title: Deletion of CD4 and CD8 coreceptors permits generation of alphabetaT cells that recognize antigens independently of the MHC.
abstract: The thymus generates major histocompatibility complex (MHC)-restricted alphabetaT cells that only recognize antigenic ligands in association with MHC or MHC-like molecules. We hypothesized that MHC specificity might be imposed on a broader alphabetaTCR repertoire during thymic selection by CD4 and CD8 coreceptors that bind and effectively sequester the tyrosine kinase Lck, thereby preventing T cell receptor (TCR) signaling by non-MHC ligands that do not engage either coreceptor. This hypothesis predicts that, in coreceptor-deficient mice, alphabeta thymocytes would be signaled by non-MHC ligands to differentiate into alphabetaT cells lacking MHC specificity. We now report that MHC-independent alphabetaT cells were indeed generated in mice deficient in both coreceptors as well as MHC ("quad-deficient" mice) and that such mice contained a diverse alphabetaT cell repertoire whose MHC independence was confirmed at the clonal level. We conclude that CD4 and CD8 coreceptors impose MHC specificity on a broader alphabetaTCR repertoire during thymic selection by preventing thymocytes from being signaled by non-MHC ligands.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: François
authors.initials: F
authors.lastname: Van Laethem
authors.forename: Sophia D
authors.initials: SD
authors.lastname: Sarafova
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Xuguang
authors.initials: X
authors.lastname: Tai
authors.forename: Leonid
authors.initials: L
authors.lastname: Pobezinsky
authors.forename: Terry I
authors.initials: TI
authors.lastname: Guinter
authors.forename: Stanley
authors.initials: S
authors.lastname: Adoro
authors.forename: Anthony
authors.initials: A
authors.lastname: Adams
authors.forename: Susan O
authors.initials: SO
authors.lastname: Sharrow
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Alfred
authors.initials: A
authors.lastname: Singer
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)