Functional expression of Fas (CD95) protein in autoimmune lpr mice.
Fas (CD95) has been shown in multiple systems to play a critical role in deletion of autoreactive lymphocytes by transducing cell death signals. The role of Fas in clonal deletion may best be exemplified in autoimmune lpr mice, in which a defect in the lpr gene leads to persistence of autoreactive clones in the periphery. Since negative selection in the lpr thymus appears not to be ablated, it has been suggested that Fas is not essential to thymic negative selection. A recent study has shown that lpr thymocytes express low levels of Fas protein. However, it is not determined whether this low level of Fas could transduce the death signal. This is a critical issue for the hypothesis that lpr thymocyte negative selection does not involve a Fas-death pathway. Here, we demonstrate that thymocytes, but not peripheral lymphocytes, from 2- to 4-week-old C3H.MRL-lpr mice are killed by Fas-dependent cytotoxicity at levels commensurate with the low levels of Fas expression. The level of lpr thymocyte killing is approximately 20% of that observed in wild-type controls. Both Fas staining and Th1 cytotoxicity are specifically blocked by a recombinant Fas-hIgG fusion protein. Thymocyte subset analyses indicate that Fas is expressed primarily on CD4+/CD8+ lpr thymocytes and that CD4+/CD8+ lpr thymocytes are the primary targets for Th1 effector cytotoxicity. The data suggest that the lpr mutation is functionally "leaky" and that the demonstration of normal negative selection in lpr thymocytes should not be taken as evidence that Fas is not involved in clonal deletion in the thymus.
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Arthritis Center, Boston University Schools of Medicine and Public Health, Massachusetts 02118, USA.
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Sherr
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D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017637:Clonal Deletion; D003602:Cytotoxicity, Immunologic; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D019014:fas Receptor / Q000032:analysis / Q000276:immunology*
D019014:fas Receptor