PD-1 was first identified as a putative mediator of apoptosis in 1992,375 and its role in maintaining peripheral tolerance by serving as a negative regulator of immune responses was elucidated in 1999 when Nishimura et al.376 found that PD-1-deficient mice developed a late onset of lupus-like autoimmune disease. This evidence concerns the gene PDCD1 and systemic lupus erythematosus.