Abstract Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple organ systems including the skin, kidneys, spleen, lungs, and brain. Severe SLE often manifests with multiple psychiatric and neurological sequelae, and may be accompanied by CNS vasculitis. However, the cellular contributors to CNS disease in lupus patients remain poorly defined. Our data demonstrate a unique lymphocyte bias in the CNS of mice expressing multiple copies of Toll-like receptor 7 (TLR7[Tg], FcgRIIB-Yaa), which present with a lupus-like disease. Lupus-prone mice have a substantial population of infiltrating CD8+ T cells in the CNS, a bias that is not present in other peripheral lymphoid or non-lymphoid tissues. These animals exhibit blood-brain barrier damage and neuropathology in the presence of the infiltrating lymphocytes. However, genetic ablation of CD8+ T cells in lupus-prone mice by removal of the major histocompatibility complex (MHC) adaptor protein b2m results in aggravation of disease, suggesting the removal of a protective population. Circulating CD8+ T cells in lupus-prone mice display an activated phenotype, express a number of surface trafficking and adhesion molecules, and can home to the CNS. The endothelium of the brain, but not of other peripheral organs in these mice is activated, expressing adhesion markers complementary to those found on infiltrating CD8+ T cells. Our ongoing studies aim to elucidate specifically how these CD8+ T cells enter the CNS and further clarify their role in neuropathology. Our findings suggest a possible mechanism regulating CNS pathology that could have applicability to human neuropsychiatric manifestations of SLE.