Glia exhibit differential susceptibility to CD8 T cell mediated effector mechanisms during neurotropic coronavirus infection. In contrast to microglia, oligodendroglia are resistant to CD8 T cell perforin‐mediated viral control in the absence of IFNγ. Kinetic induction of MHC Class I expression by microglia and oligodendroglia in vivo was thus analyzed to assess responses to distinct inflammatory signals. Flow cytometry demonstrated delayed Class I surface expression by oligodendroglia compared with microglia. Distinct kinetics of Class I protein upregulation correlated with cell type specific transcription patterns of genes encoding Class I heavy chains and antigen processing components. Microglia isolated from naïve mice expressed high levels of these mRNAs, whereas they were near detection limits in oligodendroglia; nevertheless, Class I protein was undetectable on both cell types. Infection induced modest mRNA increases in microglia, but dramatic transcriptional upregulation in oligodendroglia coincident with IFNα or IFNγ mRNA increases in infected tissue. Ultimately mRNAs reached similar levels in both cell types at their respective time points of maximal Class I expression. Expression of Class I on microglia, but not oligodendroglia, in infected IFNγ deficient mice supported distinct IFN requirements for Class I presentation. These data suggest an innate immune preparedness of microglia to present antigen and engage CD8 T cells early following infection. The delayed, yet robust, IFNγ dependent capacity of oligodendroglia to express Class I suggests strict control of immune interactions to avoid CD8 T cell recognition and potential presentation of autoantigen to preserve myelin maintenance. © 2008 Wiley‐Liss, Inc.