Inactivation of misselected CD8 T cells by CD8 gene methylation and cell death

Misselected CD8 cells that express T cell receptors (TCRs) that do not reco gnize class I major histocompatibility complex (MHC) protein can emerge fro m thymic selection. A postthymic quality control mechanism that purges thes e cells from the repertoire is defined here. The failure of mature CD8 cell s to simultaneously engage their TCR and CD8 coreceptor triggers an activat ion process that begins with inhibition of CD8 gene expression through reme thylation and concludes with up-regulation of surface Fas and pas Ligand an d cellular apoptosis. Thus, inhibition of a death signal through continued TCR-CD8 coengagement of MHC molecules is a key checkpoint for the continued survival of correctly selected T cells. Molecular defects that prevent del ivery of the death signal to mistakenly selected T cells underlie the expan sion of double-negative T cells, which is the cellular signature of a subse t of systemic autoimmune diseases.