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 not characteristic of normal resting T cells. These cells fail to acquire 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 nature and significance of DN T cells in the autoimmune disease process is not clear. In the current study, we describe a surprising finding that mAbs against CD3-TCR-alpha/beta complex can strongly trigger the lytic activity of the DN T cells to induce redirected lysis of Fc receptor-positive targets. Similar redirected lysis was also inducible using mAbs against CD44 and gp90MEL-14, molecules involved in the binding of lymphocytes to endothelial cells. The spontaneous cytotoxic potential 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 capable of mediating lysis of autologous cells bearing the specific ligands for adhesion molecules involved in the signaling of cytotoxicity. These findings provide a novel insight into the functional significance of DN T cells in lpr mice and their potential role in the pathogenesis of autoimmune disease.
Hammond
D M
DM
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061.
Nagarkatti
P S
PS
Goté
L R
LR
Seth
A
A
Hassuneh
M R
MR
Nagarkatti
M
M
D000818:Animals; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D053804:Granzymes; D007376:Interleukin-2 / Q000235:genetics; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains / Q000276:immunology; D008969:Molecular Sequence Data; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D012697:Serine Endopeptidases / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D015815:Cell Adhesion Molecules; D017931:DNA Primers; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D054353:Perforin; D053804:Granzymes; D012697:Serine Endopeptidases