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A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment
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| Zeitschriftentitel: | The Journal of Immunology |
|---|---|
| Personen und Körperschaften: | , , , , |
| In: | The Journal of Immunology, 193, 2014, 12, S. 5983-5996 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
The American Association of Immunologists
|
| Schlagwörter: |
| author_facet |
Khailaie, Sahamoddin Robert, Philippe A. Toker, Aras Huehn, Jochen Meyer-Hermann, Michael Khailaie, Sahamoddin Robert, Philippe A. Toker, Aras Huehn, Jochen Meyer-Hermann, Michael |
|---|---|
| author |
Khailaie, Sahamoddin Robert, Philippe A. Toker, Aras Huehn, Jochen Meyer-Hermann, Michael |
| spellingShingle |
Khailaie, Sahamoddin Robert, Philippe A. Toker, Aras Huehn, Jochen Meyer-Hermann, Michael The Journal of Immunology A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment Immunology Immunology and Allergy |
| author_sort |
khailaie, sahamoddin |
| spelling |
Khailaie, Sahamoddin Robert, Philippe A. Toker, Aras Huehn, Jochen Meyer-Hermann, Michael 0022-1767 1550-6606 The American Association of Immunologists Immunology Immunology and Allergy http://dx.doi.org/10.4049/jimmunol.1400889 <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment The Journal of Immunology |
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| title |
A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_unstemmed |
A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_full |
A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_fullStr |
A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_full_unstemmed |
A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_short |
A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_sort |
a signal integration model of thymic selection and natural regulatory t cell commitment |
| topic |
Immunology Immunology and Allergy |
| url |
http://dx.doi.org/10.4049/jimmunol.1400889 |
| publishDate |
2014 |
| physical |
5983-5996 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>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.</jats:p> |
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| author | Khailaie, Sahamoddin, Robert, Philippe A., Toker, Aras, Huehn, Jochen, Meyer-Hermann, Michael |
| author_facet | Khailaie, Sahamoddin, Robert, Philippe A., Toker, Aras, Huehn, Jochen, Meyer-Hermann, Michael, Khailaie, Sahamoddin, Robert, Philippe A., Toker, Aras, Huehn, Jochen, Meyer-Hermann, Michael |
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| description | <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> |
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| imprint_str_mv | The American Association of Immunologists, 2014 |
| institution | DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1 |
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| spelling | Khailaie, Sahamoddin Robert, Philippe A. Toker, Aras Huehn, Jochen Meyer-Hermann, Michael 0022-1767 1550-6606 The American Association of Immunologists Immunology Immunology and Allergy http://dx.doi.org/10.4049/jimmunol.1400889 <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment The Journal of Immunology |
| spellingShingle | Khailaie, Sahamoddin, Robert, Philippe A., Toker, Aras, Huehn, Jochen, Meyer-Hermann, Michael, The Journal of Immunology, A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment, Immunology, Immunology and Allergy |
| title | A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_full | A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_fullStr | A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_full_unstemmed | A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_short | A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| title_sort | a signal integration model of thymic selection and natural regulatory t cell commitment |
| title_unstemmed | A Signal Integration Model of Thymic Selection and Natural Regulatory T Cell Commitment |
| topic | Immunology, Immunology and Allergy |
| url | http://dx.doi.org/10.4049/jimmunol.1400889 |