Effect of homozygous lpr and gld mutations on the immune functions and induction of autoimmunity

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Virginia Tech


The murine lpr gene encodes for an aberrant form of Fas (CD95), a molecule involved in apoptosis. The mouse gld gene leads to the expression of a defective Fasligand. Mice homozygous for lpr or gld 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 lpr 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 gp90MEL-14. The DN T cells constitutively transcribed perform, TNF-α and IFN-γ genes. Unlike the DN T cells from lpr mice, similar cells from gld 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 lpr DN T cells can be activated via CD44 and gp-90MEL-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 lpr 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 in vivo may trigger an inflammatory response and contribute to the vasculitis seen in lpr and gld 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.