Neuronal expression of β2M and MHC I are essential for peripheral surveillance and targeting of neuron-restricted antigens.

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 β₂-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 β₂M ablation decreased clinical disease burden without affecting CNS T cell infiltration. Likewise, in the context of cuprizone intoxication, neuronal β₂M 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.