Non-pathogenic CD8+ T cells in lupus-prone mice regulate neurological and peripheral disease.

Abstract

Abstract Lupus is a systemic 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. We have uncovered a unique bias for CD8+ T cell infiltration in the CNS of mice expressing multiple copies of Toll-like receptor 7 (TLR7[Tg]), which present with a lupus-like disease. These animals exhibit blood brain barrier damage and neuropathology in the presence of infiltrating T cells. 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. Relative to the peripheral CD8+ T cells in lupus-prone mice, those in the CNS represent the most activated lymphocytes in the animal, display a tissue resident-memory phenotype, and can home to the brain. We have also identified a population of CD8+ T cells in the cerebrospinal fluid (CSF) of several lupus patients. Similar to our animal model findings the human CD8+ T cells in the CSF have a large increase in antigen experience by surface phenotyping relative to lymphocytes from peripheral blood. 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 of CNS pathology regulation that could have applicability to human neuropsychiatric manifestations of SLE.