Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain.

One-sentence summary. We find that IFN-γ induces transcription of MHC class I antigen processing and presentation machinery in all major parenchymal cell types in the ventral midbrain in vivo; however, neuronal responses are low amplitude and limited to a small set of genes, MHC class II expression and cellular proliferation are restricted to microglia, and dopamine neuronal responses require cell autonomous expression of IFNGR1. Dysregulated inflammation within the central nervous system (CNS) contributes to neuropathology in infectious, autoimmune, and neurodegenerative disease. With the exception of microglia, however, major histocompatibility complex (MHC) proteins are virtually undetectable in the mature, healthy central nervous system (CNS). Neurons in particular have generally been considered incapable of antigen presentation, and although interferon gamma (IFN-γ) can elicit neuronal MHC class I (MHC-I) expression and antigen presentation in vitro, it has been unclear whether similar responses occur in vivo or if such responses might be cell-autonomous or dependent on peripheral inflammation. Here we directly inject IFN-γ into the ventral midbrain of mature mice and analyze gene expression profiles of specific CNS cells. We found that IFN-γ upregulated MHC-I and associated mRNAs in ventral midbrain microglia, astrocytes, oligodendrocytes, and GABAergic, glutamatergic, and dopaminergic neurons. The core set of IFN-γ-induced genes and their response kinetics were present in both neurons and glia, with a lower amplitude of expression in neurons. A diverse repertoire of genes was upregulated in glia, particularly microglia, which were the only cells to undergo cellular proliferation and express MHC-II and associated genes. To determine if neurons respond to in a cell-autonomous manner, we produced mutant mice with a deletion of the IFN-γ-binding domain of IFNGR1 only in dopaminergic neurons, which resulted in a complete loss of dopaminergic neuronal response to IFN-γ. Our results demonstrate that neurons can respond to IFN-γ in a cell-autonomous manner by upregulating MHC-I and its related genes in vivo, although the expression level is low compared to oligodendrocytes, astrocytes, and microglia.