Impairment of TNF-receptor-1 signaling but not fas signaling diminishes T-cell apoptosis in myelin oligodendrocyte glycoprotein peptide-induced chronic demyelinating autoimmune encephalomyelitis in mice

Abstract

T-cell apoptosis in inflammatory demyelinating lesions of chronic myelin oligodendrocyte glycoprotein peptide35-55 induced autoimmune encephalomyelitis was studied in several different gene knockout mice as well as their wild-type counterparts. The gene deletions included tumor necrosis factor (TNF) alpha, lymphotoxin, TNF receptor 1 or 2, Fas-L, inducible nitric oxide synthase, perforin, and interleukin1beta-converting enzyme. Impairment of the TNF receptor 1 pathway led to a 50% reduction of T-cell apoptosis in the central nervous system lesions, whereas the other genetic deletions showed no significant effect. Our study thus identified the TNF receptor 1 signaling pathway as one mechanism responsible for the removal of T lymphocytes from inflammatory demyelinating lesions of the central nervous system.

Figure 1.

a: Apoptosis in CD3+ T-cells in MOG EAE. The different stages in apoptotic CD3+ T cells in an inflammatory infiltrate are defined through morphological criteria (arrowheads): condensation and margination of chromatin and nuclear fragmentation. Immunocytochemistry for CD3 (brown), nuclear stain with hematoxylin (blue) (×1000). b, c: Double labeling for apoptotic T cells (arrowhead) with CD3-antibody and in situ tailing to visualize DNA fragmentation (black-stained nucleus) in a larger magnification (×1250). d: Apoptotic CD3+ T cells with nuclear fragmentation in a higher magnification (×1250).

Figure 2.

Percentage of T-cell apoptosis in various models of EAE: significant difference (*) in the rate of T-cell apoptosis for the TNLT−/−, the TR1−/− and the TR12−/− model compared to the respective wild-type mice. wt B6, wild-type B6; wtx, wild-type B6x129.

Figure 3.

a: Highly significant correlation of T-cell apoptosis to the lesional activity in wild-type animals. b: No significant correlation of T-cell apoptosis to the lesional activity in knockout mice with an impairment of the TNFR1 pathway.