Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation
FoxP3+ confers suppressive properties and is confined to regulatory T cells (Treg) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4+ Treg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8+ popula...
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| Veröffentlicht in: | Blood 2012-06, Vol.119 (24), p.5898-5908 |
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| creator | Robb, Renee J. Lineburg, Katie E. Kuns, Rachel D. Wilson, Yana A. Raffelt, Neil C. Olver, Stuart D. Varelias, Antiopi Alexander, Kylie A. Teal, Bianca E. Sparwasser, Tim Hammerling, Gunter J. Markey, Kate A. Koyama, Motoko Clouston, Andrew D. Engwerda, Christian R. Hill, Geoffrey R. MacDonald, Kelli P.A. |
| description | FoxP3+ confers suppressive properties and is confined to regulatory T cells (Treg) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4+ Treg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8+ population of FoxP3+ Treg that convert from CD8+ conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8+ Treg undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4+FoxP3+ population and is more potent in exerting class I–restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8+FoxP3+ Treg are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8+FoxP3+ Treg thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I–restricted T-cell responses after bone marrow transplantation. |
| doi_str_mv | 10.1182/blood-2011-12-396119 |
| format | Article |
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In the transplant setting, natural CD4+ Treg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8+ population of FoxP3+ Treg that convert from CD8+ conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8+ Treg undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4+FoxP3+ population and is more potent in exerting class I–restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8+FoxP3+ Treg are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8+FoxP3+ Treg thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I–restricted T-cell responses after bone marrow transplantation.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2011-12-396119</identifier><identifier>PMID: 22538855</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Animals ; Antibodies - administration & dosage ; Antibodies - pharmacology ; Biological and medical sciences ; Bone Marrow Transplantation ; CD8-Positive T-Lymphocytes - cytology ; CD8-Positive T-Lymphocytes - drug effects ; CD8-Positive T-Lymphocytes - immunology ; Cell Differentiation - drug effects ; Cell Differentiation - immunology ; Cell Proliferation - drug effects ; Dendritic Cells - cytology ; Dendritic Cells - drug effects ; Dendritic Cells - immunology ; Epitopes - immunology ; Female ; Forkhead Transcription Factors - metabolism ; Graft vs Host Disease - immunology ; Graft vs Host Disease - pathology ; Hematologic and hematopoietic diseases ; Immune Tolerance - drug effects ; Immune Tolerance - immunology ; Interleukin-2 - immunology ; Lymph Nodes - drug effects ; Lymph Nodes - immunology ; Lymph Nodes - pathology ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Phenotype ; Sirolimus - administration & dosage ; Sirolimus - pharmacology ; Survival Analysis ; T-Lymphocytes, Regulatory - cytology ; T-Lymphocytes, Regulatory - drug effects ; T-Lymphocytes, Regulatory - immunology ; Transforming Growth Factor beta - pharmacology ; Transplantation, Homologous</subject><ispartof>Blood, 2012-06, Vol.119 (24), p.5898-5908</ispartof><rights>2012 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-2c6dd5364f2392ce7b407c9a3be92cd79cba019009e2684a082f77503d9950313</citedby><cites>FETCH-LOGICAL-c438t-2c6dd5364f2392ce7b407c9a3be92cd79cba019009e2684a082f77503d9950313</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25990293$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22538855$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Robb, Renee J.</creatorcontrib><creatorcontrib>Lineburg, Katie E.</creatorcontrib><creatorcontrib>Kuns, Rachel D.</creatorcontrib><creatorcontrib>Wilson, Yana A.</creatorcontrib><creatorcontrib>Raffelt, Neil C.</creatorcontrib><creatorcontrib>Olver, Stuart D.</creatorcontrib><creatorcontrib>Varelias, Antiopi</creatorcontrib><creatorcontrib>Alexander, Kylie A.</creatorcontrib><creatorcontrib>Teal, Bianca E.</creatorcontrib><creatorcontrib>Sparwasser, Tim</creatorcontrib><creatorcontrib>Hammerling, Gunter J.</creatorcontrib><creatorcontrib>Markey, Kate A.</creatorcontrib><creatorcontrib>Koyama, Motoko</creatorcontrib><creatorcontrib>Clouston, Andrew D.</creatorcontrib><creatorcontrib>Engwerda, Christian R.</creatorcontrib><creatorcontrib>Hill, Geoffrey R.