DOUBLE-NEGATIVE T-CELLS FROM MRL-LPR LPR MICE MEDIATE CYTOLYTIC ACTIVITY WHEN TRIGGERED THROUGH ADHESION MOLECULES AND CONSTITUTIVELY EXPRESS PERFORIN GENE/

The lpr gene induces in mice, accumulation of large numbers of CD4-CD8 - (double negative [DN]) T lymphocytes which bear adhesion molecules n ot characteristic of normal resting T cells. These cells fail to acqui re interleukin 2 (IL-2) receptors, produce IL-2, and proliferate when activated with mitogens or monoclonal antibodies (mAbs) against the T cell receptor (TCR). Because of these poor functions in vitro, the nat ure and significance of DN T cells in the autoimmune disease process i s not clear. In the current study, we describe a surprising finding th at mAbs against CD3-TCR-alpha/beta complex can strongly trigger the ly tic activity of the DN T cells to induce redirected lysis of Fc recept or-positive targets. Similar redirected lysis was also inducible using mAbs against CD44 and gp90MEL-14, molecules involved in the binding o f lymphocytes to endothelial cells. The spontaneous cytotoxic potentia l of the DN T cells was further corroborated by demonstrating that the lpr DN T cells constitutively transcribed perforin gene but failed to express granzyme A. The current study suggests that DN T cells are ca pable of mediating lysis of autologous cells bearing the specific liga nds for adhesion molecules involved in the signaling of cytotoxicity. These findings provide a novel insight into the functional significanc e of DN T cells in lpr mice and their potential role in the pathogenes is of autoimmune disease.