Pancreatic islet transplantation is a promising potential cure for type 1 diabetes (T1D). Islet allografts can survive long term in the liver parenchyma. Here we show that liver NK1.1⁺ cells induce allograft tolerance in a T1D mouse model. The tolerogenic effects of NK1.1⁺ cells are mediated through IL-22 production, which enhances allograft survival and increases insulin secretion. Increased expression of NKG2A by liver NK1.1⁺ cells in islet allograft-transplanted mice is involved in the production of IL-22 and in the reduced inflammatory response to allografts. Vaccination of T1D mice with a CpG oligonucleotide TLR9 agonist (ODN 1585) enhances expansion of IL-22-producing CD3-NK1.1⁺ cells in the liver and prolongs allograft survival. Our study identifies a role for liver NK1.1⁺ cells, IL-22 and CpG oligonucleotides in the induction of tolerance to islet allografts in the liver parenchyma.