A signal integration model of thymic selection and natural regulatory T cell commitment.
The extent of TCR self-reactivity is the basis for selection of a functional and self-tolerant T cell repertoire and is quantified by repeated engagement of TCRs with a diverse pool of self-peptides complexed with self-MHC molecules. The strength of a TCR signal depends on the binding properties of a TCR to the peptide and the MHC, but it is not clear how the specificity to both components drives fate decisions. In this study, we propose a 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 taking into account the TCR stimulation history. These fates are separated based on sustained accumulated signals for positive selection and transient peak signals for negative selection. This spans up the cells into a two-dimensional space where they are either neglected, positively selected, negatively selected, or selected as natural regulatory T cells (nTregs). We show that the dynamics of the integrated signal can serve as a successful basis for extracting specificity of thymocytes to MHC and detecting the existence of cognate self-peptide-MHC. It allows to select a self-MHC-biased and self-peptide-tolerant T cell repertoire. Furthermore, nTregs in the model are enriched with MHC-specific TCRs. This allows nTregs to be more sensitive to activation and more cross-reactive than conventional T cells. This study provides a mechanistic model showing that time integration of TCR-mediated signals, as opposed to single-cell interaction events, is needed to gain a full view on the properties emerging from thymic selection.
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
Sahamoddin
S
Khailaie
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique, 34293 Montpellier, France;
Philippe A
PA
Robert
Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; and.
Aras
A
Toker
Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; and.
Jochen
J
Huehn
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Institute for Biochemistry, Biotechnology, and Bioinformatics, University of Technology Braunschweig, 38106 Braunschweig, Germany mmh@theoretical-biology.de.
Michael
http://orcid.org/0000-0002-4300-2474
M
Meyer-Hermann
D000465:Algorithms; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation; D060966:Clonal Selection, Antigen-Mediated; D003429:Cross Reactions / Q000276:immunology; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D006649:Histocompatibility Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell