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 lym phocyte development to clarify the role of Fas system-mediated apoptos is in lymphopoiesis in vivo. Nonirradiated severe combined immunodefic ient (SCID) mice grafted with a fetal thymus (FT) plus fetal liver cel ls (FLC) from MRL-lpr/lpr mite (Fas Ag-defective mice), or with FT fro m C3H-gld/gld mice (Fas ligand-defective mice) plus FLC from C3H +/+ m ice, developed FLC-derived T and B cells. In contrast, SCID mice graft ed 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 splee n, and the thymus of the recipients also contained few FLC-derived T c ells. In addition, when SCID mice grafted with FT from MRL-lpr/lpr Thy -1.2 mice (H-2(k)) were co-transplanted with FLC from C57BL/10 Thy-1.1 mice (H-2(b)) (chimera 2), FLC-derived T and B cells developed normal ly. Thy-1.1(+) cells from chimera 1 expressed Fas ligand mRNA about th reefold higher than those from chimera 2, and seven- to eightfold high er than Thy-1.2(+) cells from SCID mice grafted with FT from MRL +/+ T hy-1.2 mice by Northern blot analysis. These findings indicate that ov erexpression of Fas ligand on T cells significantly impairs both T and B cell development. Furthermore, the Fas ligand overexpression suffic ient to impair lymphopoiesis appears to require MHC-restricted T cell activation. These results suggest that the Fas system suppresses lymph opoiesis in vivo.