Models of Self-Peptide Sampling by Developing T Cells Identify Candidate Mechanisms of Thymic Selection

• DOI: 10.1371/journal.pcbi.1003102
• Publication Date: 2013-07-25T22:09:16Z
• Authors: Iren Bains; Hisse M. van Santen; Benedict Seddon; Andrew J. Yates
• Keywords: Negative selection

Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for within a range responsiveness that allows detection foreign antigen without excessive responses self. Regulatory thought lie at higher end spectrum acceptable self-reactivity play crucial role control autoimmunity tolerance innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack full understanding how thymocytes integrate signals obtained by sampling self-peptides make fate decisions. To address this problem, apply stochastic models signal integration data from study quantifying development two lineages using controllable levels agonist peptide thymus. We find able explain observations; one which continually re-assess decisions on basis multiple summed proximal TCR-pMHC interactions; another TCR sensitivity is modulated over time, such contact with same pMHC ligand may lead divergent outcomes different stages development. Neither model requires differentially susceptible deletion or need qualitatively development, as been proposed. additional support variable-sensitivity model, apparently paradoxical observations regarding effect partial strong agonists