A selective role of NKG2D in inflammatory and autoimmune diseases

• Experimental autoimmune encephalitis was less severe in NKG2D knockout mice.
• Type 1 diabetes is unchanged in NKG2D-deficient NOD mice and BDC2.5 transgenic mice.
• NKG2D antibody treatment of NOD mice did not prevent type I diabetes.
• Poly(I:C)-induced intestinal inflammation was unchanged in NKG2D knockout mice.
• NKG2D antibody treatment did not prevent poly(I:C)-induced intestinal inflammation.

The NKG2D activating receptor has been implicated in numerous autoimmune diseases. We tested the role of NKG2D in models of autoimmunity and inflammation using NKG2D knockout mice and antibody blockade experiments. The severity of experimental autoimmune encephalitis (EAE) was decreased in NKG2D-deficient mice when the disease was induced with a limiting antigen dose, but unchanged with an optimal antigen dose. Surprisingly, however, NKG2D deficiency had no detectable effect in several other models, including two models of type 1 diabetes, and a model of intestinal inflammation induced by poly(I:C). NKG2D antibody blockade in normal mice also failed to inhibit disease in the NOD diabetes model or the intestinal inflammation model. Published evidence using NKG2D knockout mice demonstrated a role for NKG2D in mouse models of atherosclerosis and liver inflammation, as well as in chronic obstructive pulmonary disease. Therefore, our results suggest that NKG2D plays selective roles in inflammatory diseases.