Relapsing–Remitting Central Nervous System Autoimmunity Mediated by GFAP-Specific CD8 T Cells

Abstract

Multiple Sclerosis (MS) is an inflammatory disease of the CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons and axons. Historically, MS has been thought to be a CD4 T cell-mediated autoimmune disease of CNS white matter. However, recent studies have identified CD8 T cell infiltrates and gray matter lesions in MS patients. These findings suggest that CD8 T cells, and CNS antigens other than myelin proteins may be involved during the MS disease process. Here we show that CD8 T cells reactive to glial fibrillary acidic protein (GFAP), a protein expressed in astrocytes, can avoid tolerance mechanisms, and depending upon the T cell triggering event, drive unique aspects of inflammatory CNS autoimmunity. In GFAP-specific CD8 T cell receptor transgenic (BG1) mice, tissue resident memory-like CD8 T cells spontaneously infiltrate the gray matter and white matter of the CNS, resulting in a relapsing-remitting CNS autoimmunity. The frequency, severity and remissions from spontaneous disease are controlled by the presence of polyclonal B cells. In contrast, a viral trigger induces GFAP-specific CD8 T effector cells to exclusively target the meninges and vascular/perivascular space of the gray and white matter of the brain, causing a rapid, acute CNS disease. These findings demonstrate that the type of CD8 T cell-triggering event can determine the presentation of distinct CNS autoimmune disease pathologies.

Brain Immunohistopathology in a Patient with Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy

“…This autoimmune astrocytopathy is probably mediated by antigen-specific cytotoxic T cells [1, 4]. Cytotoxic T cells specific for GFAP-derived peptides were shown to be pathogenic in a mouse model of autoimmune GFAP meningoencephalomyelitis where GFAP-specific CD8 + cytotoxic T cells caused various forms of central nervous system inflammation [9]. Our current results also demonstrated that a few CD8 + T lymphocytes infiltrated the perivascular space and parenchyma of the brain.…”

Rituximab Efficiently Depletes Increased CD20-Expressing T Cells in Multiple Sclerosis Patients

“…Oligoclonal CD8 + T cells are overrepresented in MS lesions (15, 16), and myelin-reactive CD8 + T cells are present in peripheral blood of MS patients (17), outnumbering myelin-reactive CD4 + T cells (18). In animal models, CD8 + T cells reactive against myelin basic protein (MBP) and MOG are encephalitogenic (19), and CD8 + T cells reactive against the glial fibrillary acidic protein (GFAP) were recently shown to mediate relapsing-remitting experimental disease (20). In this context it is interesting that we find increased numbers of CD8 + cells among CD3 + CD20 dim T cells in untreated MS patients compared to healthy control subjects.…”

Age-Associated Resident Memory CD8 T Cells in the Central Nervous System Are Primed To Potentiate Inflammation after Ischemic Brain Injury

“…The majority of CNS-resident CD8 T cells were not associated with the vascular lumen as these cells were largely found extravasated beyond the vascular lumen into many parenchymal regions across the CNS. CD8 T cell-astrocyte interactions have also received growing attention (60, 66). Functional evidence that CD8 T cells are prime candidates for a role in CNS immune surveillance is based on the exquisitely specific destruction of transgenic astrocytes expressing MHCI-restricted hemagglutinin (67).…”