Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution
The immune system has the ability to suppress undesirable responses, such as those against commensal bacteria, food and paternal antigens in placenta pregnancy. The lineage-specific transcription factor Foxp3 orchestrates the development and function of regulatory T cells underlying this immunologic...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2012-05-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00113/full |
| _version_ | 1818982344727461888 |
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| author | Kristian G Andersen Jesper K Nissen Alexander G Betz |
| author_facet | Kristian G Andersen Jesper K Nissen Alexander G Betz |
| author_sort | Kristian G Andersen |
| collection | DOAJ |
| description | The immune system has the ability to suppress undesirable responses, such as those against commensal bacteria, food and paternal antigens in placenta pregnancy. The lineage-specific transcription factor Foxp3 orchestrates the development and function of regulatory T cells underlying this immunological tolerance. Despite the crucial role of Foxp3 in supporting immune homeostasis, little is known about its origin, evolution and species conservation. We explore these questions using comparative genomics, structural modeling and functional analyses. Our data reveal that key gain-of-function events occurred during the evolution of Foxp3 in higher vertebrates. We identify key conserved residues in its forkhead domain and show a detailed analysis of the N-terminal region of Foxp3, which is only conserved in mammals. These components are under purifying selection, and our mutational analyses demonstrate that they are essential for Foxp3 function. Our study points to critical functional adaptations in immune tolerance among higher vertebrates, and suggests that Foxp3-mediated transcriptional mechanisms emerged during mammalian evolution as a step-wise gain of functional domains that enabled Foxp3 to interact with a multitude of interaction partners. |
| first_indexed | 2024-12-20T17:45:44Z |
| format | Article |
| id | doaj.art-5cf17ee588714866a5a0a679da12b003 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T17:45:44Z |
| publishDate | 2012-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5cf17ee588714866a5a0a679da12b0032022-12-21T19:30:59ZengFrontiers Media S.A.Frontiers in Immunology1664-32242012-05-01310.3389/fimmu.2012.0011326243Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolutionKristian G Andersen0Jesper K Nissen1Alexander G Betz2Harvard UniversityMedical Research Council Laboratory of Molecular BiologyMedical Research Council Laboratory of Molecular BiologyThe immune system has the ability to suppress undesirable responses, such as those against commensal bacteria, food and paternal antigens in placenta pregnancy. The lineage-specific transcription factor Foxp3 orchestrates the development and function of regulatory T cells underlying this immunological tolerance. Despite the crucial role of Foxp3 in supporting immune homeostasis, little is known about its origin, evolution and species conservation. We explore these questions using comparative genomics, structural modeling and functional analyses. Our data reveal that key gain-of-function events occurred during the evolution of Foxp3 in higher vertebrates. We identify key conserved residues in its forkhead domain and show a detailed analysis of the N-terminal region of Foxp3, which is only conserved in mammals. These components are under purifying selection, and our mutational analyses demonstrate that they are essential for Foxp3 function. Our study points to critical functional adaptations in immune tolerance among higher vertebrates, and suggests that Foxp3-mediated transcriptional mechanisms emerged during mammalian evolution as a step-wise gain of functional domains that enabled Foxp3 to interact with a multitude of interaction partners.http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00113/fullRegulatory T CellFoxp3Evolution of Immune SystemLineage commitmentComparative genomics |
| spellingShingle | Kristian G Andersen Jesper K Nissen Alexander G Betz Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution Frontiers in Immunology Regulatory T Cell Foxp3 Evolution of Immune System Lineage commitment Comparative genomics |
| title | Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution |
| title_full | Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution |
| title_fullStr | Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution |
| title_full_unstemmed | Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution |
| title_short | Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution |
| title_sort | comparative genomics reveals key gain of function events in foxp3 during regulatory t cell evolution |
| topic | Regulatory T Cell Foxp3 Evolution of Immune System Lineage commitment Comparative genomics |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2012.00113/full |
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