title: Activation-threshold tuning in an affinity model for the T-cell repertoire.
abstract: 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.
authors.affiliation: Theoretical Biology/Bioinformatics, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands. almut.scherer@env.ethz.ch
authors.forename: Almut
authors.initials: A
authors.lastname: Scherer
authors.forename: André
authors.initials: A
authors.lastname: Noest
authors.forename: Rob J
authors.initials: RJ
authors.lastname: de Boer
mesh_terms: D003198:Computer Simulation; D003429:Cross Reactions / Q000276:immunology*; D018448:Models, Immunological; D017634:Self Tolerance / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*