</creatorcontrib><creatorcontrib>MacDonald, Kelli P.A.</creatorcontrib><title>Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation</title><title>Blood</title><addtitle>Blood</addtitle><description>FoxP3+ confers suppressive properties and is confined to regulatory T cells (Treg) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4+ Treg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8+ population of FoxP3+ Treg that convert from CD8+ conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8+ Treg undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4+FoxP3+ population and is more potent in exerting class I–restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8+FoxP3+ Treg are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8+FoxP3+ Treg thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I–restricted T-cell responses after bone marrow transplantation.</description><subject>Animals</subject><subject>Antibodies - administration & dosage</subject><subject>Antibodies - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bone Marrow Transplantation</subject><subject>CD8-Positive T-Lymphocytes - cytology</subject><subject>CD8-Positive T-Lymphocytes - drug effects</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Differentiation - immunology</subject><subject>Cell Proliferation - drug effects</subject><subject>Dendritic Cells - cytology</subject><subject>Dendritic Cells - drug effects</subject><subject>Dendritic Cells - immunology</subject><subject>Epitopes - immunology</subject><subject>Female</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Graft vs Host Disease - immunology</subject><subject>Graft vs Host Disease - pathology</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Immune Tolerance - drug effects</subject><subject>Immune Tolerance - immunology</subject><subject>Interleukin-2 - immunology</subject><subject>Lymph Nodes - drug effects</subject><subject>Lymph Nodes - immunology</subject><subject>Lymph Nodes - pathology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Phenotype</subject><subject>Sirolimus - administration & dosage</subject><subject>Sirolimus - pharmacology</subject><subject>Survival Analysis</subject><subject>T-Lymphocytes, Regulatory - cytology</subject><subject>T-Lymphocytes, Regulatory - drug effects</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Transforming Growth Factor beta - pharmacology</subject><subject>Transplantation, Homologous</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-KFDEQxoMo7rj6BiK5CMLSWkn6T3IRZHR1YUEP6zmkk-rZSKbTJt3rziv41KadUW9eEgp-9VXV9xHynMFrxiR_04cYXcWBsYrxSqiWMfWAbFjDZQXA4SHZAEBb1apjZ-RJzt8AWC1485iccd4IKZtmQ35eORxnP3hrZh9HakZH8X4yY16rONBbv7sNB5qXaUqYs79Dun0vLy7j_RdxQRPulmDmmA70hloMIVMzzJhWDUx-X7RNoCaEuMMRvaV9HJHuTUrxB51TGTMFU5h19lPyaDAh47PTf06-Xn642X6qrj9_vNq-u65sLeRccds614i2HrhQ3GLX19BZZUSPpXSdsr0BpgAU8lbWBiQfuq4B4ZQqLxPn5NVRd0rx-4J51nuf193NiHHJmhXzJFdMQkHrI2pTzDnhoKdylEmHAuk1Bf07Bb2moBnXxxRK24vThKXfo_vb9Mf2Arw8ASZbE4ZihPX5H9coBVyJwr09clj8uPOYdLYeR4vOJ7SzdtH_f5Nfpqqn0A</recordid><startdate>20120614</startdate><enddate>20120614</enddate><creator>Robb, Renee J.</creator><creator>Lineburg, Katie E.</creator><creator>Kuns, Rachel D.</creator><creator>Wilson, Yana A.</creator><creator>Raffelt, Neil C.</creator><creator>Olver, Stuart D.</creator><creator>Varelias, Antiopi</creator><creator>Alexander, Kylie A.</creator><creator>Teal, Bianca E.</creator><creator>Sparwasser, Tim</creator><creator>Hammerling, Gunter J.</creator><creator>Markey, Kate A.</creator><creator>Koyama, Motoko</creator><creator>Clouston, Andrew D.</creator><creator>Engwerda, Christian R.</creator><creator>Hill, Geoffrey R.</creator><creator>MacDonald, Kelli P.A.</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><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></search><sort><creationdate>20120614</creationdate><title>Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation</title><author>Robb, Renee J. ; Lineburg, Katie E. ; Kuns, Rachel D. ; Wilson, Yana A. ; Raffelt, Neil C. ; Olver, Stuart D. ; Varelias, Antiopi ; Alexander, Kylie A. ; Teal, Bianca E. ; Sparwasser, Tim ; Hammerling, Gunter J. ; Markey, Kate A. ; Koyama, Motoko ; Clouston, Andrew D. ; Engwerda, Christian R. ; Hill, Geoffrey R. ; MacDonald, Kelli P.A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-2c6dd5364f2392ce7b407c9a3be92cd79cba019009e2684a082f77503d9950313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Antibodies - administration & dosage</topic><topic>Antibodies - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bone Marrow Transplantation</topic><topic>CD8-Positive T-Lymphocytes - cytology</topic><topic>CD8-Positive T-Lymphocytes - drug effects</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Differentiation - immunology</topic><topic>Cell Proliferation - drug