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*
Microbiology and Tumor Biology Center and
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden;
Department of Oncology, IGT Laboratory, Karolinska Hospital, Stockholm, Sweden; and
§
Department of Chemistry, University of Virginia, Charlottesville, VA 22901
Given the flexible nature of TCR specificity, deletion or
permanent disabling of all T cells with the capacity to recognize self
peptides would severely limit the diversity of the repertoire and the
capacity to recognize foreign Ags. To address this, we have
investigated the patterns of CD8+ CTL reactivity to a
naturally H-2Kb-presented self peptide derived from the
elongation factor 1
(EF1). EF1 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
peptide. These CTLs required 100-fold more peptide-H-2Kb
complexes on the target cell compared with CTLs against a viral
peptide, and did not recognize the naturally expressed levels of EF1
peptides. Thus, low avidity T cells specific for these self peptides
escape tolerance by deletion, despite expression of both EF1
isoforms in dendritic cells known to mediate negative selection in the
thymus. The low avidity in CTL recognition of these peptides correlated
with low TCR affinity. However, self peptide-specific CTLs expressed
elevated levels of CD8. Furthermore, CTLs generated against altered
self peptide variants displayed intermediate avidity, indicating
cross-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.
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