title: Peptide-specific, TCR-alpha-driven, coreceptor-independent negative selection in TCR alpha-chain transgenic mice.
abstract: As thymocytes differentiate, Ag sensitivity declines, with immature CD4-CD8- double-negative (DN) cells being most susceptible to TCR signaling events. We show that expression of alphabetaTCR from the DN3 stage lowers the threshold for activation, allowing recognition of MHC peptides independently of the TCR beta-chain and without either T cell coreceptor. The MHC class I-restricted C6 TCR recognizes the Y-chromosome-derived Ag HYK(k)Smcy. Positive selection in C6 alphabetaTCR females is skewed to the CD8 compartment, whereas transgenic male mice exhibit early clonal deletion of thymocytes. We investigated the effect of the HYK(k)Smcy complex on developing thymocytes expressing the C6 TCR alpha-chain on a TCR-alpha(-/-) background. On the original selecting haplotype, the skew to the CD8 lineage is preserved. This is MHC dependent, as the normal bias to the CD4 subset is seen on an H2b background. In male H2k C6 alpha-only mice, the presence of the HYK(k)Smcy complex leads to a substantial deletion of thymocytes from the DN subset. This phenotype is replicated in H2k C6 alpha-only female mice expressing an Smcy transgene. Deletion is not dependent on the beta variable segment of the C6 TCR or on a restricted TCR-beta repertoire. In contrast, binding of HYK(k)Smcy and Ag-specific activation of mature CD8+ T cells is strictly dependent on the original C6 beta-chain. These data demonstrate that, in comparison with mature T cells, alphabetaTCR+ immature thymocytes can recognize and transduce signals in response to specific MHC-peptide complexes with relaxed binding requirements.
authors.affiliation: Department of Immunology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Furmanski
authors.forename: Istvan
authors.initials: I
authors.lastname: Bartok
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chai
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Singh
authors.forename: Cristina
authors.initials: C
authors.lastname: Ferreira
authors.forename: Diane
authors.initials: D
authors.lastname: Scott
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Holland
authors.forename: Christophe
authors.initials: C
authors.lastname: Bourdeaux
authors.forename: Tessa
authors.initials: T
authors.lastname: Crompton
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D005260:Female; D056466:Histone Demethylases; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology*; D011506:Proteins / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D012737:Sex Factors; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology; D037182:T-Cell Antigen Receptor Specificity; D013950:Thymus Gland / Q000166:cytology; D015778:Minor Histocompatibility Antigens
chemical_list: D056466:Histone Demethylases; D010455:Peptides; D011506:Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C490659:Kdm5d protein, mouse; D015778:Minor Histocompatibility Antigens