Significant role of Fas ligand-binding but defective Fas receptor (CD95) in lymph node hyperplasia composed of abnormal double-negative T cells

The functional differences between two mutations of the Fas (CD95) locus, Fas(lpr) (lpr) and Fas(lprcg) (lpr(cg) ), were investigated using bone marrow (BM) transplantation on the C3H mouse background. Both lpr/lpr and lpr(cg) /lpr(cg) BM transferred caused lymph node (LN) hyperplasia in lpr/+ and lpr(cg) /+ recipients, although it was clearly smaller than that in lpr/lpr and lpr(cg) /lpr(cg) recipients of lpr/lpr and lpr(cg) /lpr(cg) BM. In addition, both BM induced significantly larger LN hyperplasia in lpr(cg) /+ than lpr/+ recipients. Appearance of CD4(-) CD8(-) [double negative (DN)] T cells in the periphery is the most consistent phenotype of Fas mutations. Importantly, the proportion of DN T cells was higher in larger LN hyperplasia in the order of lpr/+, lpr(cg) /+ and lpr/lpr or lpr(cg) /lpr(cg) recipients. On the other hand, both lpr/lpr and lpr(cg) /lpr(cg) BM transferred into wild-type (+/+) mice caused marked LN atrophy. The former, but not the latter, induced wasting syndrome. Fasl(g1d) (gld)-homozygous lpr/lpr BM transferred into +/+ mice elicited LN hyperplasia of the same extent as that in lpr/lpr mice transferred with lpr/lpr BM, but not wasting syndrome. Taken together with the fact that DN T cells massively express Fas ligand (FasL), this study implied that FasL overexpressed on DN cells may be involved in the accumulation of DN T cells in LN, LN atrophy and wasting syndrome, and that lpr(cg) Fas, which can bind to Fas ligand but not transduce apoptosis signal into cells, may modulate these pathological conditions by interfering with the binding of FasL to Fas.