T cell tolerance based on avidity thresholds rather than complete deletionallows maintenance of maximal repertoire diversity

Given the flexible nature of TCR specificity, deletion or permanent disabli ng of all T cells with the capacity to recognize self peptides would severe ly limit the diversity of the repertoire and the capacity to recognize fore ign Ags, To address this, we have investigated the patterns of CD8(+) CTL r eactivity to a naturally H-2K(b)-presented self peptide derived from the el ongation factor 1 alpha (EF1 alpha). EF1 alpha occurs as two differentially expressed isoforms differing at one position of the relevant peptide. Low avidity CTLs could be raised against both variants of the EF1 alpha peptide . These CTLs required 100-fold more peptide-H-2K(b) complexes on the target cell compared with CTLs against a viral peptide, and did not recognize the naturally expressed levels of EF1 alpha peptides. Thus, low avidity T cell s specific for these self peptides escape tolerance by deletion, despite ex pression of both EF1 alpha isoforms in dendritic cells known to mediate neg ative selection in the thymus, The low avidity in CTL recognition of these peptides correlated with low TCR affinity. However, self peptide-specific C TLs expressed elevated levels of CD8. Furthermore, CTLs generated against a ltered self peptide variants displayed intermediate avidity, indicating cro ss-reactivity in induction of tolerance. We interpret these data, together with results previously published by others, in an avidity pit model based on avidity thresholds for maintenance of both maximal diversity and optimal self tolerance in the CD8(+) T cell repertoire.