T-cell receptor ligation by peptide/MHC induces activation of a caspase in immature thymocytes: the molecular basis of negative selection.
T-cell receptors (TCRs) are created by a stochastic gene rearrangement process during thymocyte development, generating thymocytes bearing useful, as well as unwanted, specificities. Within the latter group, autoreactive thymocytes arise which are subsequently eliminated via a thymocyte-specific apoptotic mechanism, termed negative selection. The molecular basis of this deletion is unknown. Here, we show that TCR triggering by peptide/MHC ligands activates a caspase in double-positive (DP) CD4+ CD8+ thymocytes, resulting in their death. Inhibition of this enzymatic activity prevents antigen-induced death of DP thymocytes in fetal thymic organ culture (FTOC) from TCR transgenic mice as well as apoptosis induced by anti-CD3epsilon monoclonal antibody and corticosteroids in FTOC of normal C57BL/6 mice. Hence, a common caspase mediates immature thymocyte susceptibility to cell death.
Clayton
L K
LK
Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Ghendler
Y
Y
Mizoguchi
E
E
Patch
R J
RJ
Ocain
T D
TD
Orth
K
K
Bhan
A K
AK
Dixit
V M
VM
Reinherz
E L
EL
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D008024:Ligands; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology / Q000201:enzymology
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; C099696:CD3epsilon protein, bovine; D015853:Cysteine Proteinase Inhibitors; D004792:Enzyme Precursors; D005938:Glucocorticoids; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C505409:Casp3 protein, mouse; C505516:Casp6 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D020169:Caspases; D003546:Cysteine Endopeptidases