Apoptosis of αβ T lymphocytes in the nervous system in experimental autoimmune encephalomyelitis: Its possible implications for recovery and acquired tolerance

Abstract

We have recently shown that apoptosis, an active process of cellular self-destruction, occurs in the central nervous system in Lewis rats with acute experimental autoimmune encephalomyelitis (EAE) induced by inoculation with myelin basic protein (MBP) and adjuvants. Conventional light and electron microscopic studies suggested that some of the apoptotic cells were oligodendrocytes and that others were hematogenous mono-nuclear cells. To determine whether any of the apoptotic cells were T lymphocytes, we used the technique of preembedding immunolabelling which allows sufficient preservation of the ultrastructure to permit recognition of apoptotic changes while at the same time preserving surface antigens so that the identity of the apoptotic cells can be determined by immunocytochemistry. Light microscopic immunocytochemistry using the mono-clonal antibodies OX-34 (CD2) and R73 (αβ T-cell receptor) revealed that 10% of the CD2 + cells and 5% of the αβ T lymphocytes in the parenchyma of the spinal cord were dying by apoptosis. The presence of apoptotic αβ T cells was confirmed by electron microscopy. About half of all the apoptotic cells within the spinal cord were labelled by these antibodies. It is possible that some of the unlabelled apoptotic cells were also T lymphocytes but that others were glial cells such as oligodendrocytes. One possible interpretation of this T-cell apoptosis is that it represents activation-induced cell death, which has recently been shown to provide a mechanism of clonal elimination of mature as well as immature autoreactive T cells. Another possible interpretation is that it is a result of corticosterone released during the course of EAE. The apoptotic elimination of target-antigen-specific lymphocytes within the target organ in this autoimmune disease may contribute to the subsidence of inflammation and, if ongoing, to the development of tolerance.

T-cell apoptosis in human glioblastoma multiforme: Implications for immunotherapy

“…Therefore we suggest that apoptotic deletion of T cells in GBM is due to activationinduced apoptosis following antigen presentation by glioma cells and microglia. This mechanism is similar to that which has been suggested to account for apoptosis of autoreactive T cells in the CNS during spontaneous recovery from experimental autoimmune encephalomyelitis, where astrocytes and microglia may act as non-professional antigenpresenting cells (Pender, 1999 andPender andRist, 2001). Our hypothesis that T-cell apoptosis in GBM results from overstimulation of the T-cell receptor in the absence of appropriate costimulation is consistent with the findings of Prins et al (2001) who showed that tumour-infiltrating lymphocytes functioned poorly when tested in vitro, with decreased proliferative activity and other characteristics of defective T cells.…”

“…T-cell apoptosis has been identified as a critical process in recovery from immune-mediated CNS damage (Pender et al, 1992, Tabi et al, 1994and Pender and Rist, 2001. Apoptotic T cells in the CNS are phagocytosed by macrophages, microglia, astrocytes and oligodendrocytes (Nguyen andMagnus et al, 2002).…”

“…Apoptotic T cells in the CNS are phagocytosed by macrophages, microglia, astrocytes and oligodendrocytes (Nguyen andMagnus et al, 2002). It has been proposed that activation-induced apoptosis of previously activated autoreactive T cells in the target organ is a major mechanism for maintaining tolerance (Pender, 1999).…”

Effects of cyclosporin A treatment on clinical course and inflammatory cell apoptosis in experimental autoimmune encephalomyelitis induced in Lewis rats by inoculation with myelin basic protein

“…During spontaneous recovery from MBP-EAE, there is apoptosis of T cells (Pender et al, 1991 andPender et al, 1992;Schmied et al, 1993) and macrophages/microglia in the CNS (Nguyen et al, 1994;White et al, 1998a). There is selective apoptosis of V 8.2 + MBP-reactive T cells (Tabi et al, 1994 andTabi et al, 1995;McCombe et al, 1996a), which may be due to CD95-mediated antigen-specific activation-induced apoptosis (White et al, 1998b).…”

“…The relapsing disease produced by treatment with CsA may result from the suppression of the immunoregulatory mechanisms that normally prevent further episodes of disease. In EAE, such regulatory mechanisms may include suppressor cells (Karpus et al, 1992), downregulatory cytokines, and apoptosis of T cells in the central nervous system (CNS) (Pender et al, 1991 andPender et al, 1992;Schmied et al, 1993;Tabi et al, 1994 andTabi et al, 1995;McCombe et al, 1996a). …”