Granulomatous inflammatory responses are elicited in the liver of PD-1 knockout mice byde novogenome mutagenesis

Abstract Aims programmed death-1 (PD-1) is a negative regulator of immune responses. Upon deletion of PD-1 in mice, symptoms of autoimmunity developed only after they got old. In a model experiment in cancer immunotherapy, PD-1 was shown to prevent cytotoxic T lymphocytes from attacking cancer cells that expressed neoantigens derived from genome mutations. Furthermore, the larger number of genome mutations in cancer cells led to the more robust anti-tumor immune responses after the PD-1 blockade. In order to understand the common molecular mechanisms underlying these findings, we hypothesize that we might have acquired PD-1 during evolution in order to avoid/suppress autoimmune reactions against neoantigens derived from mutations in the genome of aged individuals. Main methods: to test the hypothesis, we introduced random mutations into the genome of young PD-1 -/- and PD-1 +/+ mice. We employed two different procedures of random mutagenesis: administration of a potent chemical mutagen N-ethyl-N-nitrosourea (ENU) into the peritoneal cavity of mice and deletion of MSH2 , which is essential for the mismatch-repair activity in the nucleus and, therefore, for the suppression of accumulation of random mutations in the genome. Key findings we observed granulomatous inflammatory changes in the liver of the ENU-treated PD-1 knockout (KO) mice, but not in the wild-type (WT) counterparts. Such lesions also developed in the PD-1/MSH2 double KO mice, but not in the MSH2 single KO mice. Significance: the results we obtained support our hypothesis: PD-1 probably functions to avoid/suppress inflammatory responses against neoantigens derived from genome mutations in aged individuals.