T-cell receptor ligation by peptide/MHC induces activation of a caspase in immature thymocytes: the molecular basis of negative selection.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print Cited Medium: Print ISSN: 0261-4189 (Print) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

Apoptosis* ; Caspases* ; Major Histocompatibility Complex*; Cysteine Endopeptidases/*metabolism ; Peptides/*metabolism ; Receptors, Antigen, T-Cell/*metabolism ; T-Lymphocytes/*enzymology; Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Antibodies, Monoclonal ; Caspase 3 ; Caspase 6 ; Caspase 7 ; Cysteine Proteinase Inhibitors/pharmacology ; Enzyme Activation ; Enzyme Precursors/metabolism ; Female ; Glucocorticoids/pharmacology ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, Antigen, T-Cell/immunology ; Signal Transduction ; T-Lymphocytes/cytology ; Thymus Gland/cytology ; Thymus Gland/embryology ; Thymus Gland/enzymology

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.

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AI19807 United States AI NIAID NIH HHS; DK43551 United States DK NIDDK NIH HHS; DK47677 United States DK NIDDK NIH HHS

0 (Amino Acid Chloromethyl Ketones)
0 (Antibodies, Monoclonal)
0 (CD3epsilon protein, bovine)
0 (Cysteine Proteinase Inhibitors)
0 (Enzyme Precursors)
0 (Glucocorticoids)
0 (Ligands)
0 (Peptides)
0 (Receptors, Antigen, T-Cell)
0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
EC 3.4.22.- (Casp3 protein, mouse)
EC 3.4.22.- (Casp6 protein, mouse)
EC 3.4.22.- (Casp7 protein, mouse)
EC 3.4.22.- (Caspase 3)
EC 3.4.22.- (Caspase 6)
EC 3.4.22.- (Caspase 7)
EC 3.4.22.- (Caspases)
EC 3.4.22.- (Cysteine Endopeptidases)

Date Created: 19970501 Date Completed: 19970703 Latest Revision: 20181113

20250114

PMC1169830

10.1093/emboj/16.9.2282

9171343