CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance
Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3(+) regulatory T cells. CTLA-4-deficient mice develop fatal, early onset lymphoproliferative disease. However, chimer...
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| Veröffentlicht in: | The Journal of experimental medicine 2009-02, Vol.206 (2), p.421-434 |
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| container_title | The Journal of experimental medicine |
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| creator | Friedline, Randall H Brown, David S Nguyen, Hai Kornfeld, Hardy Lee, Jinhee Zhang, Yi Appleby, Mark Der, Sandy D Kang, Joonsoo Chambers, Cynthia A |
| description | Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3(+) regulatory T cells. CTLA-4-deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4-deficient and -sufficient bone marrow (BM)-derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-sufficient T cells is a reversible process that requires the persistent presence of FOXP3(+) regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3(+) regulatory T cell function in vivo. |
| doi_str_mv | 10.1084/jem.20081811 |
| format | Article |
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CTLA-4-deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4-deficient and -sufficient bone marrow (BM)-derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-sufficient T cells is a reversible process that requires the persistent presence of FOXP3(+) regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3(+) regulatory T cell function in vivo.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20081811</identifier><identifier>PMID: 19188497</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Adoptive Transfer ; Animals ; Antigens, CD - genetics ; Antigens, CD - immunology ; Bromodeoxyuridine ; CTLA-4 Antigen ; DNA Primers - genetics ; Flow Cytometry ; Forkhead Transcription Factors - immunology ; Gene Expression Regulation - immunology ; Mice ; Mice, Knockout ; Reverse Transcriptase Polymerase Chain Reaction ; Self Tolerance - immunology ; T-Lymphocytes, Regulatory - immunology</subject><ispartof>The Journal of experimental medicine, 2009-02, Vol.206 (2), p.421-434</ispartof><rights>2009 Friedline et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c382t-c51e4bfbefcb5d33980a53268dd68f395c4f0264d52514f96cdd762221c820853</citedby><cites>FETCH-LOGICAL-c382t-c51e4bfbefcb5d33980a53268dd68f395c4f0264d52514f96cdd762221c820853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19188497$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Friedline, Randall H</creatorcontrib><creatorcontrib>Brown, David S</creatorcontrib><creatorcontrib>Nguyen, Hai</creatorcontrib><creatorcontrib>Kornfeld, Hardy</creatorcontrib><creatorcontrib>Lee, Jinhee</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Appleby, Mark</creatorcontrib><creatorcontrib>Der, Sandy D</creatorcontrib><creatorcontrib>Kang, Joonsoo</creatorcontrib><creatorcontrib>Chambers, Cynthia A</creatorcontrib><title>CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3(+) regulatory T cells. CTLA-4-deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4-deficient and -sufficient bone marrow (BM)-derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-sufficient T cells is a reversible process that requires the persistent presence of FOXP3(+) regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3(+) regulatory T cell function in vivo.</description><subject>Adoptive Transfer</subject><subject>Animals</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - immunology</subject><subject>Bromodeoxyuridine</subject><subject>CTLA-4 Antigen</subject><subject>DNA Primers - genetics</subject><subject>Flow Cytometry</subject><subject>Forkhead Transcription Factors - immunology</subject><subject>Gene Expression Regulation - immunology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Self Tolerance - immunology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkEtLw0AURgdRbK3uXMvsNXWeyWQjlPiEgi7qephM7rQpedSZROi_N6X1tbrw3e-eCwehS0qmlChxu4Z6yghRVFF6hMZUChKlkqtjNCaEsYgSkozQWQhrQqgQMj5FI5pSpUSajNFbdi-usYdlX5mu9Vu8wBaqKgzRR196wNliPosEdq3H3Qpwbcqmg8Y0FnDrcNiGDurS4q6twO_Sc3TiTBXg4jAn6P3xYZE9R_PXp5dsNo8sV6yLrKQgcpeDs7ksOE8VMZKzWBVFrBxPpRWOsFgUkkkqXBrbokhixhi1ihEl-QTd7bmbPq-hsNB03lR648va-K1uTan_b5pypZftpx6gsUzUALjZA6xvQ_Dgfm4p0TuzejCrv80O9au__37LB5X8CzTNdIA</recordid><startdate>20090216</startdate><enddate>20090216</enddate><creator>Friedline, Randall H</creator><creator>Brown, David S</creator><creator>Nguyen, Hai</creator><creator>Kornfeld, Hardy</creator><creator>Lee, Jinhee</creator><creator>Zhang, Yi</creator><creator>Appleby, Mark</creator><creator>Der, Sandy D</creator><creator>Kang, Joonsoo</creator><creator>Chambers, Cynthia A</creator><general>The Rockefeller University Press</general><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>5PM</scope></search><sort><creationdate>20090216</creationdate><title>CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance</title><author>Friedline, Randall H ; Brown, David S ; Nguyen, Hai ; Kornfeld, Hardy ; Lee, Jinhee ; Zhang, Yi ; Appleby, Mark ; Der, Sandy D ; Kang, Joonsoo ; Chambers, Cynthia A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c382t-c51e4bfbefcb5d33980a53268dd68f395c4f0264d52514f96cdd762221c820853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adoptive Transfer</topic><topic>Animals</topic><topic>Antigens, CD - genetics</topic><topic>Antigens, CD - immunology</topic><topic>Bromodeoxyuridine</topic><topic>CTLA-4 Antigen</topic><topic>DNA Primers - genetics</topic><topic>Flow Cytometry</topic><topic>Forkhead Transcription Factors - immunology</topic><topic>Gene Expression Regulation - immunology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Self Tolerance - immunology</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Friedline, Randall H</creatorcontrib><creatorcontrib>Brown, David S</creatorcontrib><creatorcontrib>Nguyen, Hai</creatorcontrib><creatorcontrib>Kornfeld, Hardy</creatorcontrib><creatorcontrib>Lee, Jinhee</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Appleby, Mark</creatorcontrib><creatorcontrib>Der, Sandy D</creatorcontrib><creatorcontrib>Kang, Joonsoo</creatorcontrib><creatorcontrib>Chambers, Cynthia A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Friedline, Randall H</au><au>Brown, David S</au><au>Nguyen, Hai</au><au>Kornfeld, Hardy</au><au>Lee, Jinhee</au><au>Zhang, Yi</au><au>Appleby, Mark</au><au>Der, Sandy D</au><au>Kang, Joonsoo</au><au>Chambers, Cynthia A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2009-02-16</date><risdate>2009</risdate><volume>206</volume><issue>2</issue><spage>421</spage><epage>434</epage><pages>421-434</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><abstract>Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3(+) regulatory T cells. CTLA-4-deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4-deficient and -sufficient bone marrow (BM)-derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-sufficient T cells is a reversible process that requires the persistent presence of FOXP3(+) regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3(+) regulatory T cell function in vivo.</abstract><cop>United States</cop><pub>The Rockefeller University Press</pub><pmid>19188497</pmid><doi>10.1084/jem.20081811</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of experimental medicine, 2009-02, Vol.206 (2), p.421-434 |
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| source | Electronic Journals Library; MEDLINE |
| subjects | Adoptive Transfer Animals Antigens, CD - genetics Antigens, CD - immunology Bromodeoxyuridine CTLA-4 Antigen DNA Primers - genetics Flow Cytometry Forkhead Transcription Factors - immunology Gene Expression Regulation - immunology Mice Mice, Knockout Reverse Transcriptase Polymerase Chain Reaction Self Tolerance - immunology T-Lymphocytes, Regulatory - immunology |
| title | CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance |
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