The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4⁺ T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8⁺ T cells are controversial. We have generated humanized mice expressing the multiple sclerosis–associated MHC class I alleles HLA-A^*0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A^*0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8⁺ T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3–restricted CD8⁺ T cells in induction of multiple sclerosis–like disease and for CD4⁺ T cells in its progression, and we also define a possible mechanism for HLA-A^*0201–mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8⁺ T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.