The murine <i>lpr</i> gene encodes for an aberrant form of Fas (CD95), a molecule involved in apoptosis. The mouse <i>gld</i> gene leads to the expression of a defective Fasligand. Mice homozygous for <i>lpr</i> or <i>gld</i> mutations develop severe lymphoproliferative and autoimmune disease characterized by the accumulation of unique CD4⁻CD8⁻ (double-negative, DN) T cells. Because of these poor functions in vitro, the nature and significance of DN T cells in the autoimmune disease process is not clear. In the current study we found that <i>lpr</i> DN T cells could mediate spontaneous lysis of certain tumor cells as well as mediate redirected lysis of various tumor targets when stimulated through the CD3/αβTCR complex and certain adhesion molecules, such as, CD44 and gp90^MEL-14. The DN T cells constitutively transcribed perform, TNF-α and IFN-γ genes. Unlike the DN T cells from <i>lpr</i> mice, similar cells from <i>gld</i> mice failed to exhibit spontaneous cytotoxicity despite expression of similar levels of cytokines and adhesion molecules. Furthermore, lpr DN T cells could mediate redirected lysis of Fas⁺ but not Fas⁻ target cells. Together, these studies suggested that lysis of target cells by DN T cells was dependent on the interaction between Fas and Fas-ligand. The fact that <i>lpr</i> DN T cells can be activated via CD44 and gp-90^MEL-14 suggested that these T cells may be able to mediate lysis of endothelial cells which bear the ligand for these adhesion molecules. Further studies revealed that the <i>lpr</i> DN T cells could mediate spontaneous lysis of endothelial cells and that CD44-hyaluronate interactions were important for endothelial cell lysis. Thus, interactions between DN T cells and endothelial cells <i>in vivo</i> may trigger an inflammatory response and contribute to the vasculitis seen in <i>lpr</i> and <i>gld</i> mice. We also addressed the hypothesis that acquired immunodeficiency syndrome (AIDS) may be a consequence of destabilization of the idiotypic network. These studies demonstrated that auto- or allo-immunizations involving recognition of class II MHC antigens can trigger an anti-HIV response and such possibilities should be taken into consideration while delineating the pathogenesis of AIDS. / Ph. D.