title: Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.
abstract: Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection required CD28-mediated costimulation of autoreactive thymocytes at the CD4(+)CD8(lo) intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either a lack of CD28 costimulation or transgenic overexpression of the antiapoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic CD4(-)CD8(-) double-negative thymocytes positive for the T cell antigen receptor αβ subtype (TCRαβ) that 'preferentially' migrated to the intestine, where they re-expressed CD8α and were sequestered as CD8αα(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8αα(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Leonid A
authors.initials: LA
authors.lastname: Pobezinsky
authors.forename: Georgi S
authors.initials: GS
authors.lastname: Angelov
authors.forename: Xuguang
authors.initials: X
authors.lastname: Tai
authors.forename: Susanna
authors.initials: S
authors.lastname: Jeurling
authors.forename: François
authors.initials: F
authors.lastname: Van Laethem
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Alfred
authors.initials: A
authors.lastname: Singer
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D017637:Clonal Deletion / Q000276:immunology*; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell