title: Double-positive T cell receptor(high) thymocytes are resistant to peptide/major histocompatibility complex ligand-induced negative selection.
abstract: To investigate negative selection events during intrathymic ontogeny, we established T cell receptor (TCR)-transgenic mice [N15tg/RAG-2-/- (H-2b)] expressing a single TCR specific for vesicular stomatitis virus nuclear octapeptide N52-59 (VSV8) in the context of the major histocompatibility complex (MHC) class I molecule, K(b). Administration of VSV8 in vivo induced apoptosis in less than 4 h, deleting the majority of immature double-positive (DP) thymocytes by 24 h. In contrast, DP TCRhigh as well as single-positive (SP) thymocytes were refractory to this death process. Moreover, DP TCRhigh cells differentiated into SP thymocytes in vitro and in vivo, maturing into functional cytotoxic T lymphocytes upon intrathymic transfer to beta RAG 2-/- recipients. Hence, negative selection processes involving MHC-bound peptide ligands are operative only prior to the late DP thymocyte stage in this MHC class I-restricted TCR transgene system.
authors.affiliation: Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. yoseph_ghendler@dfci.harvard.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Ghendler
authors.forename: R E
authors.initials: RE
authors.lastname: Hussey
authors.forename: T
authors.initials: T
authors.lastname: Witte
authors.forename: E
authors.initials: E
authors.lastname: Mizoguchi
authors.forename: L K
authors.initials: LK
authors.lastname: Clayton
authors.forename: A K
authors.initials: AK
authors.lastname: Bhan
authors.forename: S
authors.initials: S
authors.lastname: Koyasu
authors.forename: H C
authors.initials: HC
authors.lastname: Chang
authors.forename: E L
authors.initials: EL
authors.lastname: Reinherz
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000502:physiology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D004268:DNA-Binding Proteins; D010455:Peptides; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; C064655:V(D)J recombination activating protein 2