PD-1はde novoゲノム変異によって引き起こされる免疫応答を抑制する

抄録

Programmed death-1 (PD-1) is a negative regulator of immune responses. In PD-1-deficient mice, autoimmune symptoms develop only as they age. In cancer immunotherapy models, PD-1 has been shown to prevent cytotoxic T lymphocytes from attacking cancer cells that express mutation-derived neoantigens. To understand the common molecular mechanisms underlying these findings, we hypothesize that PD-1 suppresses excessive immune responses against neoantigens in normal somatic cells of aged individuals. To test this, we introduced random mutations into the genome of wild-type (WT) and PD-1 knockout (KO) mice. We employed a genetic approach of random mutagenesis by deleting the Msh2 gene, which is essential for the mismatch-repair activity in the nucleus and, therefore, for the suppression of accumulation of random mutations in the genome. Granulomatous inflammatory responses were elicited in Msh2/PD-1 double KO mice but not in Msh2 single KO mice. In parabiosis experiments, surgical connection of an Msh2 KO mouse with a PD-1 KO mouse resulted in the development of inflammatory lesions in the Msh2 KO mouse but not in the Msh2 KO mouse surgically connected with a WT mouse. These results strongly support our hypothesis about the physiological function(s) of PD-1.