Fas modulation of apoptosis during negative selection of thymocytes.
A major mechanism maintaining immune tolerance is the deletion of potentially autoreactive thymocytes by apoptosis during development in the thymus. Previous reports suggest that apoptosis is induced by high avidity signals transduced via the T cell receptor; however, the role of signals transduced by other cell surface receptors during thymic selection remains poorly understood. Fas, a member of the TNF receptor family, has been shown to induce apoptosis in mature peripheral T cells; however, the effects of Fas on negative selection of thymocytes have not been previously detected. Using a sensitive terminal deoxynucleotidyl transferase method to detect apoptotic cells, we found that mutant Fas molecules in lpr mice decrease the sensitivity of thymocytes to T cell receptor-mediated apoptosis and that blockade of Fas-Fas ligand interactions in vivo can inhibit antigen-induced apoptosis of thymocytes in non-lpr mice. Thus, we have shown that Fas, in conjunction with antigen-specific signals, can modulate apoptosis during negative selection of thymocytes.
Castro
J E
JE
Pulmonary Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Listman
J A
JA
Jacobson
B A
BA
Wang
Y
Y
Lopez
P A
PA
Ju
S
S
Finn
P W
PW
Perkins
D L
DL
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D053222:Fas Ligand Protein; D007108:Immune Tolerance; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007141:Immunoglobulin Fc Fragments; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D019014:fas Receptor