Schille, Melanie E.

Neurons upregulate major histocompatibility complex class I (MHC I) during demyelination, enabling the presentation of self-antigens to cytotoxic CD8 + T cells. While this phenomenon is well described in multiple sclerosis lesions, its functional significance for disease progression remains poorly understood. Here, we test the hypothesis that neuronal MHC I expression promotes CD8 + T cell-mediated neurodegeneration in demyelinating disease. Using genetic and viral approaches to selectively ablate β ₂-microglobulin (β₂M) in neurons, we demonstrate that the loss of neuronal MHC I limits antigen presentation, attenuates the activation of neuron-antigen–specific CD8 + T cells, and reduces the recruitment of these cells to the demyelinated central nervous system (CNS). In myelin oligodendrocyte glycoprotein (MOG₃₅–₅₅)-induced experimental autoimmune encephalomyelitis, CD8 + T cell ablation during active disease limited neuronal injury and improved clinical recovery. Similarly, neuronal β ₂M ablation decreased clinical disease burden without affecting CNS T cell infiltration. Likewise, in the context of cuprizone intoxication, neuronal β ₂M deletion reduced peripheral activation and CNS recruitment of CD8 + T cells recognizing a neuron-restricted neoantigen. It protected neoantigen-expressing neurons from cognate CD8 + T cell-mediated cytotoxicity. Collectively, these findings identify neuronal MHC I–dependent antigen presentation as a driver of both the immune surveillance of neuronal antigens and neuronal injury during demyelination.