Mice lacking the CTLA-4 gene developed lymphoproliferative diseases and died by 3–4 weeks of age,446,447 whereas mice lacking PD-1 had more limited and variable, model-dependent autoimmunity, including glomerulonephritis, arthritis and cardiomyopathy.376,448–450 Spatially, CTLA-4 regulation occurs primarily within lymphoid organs, whereas PD-1 limits T-cell activation locally within peripheral tissues.451,452 Temporally, PD-1 acts later during T-cell activation for long-term tolerance. Here, PDCD1 is linked to arthritic joint disease.