Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus
Regulatory T cells (Tregs) differentiate in the thymus, but the mechanisms that control this process are not fully understood. We generated a comprehensive quantitative and differential proteome of murine Tregs and conventional T cells. We identified 5225 proteins, 164 of which were differentially e...
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| Veröffentlicht in: | The Journal of immunology (1950) 2015-10, Vol.195 (7), p.3058-3070 |
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| container_title | The Journal of immunology (1950) |
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| creator | Barra, Melanie M Richards, David M Hansson, Jenny Hofer, Ann-Cathrin Delacher, Michael Hettinger, Jan Krijgsveld, Jeroen Feuerer, Markus |
| description | Regulatory T cells (Tregs) differentiate in the thymus, but the mechanisms that control this process are not fully understood. We generated a comprehensive quantitative and differential proteome of murine Tregs and conventional T cells. We identified 5225 proteins, 164 of which were differentially expressed in Tregs. Together with the comparative analysis of proteome and gene expression data, we identified TCF7 as a promising candidate. Genetic elimination of transcription factor 7 (TCF7) led to increased fractions of Tregs in the thymus. Reduced levels of TCF7, found in the heterozygote, resulted in a greater potential for Treg precursors to differentiate into the Treg lineage. In contrast, activation of TCF7 through β-catenin had the opposite effect. TCF7 levels influenced the required TCR signaling strength of Treg precursors, and TCF7 deficiency broadened the repertoire and allowed lower TCR affinities to be recruited into the Treg lineage. FOXP3 was able to repress TCF7 protein expression. In summary, we propose a regulatory role for TCF7 in limiting access to the Treg lineage. |
| doi_str_mv | 10.4049/jimmunol.1500821 |
| format | Article |
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We generated a comprehensive quantitative and differential proteome of murine Tregs and conventional T cells. We identified 5225 proteins, 164 of which were differentially expressed in Tregs. Together with the comparative analysis of proteome and gene expression data, we identified TCF7 as a promising candidate. Genetic elimination of transcription factor 7 (TCF7) led to increased fractions of Tregs in the thymus. Reduced levels of TCF7, found in the heterozygote, resulted in a greater potential for Treg precursors to differentiate into the Treg lineage. In contrast, activation of TCF7 through β-catenin had the opposite effect. TCF7 levels influenced the required TCR signaling strength of Treg precursors, and TCF7 deficiency broadened the repertoire and allowed lower TCR affinities to be recruited into the Treg lineage. FOXP3 was able to repress TCF7 protein expression. In summary, we propose a regulatory role for TCF7 in limiting access to the Treg lineage.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1500821</identifier><identifier>PMID: 26324778</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; beta Catenin - metabolism ; Cell Lineage - immunology ; Cell Proliferation ; Forkhead Transcription Factors - metabolism ; Gene Expression Profiling ; Hematopoiesis - genetics ; Hematopoiesis - immunology ; Hepatocyte Nuclear Factor 1-alpha - genetics ; Hepatocyte Nuclear Factor 1-alpha - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Proteome - analysis ; Signal Transduction - immunology ; T-Lymphocytes, Regulatory - cytology ; T-Lymphocytes, Regulatory - immunology ; Thymus Gland - immunology</subject><ispartof>The Journal of immunology (1950), 2015-10, Vol.195 (7), p.3058-3070</ispartof><rights>Copyright © 2015 by The American Association of Immunologists, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c374t-99527c1db0e7e243df5c5015ef70dff9446fe5b1435f7712fe65581d8d1fddf33</citedby><cites>FETCH-LOGICAL-c374t-99527c1db0e7e243df5c5015ef70dff9446fe5b1435f7712fe65581d8d1fddf33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26324778$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barra, Melanie M</creatorcontrib><creatorcontrib>Richards, David M</creatorcontrib><creatorcontrib>Hansson, Jenny</creatorcontrib><creatorcontrib>Hofer, Ann-Cathrin</creatorcontrib><creatorcontrib>Delacher, Michael</creatorcontrib><creatorcontrib>Hettinger, Jan</creatorcontrib><creatorcontrib>Krijgsveld, Jeroen</creatorcontrib><creatorcontrib>Feuerer, Markus</creatorcontrib><title>Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Regulatory T cells (Tregs) differentiate in the thymus, but the mechanisms that control this process are not fully understood. We generated a comprehensive quantitative and differential proteome of murine Tregs and conventional T cells. We identified 5225 proteins, 164 of which were differentially expressed in Tregs. Together with the comparative analysis of proteome and gene expression data, we identified TCF7 as a promising candidate. Genetic elimination of transcription factor 7 (TCF7) led to increased fractions of Tregs in the thymus. Reduced levels of TCF7, found in the heterozygote, resulted in a greater potential for Treg precursors to differentiate into the Treg lineage. In contrast, activation of TCF7 through β-catenin had the opposite effect. TCF7 levels influenced the required TCR signaling strength of Treg precursors, and TCF7 deficiency broadened the repertoire and allowed lower TCR affinities to be recruited into the Treg lineage. FOXP3 was able to repress TCF7 protein expression. In summary, we propose a regulatory role for TCF7 in limiting access to the Treg lineage.