One of the early proofs of PD-1 being involved in maintenance of self-tolerance came in 1999, where a knock-out mouse model showed that a defect in the PD-1 gene specifically predisposes to development of lupus-like autoimmune disease suggesting that PD-1 serves as a negative regulator of immune responses (103). This evidence concerns the gene PDCD1 and systemic lupus erythematosus.