effects</topic><topic>Dendritic Cells - cytology</topic><topic>Dendritic Cells - drug effects</topic><topic>Dendritic Cells - immunology</topic><topic>Epitopes - immunology</topic><topic>Female</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Graft vs Host Disease - immunology</topic><topic>Graft vs Host Disease - pathology</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Immune Tolerance - drug effects</topic><topic>Immune Tolerance - immunology</topic><topic>Interleukin-2 - immunology</topic><topic>Lymph Nodes - drug effects</topic><topic>Lymph Nodes - immunology</topic><topic>Lymph Nodes - pathology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Phenotype</topic><topic>Sirolimus - administration & dosage</topic><topic>Sirolimus - pharmacology</topic><topic>Survival Analysis</topic><topic>T-Lymphocytes, Regulatory - cytology</topic><topic>T-Lymphocytes, Regulatory - drug effects</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Transforming Growth Factor beta - pharmacology</topic><topic>Transplantation, Homologous</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Robb, Renee J.</creatorcontrib><creatorcontrib>Lineburg, Katie E.</creatorcontrib><creatorcontrib>Kuns, Rachel D.</creatorcontrib><creatorcontrib>Wilson, Yana A.</creatorcontrib><creatorcontrib>Raffelt, Neil C.</creatorcontrib><creatorcontrib>Olver, Stuart D.</creatorcontrib><creatorcontrib>Varelias, Antiopi</creatorcontrib><creatorcontrib>Alexander, Kylie A.</creatorcontrib><creatorcontrib>Teal, Bianca E.</creatorcontrib><creatorcontrib>Sparwasser, Tim</creatorcontrib><creatorcontrib>Hammerling, Gunter J.</creatorcontrib><creatorcontrib>Markey, Kate A.</creatorcontrib><creatorcontrib>Koyama, Motoko</creatorcontrib><creatorcontrib>Clouston, Andrew D.</creatorcontrib><creatorcontrib>Engwerda, Christian R.</creatorcontrib><creatorcontrib>Hill, Geoffrey R.</creatorcontrib><creatorcontrib>MacDonald, Kelli P.A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><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><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Robb, Renee J.</au><au>Lineburg, Katie E.</au><au>Kuns, Rachel D.</au><au>Wilson, Yana A.</au><au>Raffelt, Neil C.</au><au>Olver, Stuart D.</au><au>Varelias, Antiopi</au><au>Alexander, Kylie A.</au><au>Teal, Bianca E.</au><au>Sparwasser, Tim</au><au>Hammerling, Gunter J.</au><au>Markey, Kate A.</au><au>Koyama, Motoko</au><au>Clouston, Andrew D.</au><au>Engwerda, Christian R.</au><au>Hill, Geoffrey R.</au><au>MacDonald, Kelli P.A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2012-06-14</date><risdate>2012</risdate><volume>119</volume><issue>24</issue><spage>5898</spage><epage>5908</epage><pages>5898-5908</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>FoxP3+ confers suppressive properties and is confined to regulatory T cells (Treg) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4+ Treg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8+ population of FoxP3+ Treg that convert from CD8+ conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8+ Treg undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4+FoxP3+ population and is more potent in exerting class I–restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8+FoxP3+ Treg are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8+FoxP3+ Treg thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I–restricted T-cell responses after bone marrow transplantation.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>22538855</pmid><doi>10.1182/blood-2011-12-396119</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Antibodies - administration & dosage Antibodies - pharmacology Biological and medical sciences Bone Marrow Transplantation CD8-Positive T-Lymphocytes - cytology CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology Cell Differentiation - drug effects Cell Differentiation - immunology Cell Proliferation - drug effects Dendritic Cells - cytology Dendritic Cells - drug effects Dendritic Cells - immunology Epitopes - immunology Female Forkhead Transcription Factors - metabolism Graft vs Host Disease - immunology Graft vs Host Disease - pathology Hematologic and hematopoietic diseases Immune Tolerance - drug effects Immune Tolerance - immunology Interleukin-2 - immunology Lymph Nodes - drug effects Lymph Nodes - immunology Lymph Nodes - pathology Medical sciences Mice Mice, Inbred C57BL Phenotype Sirolimus - administration & dosage Sirolimus - pharmacology Survival Analysis T-Lymphocytes, Regulatory - cytology T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - immunology Transforming Growth Factor beta - pharmacology Transplantation, Homologous |
| title | Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation |
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