PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance

TLDR

PD‑1 signaling regulates T‑cell activation, tolerance, and exhaustion, yet its role in regulatory T cells has been largely unexplored compared to effector T cells. The study aimed to determine how PD‑1 functions within regulatory T cells. To address this, the authors generated mice with T‑reg‑specific deletion of PD‑1. PD‑1‑deficient regulatory T cells displayed an activated phenotype, heightened suppressive capacity, and, in vivo, reduced experimental autoimmune encephalomyelitis and diabetes incidence, a phenotype linked to diminished PI3K‑AKT signaling, demonstrating that PD‑1 restrains T‑reg function to maintain tolerance and prevent autoimmunity.

Abstract

Inhibitory signals through the PD-1 pathway regulate T cell activation, T cell tolerance, and T cell exhaustion. Studies of PD-1 function have focused primarily on effector T cells. Far less is known about PD-1 function in regulatory T (T reg) cells. To study the role of PD-1 in T reg cells, we generated mice that selectively lack PD-1 in T reg cells. PD-1–deficient T reg cells exhibit an activated phenotype and enhanced immunosuppressive function. The in vivo significance of the potent suppressive capacity of PD-1–deficient T reg cells is illustrated by ameliorated experimental autoimmune encephalomyelitis (EAE) and protection from diabetes in nonobese diabetic (NOD) mice lacking PD-1 selectively in T reg cells. We identified reduced signaling through the PI3K–AKT pathway as a mechanism underlying the enhanced suppressive capacity of PD-1–deficient T reg cells. Our findings demonstrate that cell-intrinsic PD-1 restraint of T reg cells is a significant mechanism by which PD-1 inhibitory signals regulate T cell tolerance and autoimmunity.