Important Roles for Gamma Interferon and NKG2D in T-Cell-Induced Demyelination in T-Cell Receptor -Deficient Mice Infected with a Coronavirus

T cells mediate demyelination in athymic (nude) mice infected with the neurotropic coronavirus mouse hepatitis virus strain JHM. Now, we show that these cells also mediate the same process in mice lacking T cells (T-cell receptor -deficient [TCR / ] mice) and demyelination is gamma interferon (IFN) dependent. Most strikingly, our results also show a major role for NKG2D, expressed on T cells, in the demyelinating process with in vivo blockade of NKG2D interactions resulting in a 60% reduction in demyelination. NKG2D may serve as a primary recognition receptor or as a costimulatory molecule. We show that NKG2D T cells in the JHM-infected central nervous system express the adaptor molecule DAP12 and an NKG2D isoform (NKG2D short), both required for NKG2D to serve as a primary receptor. These results are consistent with models in which T cells mediate demyelination using the same effector cytokine, IFN, as CD8 T cells and do so without a requirement for signaling through the TCR.