplantation of syngeneic islets into diabetic recipients. PD-L1 inhibits pathogenic self-reactive CD4+ T cell-mediated tissue destruction and effector cytokine production. These data provide evidence that PD-L1 expression on parenchymal cells rather than hematopoietic cells protects against autoimmune diabetes and point to a novel role for PD-1-PD-L1 interactions in mediating tissue tolerance.