Reconfigured immunity in Adar heterozygous and Adar Mavs Eif2ak2 (PKR) triple mutant mice.

Adenosine deaminase acting on RNA 1 (ADAR1) deaminates adenosine to inosine in dsRNA. ADAR1 RNA editing marks cellular dsRNA as self, preventing aberrant activation of the antiviral dsRNA sensor MDA5. Adar Ifih1 (MDA5) or Adar Mavs double mutant pups escape Adar mutant aberrant interferon induction but die early. Here, we show that long-lived Adar Mavs Eif2ak2 (PKR) mice display a new residual defect: failure to maintain blood CD8+ T cells due to loss of an editing-independent function of ADAR1. Further dsRNA sensor-stripping in Adar Mavs Eif2ak2 Zbp1 mutants shows that loss of blood CD8+ T cells is not prevented. Challenging Adar+/- heterozygous or Adar Mavs Eif2ak2 mice with blood stage Plasmodium yoelii infection led to reduced parasitemia in Adar+/- mice by increased basal interferon. Unexpected reduced parasitemia in Adar Mavs Eif2ak2 mice is also likely due to interferon-related defects specific to hemopoietic cells, leading to altered populations of γδ T cells and other immune cells. The defects observed in this partially dsRNA sensor-stripped mouse suggest that different antiviral dsRNA sensors normally complement each other.