Activation–threshold tuning in an affinity model for the T–cell repertoire

Naive T cells respond to peptides from foreign proteins and remain tolerant to self peptides from endogenous proteins. It has been suggested that self tolerance comes about by a ‘tuning’ mechanism, i.e. by increasing the T–cell activation threshold upon interaction with self peptides. Here, we explore how such an adaptive mechanism of T–cell tolerance would influence the reactivity of the T–cell repertoire to foreign peptides. We develop a computer simulation model in which T cells are tolerized by increasing their activation–threshold dependent on the affinity with which they see self peptides presented in the thymus. Thus, different T cells acquire different activation thresholds (i.e. different cross–reactivities). In previous mathematical models, T–cell tolerance was deletional and based on a fixed cross–reactivity parameter, which was assumed to have evolved to an optimal value. Comparing these two different tolerance–induction mechanisms, we found that the tuning model performs somewhat better than an optimized deletion model in terms of the reactivity to foreign antigens. Thus, evolutionary optimization of clonal cross–reactivity is not required. A straightforward extension of the tuning model is to delete T–cell clones that obtain a too high activation threshold, and to replace these by new clones. The reactivity of the immune repertoires of such a replacement model is enchanced compared with the basic tuning model. These results demonstrate that activation–threshold tuning is a functional mechanism for self tolerance induction.