Signal integration in thymocytes is crucial for thymic selection
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1
Department of Systems Immunology, Helmholtz Center for Infection Research, Germany
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2
Department of Experimental Immunology, Helmholtz Center for Infection Research, Germany
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3
Bio Center for Life Science, Technische Universität Braunschweig, Germany
Thymocytes are generated, selected and mature in the thymus to create a diverse, functional and self-tolerant T cell repertoire. Selection of thymocytes relies on the level of their T cell receptor (TCR) self-reactivity. Self-reactivity of thymocytes is quantified by repeated engagement of their TCRs with a diverse repertoire of self-peptides complexed with self-MHC molecule (spMHC) and may originate from either part of the complex. The role and relative importance of MHC versus self-peptides in thymic selection is not resolved. The fact that the selected T cell repertoire is MHC-restricted, requires a good mechanistic explanation of how thymocytes are able to quantify their affinity to MHC. In order to analyze how thymocytes quantify their self-reactivity, extract their MHC affinity, and how they use this information for cell fate determination, we developed a signal integration model for thymic selection, mimicking the requirement of repeated TCR signaling for successful selection and cell maturation. In this model, a polyclonal repertoire of thymocytes sequentially interact with diverse spMHCs and integrate the affinity-dependent TCR ligation signals. The strength and dynamics of the integrated signal is taken as a reference for cell fate determination. Quantification of the integrated signal and discrimination between its sustained and transient dynamics turns out as a successful basis for extracting affinity of thymocytes to MHC, detecting the existence of cognate self-peptide, and selecting a MHC-restricted self-tolerant T cell repertoire. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes is discussed with this model.
Keywords:
Thymic selection,
T cell signaling,
MHC restriction,
Clonal Deletion,
Regulatory T cell differentiation
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Adaptive Immunity
Citation:
Khailaie
S,
Toker
A,
Huehn
J and
Meyer-Hermann
M
(2013). Signal integration in thymocytes is crucial for thymic selection.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00479
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Received:
31 Mar 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Prof. Michael Meyer-Hermann, Department of Systems Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany, mmh@theoretical-biology.de