Fas system-mediated apoptosis suppresses lymphopoiesis

The lymphoproliferation (lpr) mutation causes the defective expression of Fas Ag, which normally transduces an apoptotic signal into cells. T cells from mice homozygous for this mutation overexpress the counter-receptor, Fas ligand. In this study, we investigated the effects and regulatory influences attributable to Fas ligand overexpression on lymphocyte development to clarify the role of Fas system-mediated apoptosis in lymphopoiesis in vivo. Nonirradiated severe combined immunodeficient (SCID) mice grafted with a fetal thymus (FT) plus fetal liver cells (FLC) from MRL-lpr/lpr mice (Fas Ag-defective mice), or with FT from C3H-gld/gld mice (Fas ligand-defective mice) plus FLC from C3H +/+ mice, developed FLC-derived T and B cells. In contrast, SCID mice grafted with FT from MRL-lpr/lpr Thy-1.1 mice plus FLC from MRL +/+ Thy-1.2 mice (chimera 1) developed few FLC-derived T and B cells in the spleen, and the thymus of the recipients also contained few FLC-derived T cells. In addition, when SCID mice grafted with FT from MRL-lpr/lpr Thy-1.2 mice (H-2k) were co-transplanted with FLC from C57BL/10 Thy-1.1 mice (H-2b) (chimera 2), FLC-derived T and B cells developed normally. Thy-1.1 + cells from chimera 1 expressed Fas ligand mRNA about threefold higher than those from chimera 2, and seven- to eightfold higher than Thy-1.2+ cells from SCID mice grafted with FT from MRL +/+ Thy-1.2 mice by Northern blot analysis. These findings indicate that overexpression of Fas ligand on T cells significantly impairs both T and B cell development. Furthermore, the Fas ligand overexpression sufficient to impair lymphopoiesis appears to require MHC-restricted T cell activation. These results suggest that the Fas system suppresses lymphopoiesis in vivo.