Programmed cell death 1 (PD-1) was isolated in 1992 by subtractive-hybridization technique, as a molecule whose expression is enhanced by apoptotic stimuli. Since then we have been analyzing the function of PD-1 in the regulation of immune responses. Generation of PD-1 deficient mice, pathophysiological analyses of autoimmune diseases in PD-1 deficient mice, identification of two ligands, and analyses of downstream events of PD-1 revealed that PD-1 prevents autoimmunity by inhibiting activation of self-reactive lymphocytes. These findings were further applied on human autoimmune diseases and single nucleotide polymorphisms (SNPs) on human PD-1 gene have been reported to link with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and type I diabetes.