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 ?? subtype (TCR??) that 'preferentially' migrated to the intestine, where they re-expressed CD8? and were sequestered as CD8??(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8??(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection.

SUBMITTER: Pobezinsky LA 

PROVIDER: S-EPMC3362677 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature