Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

A signal integration model of thymic selection and natural regulatory T cell commitment
Sahamoddin Khailaie, Philippe A Robert, Toker Arras, Jochen Hühn, Michael Meyer-Hermann

Last modified: 2014-03-27


T cells complete their development in the thymus where the ability of their receptor (TCR) to recognize peptides loaded on MHC complexes (pMHC) is checked through scanning of antigen presenting cells (APC). Thymic selection restricts the pool of T cells leaving the thymus to both MHC-restricted (able to recognize MHC complexes), and self-tolerant (not mounting an immune reaction against self-peptides). However, the mechanisms of thymic selection are still a matter of debate, and it is not clear how the TCR specifities for MHC and loaded peptide are temporally encoded into TCR signaling.
Here, we propose a temporal TCR signal-integration model of thymic selection that describes how thymocytes decide among distinct fates, not only based on a single TCR-ligand interaction, but by taking into account the TCR stimulation history.
TCR and MHC-peptides complexes are encoded by binary sequences.T cells are generated with a random TCR, and are sequentially allocated to APC carrying the same MHC but varying peptides from a predefined pool of self-peptides. The TCR signaling level of each cell is increased at each interaction based on the TCR-pMHC affinities, but constantly decays with a fixed rate.
This stochastic integration process allows the definition of the strength and the dynamics
of the integrated signal which turns out as a suitable measure for thymocyte selection. Sustained signals lead to positive selection while transient overcritical signals lead to negative selection. In this way a MHC-restricted T cell repertoire is selected while self-reactive cells are efficiently removed.
Based on the observation that selected cells with higher sustained signaling differentiate into regulatory T cells, we predict that they have a higher affinity to MHC but are more cross-reactive to peptides, and exhibit the ability of recognising both, self and foreign antigens. Additionally, according to the model results, a high diversity as well as a limited density of self-peptide in the thymus are required in order to generate this MHC-restricted set of T cells, which should be taken into account in experiments where peptides are overexpressed in the thymus.


thymus; positive selection; negative selection; regulatory T cell; time integration