Peripheral blood γ‐δ T cells lyse fresh human brain—Derived oligodendrocytes

Abstract

T cells are postulated to contribute to the injury of the oligodendrocyte-myelin complex underlying the demyelinating disease multiple sclerosis (MS). The apparent lack of class I or II major histocompatibility complex (MHC) expression in situ on human oligodendrocytes and the consistent failure to identify a universal myelin antigen in MS suggest that the immune damage might be mediated by effector T cells that are capable of reacting in an antigen-nonspecific and possibly MHC-unrestricted manner, such as T cells expressing the gamma-delta T-cell receptor. Since gamma-delta T cells are reported to be present in MS plaques and an increased number are found in the cerebrospinal fluid of patients with MS, we directly examined whether gamma-delta T cells are capable of inducing injury to human oligodendrocytes. We found, using a 6-hour 51Cr release assay, that oligodendrocytes cultured from surgically resected human brain specimens were effectively lysed in a dose-dependent manner by human gamma-delta T cells (28 +/- 5% mean specific lysis, n = 6, at an effector-target ratio of 20:1). Although heat shock protein HSP72, a putative gamma-delta T-cell recognition molecule, could be induced in vitro in our oligodendrocytes, an antibody to HSP72 did not inhibit gamma-delta T cell-mediated lysis of oligodendrocytes. These results suggest that gamma-delta T cells gaining entry into the central nervous system may be deleterious to oligodendrocytes and thus may contribute to the pathogenesis of MS.

Transendothelial Migratory Pathways of Vδ1+TCRγδ+ and Vδ2+TCRγδ+ T Lymphocytes from Healthy Donors and Multiple Sclerosis Patients: Involvement of Phosphatidylinositol 3 Kinase and Calcium Calmodulin-Dependent Kinase II

“…In MS, ␥␦ T cells have been found in the lesions and in CSF (7,8,12), suggesting not only that they contribute to demyelinization but also that they egress from the bloodstream and reach the CNS to exert their pathogenic role. In agreement with this, we have previously found that circulating V␦2…”

“…Several cell types and soluble mediators contribute to the onset and progression of demyelinization, including T lymphocytes (2-4); in particular, some previous reports point to an active role played by the ␥␦ T cell subset in the pathogenesis of MS (5)(6)(7).…”

“…In contrast, cells of the V␦2 subset infiltrate chronic lesions and are detectable in the cerebrospinal fluid (CSF) in relapsing-remitting MS (7,8,12). To reach the site of lesion(s), ␥␦ T lymphocytes must leave the bloodstream and migrate across the endothelial barrier.…”

Inflammatory cells, microglia and MHC class II antigen-positive cells in the spinal cord of Lewis rats with acute and chronic relapsing experimental autoimmune encephalomyelitis

“…CD2 + TCRαβ + cells in the CNS in EAE could include γδ T cells, natural killer (NK) cells or cells which have down-regulated the expression of TCRαβ. γδ T cells have been found in the CNS in multiple sclerosis (Selmaj et al, 1991) and may be cytotoxic towards oligodendrocytes (Freedman et al, 1991). NK cells are large granular lymphocytes which might be predicted to have higher FSC and SSC than small lymphocytes.…”

Innate Immunity to Viruses: Control of Vaccinia Virus Infection by γδ T Cells

“…It has been suggested that they may target heat-shock protein-displaying macrophages and play a housekeeping role during the resolution phase of the inflammatory response (18,20,21). ␥␦ T cells may also have a role in the pathogenesis of various autoimmune diseases and diseases of unknown etiology, as elevated levels of ␥␦ T cells have been reported in rheumatoid arthritis (22), multiple sclerosis (23,24), pulmonary sarcoidosis (25), inflammatory bowel disease (26), and polymyositis (27). Some of these diseases might be precipitated or exacerbated by viral infections, and recent evidence has indicated that ␥␦ T cells may contribute to myocarditis in mice infected with encephalomyocarditis virus (19).…”