Programmed Death-1 Culls Peripheral Accumulation of High-Affinity Autoreactive CD4 T Cells to Protect against Autoimmunity.
Self-reactive CD4 T cells are incompletely deleted during thymic development, and their peripheral seeding highlights the need for additional safeguards to avert autoimmunity. Here, we show an essential role for the coinhibitory molecule programmed death-1 (PD-1) in silencing the activation of high-affinity autoreactive CD4 T cells. Each wave of self-reactive CD4 T cells that escapes thymic deletion autonomously upregulates PD-1 to maintain self-tolerance. By tracking the progeny derived from individual autoreactive CD4 T cell clones, we demonstrate that self-reactive cells with the greatest autoimmune threat and highest self-antigen affinity express the most PD-1. Reciprocally, PD-1 deprivation unleashes high-affinity self-reactive CD4 T cells in target tissues to exacerbate neuronal inflammation and autoimmune diabetes. Reliance on PD-1 to actively maintain self-tolerance may explain why exploiting this pathway by cancerous cells and invasive microbes efficiently subverts protective immunity, and why autoimmune side effects can develop after PD-1-neutralizing checkpoint therapies.
Division of Infectious Diseases and Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Tony T
TT
Jiang
Center for Immunology, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
Tijana
T
Martinov
Division of Infectious Diseases and Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Lijun
L
Xin
Division of Infectious Diseases and Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Jeremy M
JM
Kinder
Center for Immunology, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.
Justin A
JA
Spanier
Center for Immunology, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA. Electronic address: bfife@umn.edu.
Brian T
BT
Fife
Division of Infectious Diseases and Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. Electronic address: singsing.way@cchmc.org.
Sing Sing
SS
Way
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002999:Clone Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology
D001324:Autoantigens; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell
T cell activation; autoimmunity; costimulation; peripheral immune tolerance