Programmed PD-1 Cells Protect Against Autoimmunity by Culling the Peripheral Accumulation of Autoreactive CD4 T Cells
Published Nov. 8, 2016
Cell Reports
In unpeeling the complexities of autoimmune development, a study led by researchers at Cincinnati Children’s demonstrates an essential role played by the coinhibitory molecule, programmed death-1 (PD-1).
The findings are significant because they may help explain why some cancers and infectious pathogens become so effective at subverting the body’s immune defenses, as well as why autoimmune side effects can develop after PD-1-neutralizing checkpoint therapies.
The study was led by Sing Sing Way, MD, PhD, the Pauline and Lawson Reed Chair in the Division of Infectious Diseases. The team also included two colleagues from the Division of Infectious Diseases and two researchers from University of Minnesota School of Medicine.
The team examined the incomplete way self-reactive CD4 T cells are deleted during thymic development. They reported that each wave of CD4 T cells that eludes this deletion process autonomously upregulates PD-1. In doing so, these cells maintain self-tolerance, which has long been a challenge for researchers to solve.
“Under normal laws of science and immunology,” Way says, “the immune cells that are self-reactive, or potentially cause harm, are eliminated during development. We developed a new model to track all these cells and how they respond to our bodies’ own self-antigens by quickly expanding.”
That model involved tracking the progeny derived from clones of individual autoreactive CD4 T cells. The model revealed that the self-reactive cells with the greatest autoimmune threat and highest self-antigen affinity also express the most PD-1.
Reciprocally, PD-1 deprivation unleashes high-affinity self-reactive CD4 T cells in target tissues, a process that worsens neuronal inflammation and autoimmune diabetes.
