Clonal Deletion Prunes but Does Not Eliminate Self-Specific αβ CD8+ T Lymphocytes

It has long been thought that clonal deletion efficiently removes almost all self-specific T cells from the peripheral repertoire. We found that self-peptide MHC-specific CD8+ T cells in the blood of healthy humans were present in frequencies similar to those specific for non-self antigens. For the Y chromosome-encoded SMCY antigen, self-specific T cells exhibited only a 3-fold lower average frequency in males versus females and were anergic with respect to peptide activation, although this inhibition could be overcome by a stronger stimulus. We conclude that clonal deletion prunes but does not eliminate self-specific T cells and suggest that to do so would create holes in the repertoire that pathogens could readily exploit. In support of this hypothesis, we detected T cells specific for all 20 amino acid variants at the p5 position of a hepatitis C virus epitope in a random group of blood donors. •Similar numbers of human blood CD8+ T cells recognize self versus novel foreign antigens•H-Y T cells in men are 1/3 as frequent as in women but have similar functional avidity•Self-specific CD8+ T cells are resistant to activation and/or expansion•Inefficient self-specific T cell deletion might allow better protection from infection Clonal deletion is thought to efficiently remove almost all self-specific T cells. Davis and colleagues find instead that many human CD8+ T cells specific for endogenous peptides escape deletion and are anergic. They propose that the inefficient deletion of self-specific T cells might allow for better protection against infection.