</description><subject>Animals</subject><subject>beta Catenin - metabolism</subject><subject>Cell Lineage - immunology</subject><subject>Cell Proliferation</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Gene Expression Profiling</subject><subject>Hematopoiesis - genetics</subject><subject>Hematopoiesis - immunology</subject><subject>Hepatocyte Nuclear Factor 1-alpha - genetics</subject><subject>Hepatocyte Nuclear Factor 1-alpha - physiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Proteome - analysis</subject><subject>Signal Transduction - immunology</subject><subject>T-Lymphocytes, Regulatory - cytology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Thymus Gland - immunology</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtLw0AUhQdRbK3uXcks3aTeO89kKcW2QkGQug5pZsZOyaPOJIv-e6Nt3bq6cPjO4fIRco8wFSCyp52v675pqylKgJThBRmjlJAoBeqSjAEYS1ArPSI3Me4AQAET12TEFGdC63RMlutQNLEMft_5tqHzouzaQDVd-dp3kb7bz74qhuhA13Rmq4oubGND8Qv7hnZbS9fbQ93HW3Lliirau9OdkI_5y3q2TFZvi9fZ8yopuRZdkmWS6RLNBqy2THDjZCkBpXUajHOZEMpZuUHBpdMambNKyhRNatAZ4zifkMfj7j60X72NXV77WA6fFY1t-5hjCqkGzED_j2rkmRyE4YDCES1DG2OwLt8HXxfhkCPkP6rzs-r8pHqoPJzW-01tzV_h7JZ_AyaOewU</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Barra, Melanie M</creator><creator>Richards, David M</creator><creator>Hansson, Jenny</creator><creator>Hofer, Ann-Cathrin</creator><creator>Delacher, Michael</creator><creator>Hettinger, Jan</creator><creator>Krijgsveld, Jeroen</creator><creator>Feuerer, Markus</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>20151001</creationdate><title>Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus</title><author>Barra, Melanie M ; Richards, David M ; Hansson, Jenny ; Hofer, Ann-Cathrin ; Delacher, Michael ; Hettinger, Jan ; Krijgsveld, Jeroen ; Feuerer, Markus</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c374t-99527c1db0e7e243df5c5015ef70dff9446fe5b1435f7712fe65581d8d1fddf33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>beta Catenin - metabolism</topic><topic>Cell Lineage - immunology</topic><topic>Cell Proliferation</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Gene Expression Profiling</topic><topic>Hematopoiesis - genetics</topic><topic>Hematopoiesis - immunology</topic><topic>Hepatocyte Nuclear Factor 1-alpha - genetics</topic><topic>Hepatocyte Nuclear Factor 1-alpha - physiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Proteome - analysis</topic><topic>Signal Transduction - immunology</topic><topic>T-Lymphocytes, Regulatory - cytology</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Thymus Gland - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barra, Melanie M</creatorcontrib><creatorcontrib>Richards, David M</creatorcontrib><creatorcontrib>Hansson, Jenny</creatorcontrib><creatorcontrib>Hofer, Ann-Cathrin</creatorcontrib><creatorcontrib>Delacher, Michael</creatorcontrib><creatorcontrib>Hettinger, Jan</creatorcontrib><creatorcontrib>Krijgsveld, Jeroen</creatorcontrib><creatorcontrib>Feuerer, Markus</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barra, Melanie M</au><au>Richards, David M</au><au>Hansson, Jenny</au><au>Hofer, Ann-Cathrin</au><au>Delacher, Michael</au><au>Hettinger, Jan</au><au>Krijgsveld, Jeroen</au><au>Feuerer, Markus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>195</volume><issue>7</issue><spage>3058</spage><epage>3070</epage><pages>3058-3070</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Regulatory T cells (Tregs) differentiate in the thymus, but the mechanisms that control this process are not fully understood. We generated a comprehensive quantitative and differential proteome of murine Tregs and conventional T cells. We identified 5225 proteins, 164 of which were differentially expressed in Tregs. Together with the comparative analysis of proteome and gene expression data, we identified TCF7 as a promising candidate. Genetic elimination of transcription factor 7 (TCF7) led to increased fractions of Tregs in the thymus. Reduced levels of TCF7, found in the heterozygote, resulted in a greater potential for Treg precursors to differentiate into the Treg lineage. In contrast, activation of TCF7 through β-catenin had the opposite effect. TCF7 levels influenced the required TCR signaling strength of Treg precursors, and TCF7 deficiency broadened the repertoire and allowed lower TCR affinities to be recruited into the Treg lineage. FOXP3 was able to repress TCF7 protein expression. In summary, we propose a regulatory role for TCF7 in limiting access to the Treg lineage.</abstract><cop>United States</cop><pmid>26324778</pmid><doi>10.4049/jimmunol.1500821</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals beta Catenin - metabolism Cell Lineage - immunology Cell Proliferation Forkhead Transcription Factors - metabolism Gene Expression Profiling Hematopoiesis - genetics Hematopoiesis - immunology Hepatocyte Nuclear Factor 1-alpha - genetics Hepatocyte Nuclear Factor 1-alpha - physiology Mice Mice, Inbred C57BL Mice, Knockout Proteome - analysis Signal Transduction - immunology T-Lymphocytes, Regulatory - cytology T-Lymphocytes, Regulatory - immunology Thymus Gland - immunology |
| title | Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus |
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