The roles of Fas, Fas ligand and Bcl-2 in T cell apoptosis in the central nervous system in experimental autoimmune encephalomyelitis

Abstract

The selective apoptotic elimination of autoreactive T cells in the central nervous system (CNS) contributes to the resolution of inflammation and the spontaneous clinical recovery from experimental autoimmune encephalomyelitis (EAE). To assess the molecular mechanisms involved in this process, we used three-colour flow cytometry to examine the expression of apoptosis-regulating proteins by inflammatory cells isolated from the spinal cords of Lewis rats immunized with myelin basic protein (MBP) and complete Freund's adjuvant. Throughout the course of the disease, which peaked 12-14 days after inoculation and was followed by clinical recovery, we analyzed the DNA content of the spinal cord inflammatory cells to assess apoptosis and, simultaneously, we measured the expression of five proteins (Fas, Fas ligand (Fas-L), Bcl-2, Bcl-x and Bax) which modulate the apoptotic process. Cells expressing the death effector molecules Fas and Fas-L were particularly prone to undergo apoptosis, and were over-represented in the apoptotic population. Of the cells expressing the cell death inhibitor Bcl-2, a low proportion were undergoing apoptosis compared to the proportion of the total inflammatory cell population undergoing apoptosis, indicating that expression of Bcl-2 protects against T cell apoptosis in this disease. There was no evidence, however, that the apoptotic regulators Bcl-x and Bax influenced the susceptibility to apoptosis. We also found that V 8.2 + T cells, which constitute the predominant encephalitogenic MBP-reactive T cell population in the Lewis rat, have a high frequency of Fas and Fas-L expression compared to other inflammatory cells. This would account for the previously demonstrated susceptibility of V 8.2 + T cells to apoptosis in the CNS in EAE. These findings support the hypothesis that autoreactive T cells are eliminated from the CNS during spontaneous recovery from EAE by activation-induced apoptosis involving the Fas pathway.

B cell Apoptosis in the Central Nervous System in Experimental Autoimmune Encephalomyelitis: Roles of B cell CD95, CD95L and Bcl-2 Expression

“…In the present study we have shown that B cells expressing CD95 or CD95L in the CNS are much more vulnerable to apoptosis than B cells not expressing these proteins. This strongly suggests that B cell apoptosis in the CNS in EAE is mediated by the interaction of CD95L and CD95 on the same B cell, just as the interaction of CD95L and CD95 on the same T cell appears to lead to T cell apoptosis in the CNS [19]. We also found that Bcl-2 expression appears to protect against B cell apoptosis in the CNS.…”

“…We have previously shown that CD95+ T cells and CD95L+ T cells are particularly vulnerable to apoptosis in the CNS in EAE whereas Bcl-2+ T cells are relatively protected from apoptosis [19]. To determine whether apoptosis-regulating proteins play a similar role in B cell apoptosis, we analysed the expression of these proteins by CNS-infiltrating CD45RA/B+ cells 13 days after inoculation.…”

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

“…Although we did not measure Fas expression on apoptotic T cells, Fas is known to be expressed on apoptotic T cells in GBM (Didenko et al, 2002). Our finding that T cells expressing Fas-L are much more likely to undergo apoptosis than T cells not expressing Fas-L is similar to what occurs in the CNS during spontaneous recovery from experimental autoimmune encephalomyelitis (White et al, 1998) and suggests that T-cell apoptosis in GBM is activation-induced and is occurring via the ligation of Fas by Fas-L on the same T cell. Apoptosis of T cells within GBM may explain, to a significant extent, the ineffectiveness of cell-mediated immunity towards gliomas.…”

Differential Regulation and Function of Fas Expression on Glial Cells

“…However, in another study we have found that Ab cross-linking of Fas on human astrocytes can induce inflammatory chemokine and cytokine expression at both the mRNA and protein levels (C. Choi, X. Xu, J. W. Oh, S. J. Lee, and E. N. Benveniste, manuscript in preparation). To date, CNS-infiltrating activated T cells, microglia, and astrocytes have been reported to express FasL (16,68,69). However, it is not clear which cell type(s) contributes to the ongoing inflammatory response by engaging Fas on astrocytes in vivo.…”