PD-1 cooperates with AIRE-mediated tolerance to prevent lethal autoimmune disease

Abstract

Significance A variety of mechanisms safeguard the body from autoimmune reactions, yet how these processes cooperate is largely unclear. Using a range of mouse genetic models, we uncover a critical tolerogenic axis between the autoimmune regulator, AIRE, and the immune checkpoint molecule, PD-1. Their combined loss induced an early-onset lethal autoimmune syndrome driven by autoreactive CD4 + T cells that could not be restrained by regulatory T cells. These data shed light on how central and peripheral tolerance mechanisms work together, and highlight thymic function as a potentially key modifier of responses to anti–PD-1 therapies.