T Cell Tolerance Based on Avidity Thresholds Rather Than Complete Deletion Allows Maintenance of Maximal Repertoire Diversity

Abstract

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 1α (EF1α). EF1α 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 EF1α 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 EF1α peptides. Thus, low avidity T cells specific for these self peptides escape tolerance by deletion, despite expression of both EF1α 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.

DNA vaccination with T‐cell epitopes encoded within Ab molecules induces high‐avidity anti‐tumor CD8+ T cells

“…In both viral infection and tumor models, only high-avidity and not low-avidity CTL mediate viral clearance and tumor eradication [1,3,5]. Avidity is defined by the amount of peptide required for activation of effector function [3,6,7] and is therefore a measure of the overall strength of the interaction between a CTL and a target cell [3,8,9]. Although avidity has been shown to be important, the mechanisms by which high CTL are generated in vivo remains unclear.…”

Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent

“…Single cell suspensions were prepared as described and 25610 6 splenocytes were restimulated with 25610 6 syngeneic irradiated (20 Gy) splenocytes pulsed with 0?05 mM of peptide, as described previously (Sandberg et al, 2000). Restimulation cultures were set in 12 ml complete RPMI medium.…”

The Impact of Self-Tolerance on the Polyclonal CD8+ T Cell Repertoire

“…In line with this, Pircher et al (11) have demonstrated that neonatal infection of mice with a lymphocytic choriomeningitis virus (LCMV)-strain encoding a variant T cell epitope resulted in clonal deletion of immature TCR-transgenic T cells specific for the wild-type LCMV epitope, whereas this variant LCMV virus was unable to trigger activation of the mature TCR-transgenic T cells. Likewise, Sandberg et al (16) showed that T cells that recognized variants of a self-Ag were of lower avidity than T cells specific for a foreign Ag. In apparent contrast, anecdotal evidence that T cell immunity can be evoked toward foreign Ags that differ from a self-Ag by one or a few amino acids has been provided (17,18).…”