title: Optimal T cell cross-reactivity and the role of regulatory T cells.
abstract: The T lymphocytes of the adaptive immune system constitute a highly diverse repertoire of clones expressing a unique T cell receptor (TCR). It has been argued that TCRs are cross-reactive, meaning that one receptor can recognize a multitude of epitopes. Cross-reactivity between self and foreign epitopes can potentially lead to autoimmune responses. Regulatory T cells (Tregs) down-regulate immune reactions, and play an important role in the avoidance of autoimmunity. We use a probabilistic modeling approach to investigate how suppression of antigen-presenting dendritic cells (DCs) by Tregs influences the probability of mounting a successful immune response against a pathogen while remaining self-tolerant. For T cell cross-reactivity values close to experimental estimates, we find that the presence of Tregs increases this success probability somewhat. However, the probability of a successful immune response remains relatively low for these cross-reactivity values, and the probability of success is optimized when T cells are more specific and no Tregs are formed. We conclude that DC suppression on its own is insufficient to provide an evolutionary benefit of regulatory T cells. Rejecting one intuitively likely hypothesis for the function of Tregs thus narrows down the search for the mechanisms by which they are suppressing inappropriate immune responses.
authors.affiliation: Department of Evolutionary Studies of Biosystems, School of Advanced Sciences, The Graduate University for Advanced Studies, Shonan Village, Hayama, Kanagawa 240-0193, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Saeki
authors.affiliation: Theoretical Biology and Bioinformatics, Department of Biology, Utrecht University, The Netherlands.
authors.forename: Hilje M
authors.initials: HM
authors.lastname: Doekes
authors.affiliation: Theoretical Biology and Bioinformatics, Department of Biology, Utrecht University, The Netherlands.
authors.forename: Rob J
authors.initials: RJ
authors.lastname: De Boer
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D017209:Apoptosis; D015551:Autoimmunity / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008954:Models, Biological; D011336:Probability; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000941:Antigens; D000939:Epitopes; D011948:Receptors, Antigen, T-Cell
keywords: Self-non-self discrimination