DEFECTIVE T-CELLS FROM GLD MICE PLAY A PIVOTAL ROLE IN DEVELOPMENT OFTHY-1.2(+)B220(+) CELLS AND AUTOIMMUNITY

The gld mouse represents a fascinating animal model of autoimmune dise ase, which is characterized by massive development of Thy-1.2(+)B220()CD4(-)CD8(-) cells. These eel Is thus have double positive markers fo r T and B cells, but are double negative for CD4 and CD8 markers and a re thus designated DN cells in the present context. An additional impo rtant feature in gld mice is a defect in expression of Fas ligand. To investigate the regulatory role of bone marrow-derived cells for the d evelopment of these DN cells and of gld autoimmunity, we constructed c himeric mice transplanted with fetal liver cells or fetal thymus from gld mice into nonirradiated severe combined immunodeficient (SCID) mic e. These chimeric mice regenerated, developed both these DN cells and the gld autoimmune syndrome and also generalized lymphoproliferative d isorders. However, when fetal liver cells from both gld and non-gld mi ce (C57BL/10 Thy-1.1 mice) were co-transplanted into SCID mice, the de velopment of DN cells was apparently inhibited. Further, th is inhibit ion was also seen in SCID mice that had been grafted with both gld and non-gld fetal thymus revealing the pivotal role played by T cells in development of DN cells. When B cells purified from non-gld (C3H(+/+)) mice were transplanted into SCID mice grafted with gld fetal thymus, the development of DN cells was not inhibited. Taken together, these f indings indicate that T cells from non-gld mice inhibit the expression of gld features, e.g., lymphoproliferation, immune-based nephritic di sease, and autoantibody production. These findings also suggest that t he Fas ligand is selectively expressed on T cells.