Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.

TitleClonal deletion and the fate of autoreactive thymocytes that survive negative selection.
Publication TypeJournal Article
Year of Publication2012
AuthorsPobezinsky LA, Angelov GS, Tai X, Jeurling S, Van Laethem F, Feigenbaum L, Park J-H, Singer A
JournalNat Immunol
Volume13
Issue6
Pagination569-78
Date Published2012 Jun
ISSN1529-2916
KeywordsAnimals, Antigens, CD28, Antigens, CD4, Antigens, CD8, Cell Differentiation, Clonal Deletion, Flow Cytometry, Immune Tolerance, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Receptors, Antigen, T-Cell, Signal Transduction, Thymocytes, Thymus Gland
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.

DOI10.1038/ni.2292
Alternate JournalNat. Immunol.
PubMed ID22544394