Ipr and gld mice develop systemic autoimmune diseases with nearly indistinguishable manifestations, including the accumulation of massive numbers of CD4-CD8- T lymphocytes. In vivo chimera experiments have shown that the Ipr mutation is functionally expressed in both T and B cells. When lethally irradiated Ipr mice were given a combination of normal and Ipr bone marrow, only Ipr-derived B cells produced autoantibodies and only Ipr-derived T cells hyperproliferated. In contrast, analogous experiments with gld mice showed that the co-infusion of normal bone marrow greatly reduced autoantibody production. These results indicated that the gld B cell defect was extrinsic to those cells producing autoantibodies, in agreement with the recent molecular data showing that the normal gene products of the Ipr and gld loci form an interacting receptor-ligand pair. In the present study, we have extended our functional studies with gld mice using T cell-marked congenic donors. Lymphadenopathy was reduced three- to fourfold in gld mice given a combination of congenic normal and gld bone marrow compared with mice given gld bone marrow alone, and the absolute number of CD4-CD8- T cells was reduced by a factor of 7. Surprisingly, the residual CD4-CD8- T cells present in the mixed chimeras were derived entirely from the gld donor marrow. This suggests that the gld mutation results in both an extrinsic and intrinsic defect in T cells.

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