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.
Bibliographical noteFunding Information:
We thank Drs. Theresa Alenghat, Hitesh Deshmukh, David Haslam, David Hildeman, Jonathan Katz, and Joseph Qualls for helpful discussions; Dr. Baolin Wu for help with statistical analysis; Linnea Swanson and Nathanael Sahli for technical assistance; and the NIH Tetramer Core Facility (Contract HHSN272201300006C ) for provision of class II MHC tetramers (MOG 35-55 :I-A b , influenza A virus NP 311-325 :I-A b ). This work was supported by NIH Grants F30-DK107199 and T32-GM063483 (T.T.J.), R01-AI106791 (B.T.F.), and R01-AI120202 (S.S.W.); Juvenile Diabetes Research Foundation Grant 2-2011-662 (to B.T.F.); and March of Dimes Foundation Grant 6-FY15-254 (to S.S.W.). S.S.W. holds a Pathogenesis of Infectious Disease Award ( #1011031 ) from the Burroughs Wellcome Fund .
- T cell activation
- peripheral immune tolerance