Cooperative roles of CTLA-4 and regulatory T cells in tolerance to an islet cell antigen
Adoptive transfer of ovalbumin (OVA)-specific T cells from the DO.11 TCR transgenic mouse on a Rag(-/-) background into mice expressing OVA in pancreatic islet cells induces acute insulitis and diabetes only if endogenous lymphocytes, including regulatory T cells, are removed. When wild-type OVA-spe...
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| Veröffentlicht in: | The Journal of experimental medicine 2004-06, Vol.199 (12), p.1725-1730 |
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| container_title | The Journal of experimental medicine |
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| creator | Eggena, Mark P Walker, Lucy S K Nagabhushanam, Vijaya Barron, Luke Chodos, Anna Abbas, Abul K |
| description | Adoptive transfer of ovalbumin (OVA)-specific T cells from the DO.11 TCR transgenic mouse on a Rag(-/-) background into mice expressing OVA in pancreatic islet cells induces acute insulitis and diabetes only if endogenous lymphocytes, including regulatory T cells, are removed. When wild-type OVA-specific/Rag(-/-) T cells, which are all CD25(-), are transferred into islet antigen-expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4(-/-)/Rag(-/-) OVA-specific T cells (also CD25(-)) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. Further, CTLA-4 and regulatory T cells act cooperatively to maintain tolerance, indicating that the function of CTLA-4 is independent of regulatory cells, and deficiency of both is required to induce pathologic immune responses against the islet self-antigen. |
| doi_str_mv | 10.1084/jem.20040124 |
| format | Article |
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When wild-type OVA-specific/Rag(-/-) T cells, which are all CD25(-), are transferred into islet antigen-expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4(-/-)/Rag(-/-) OVA-specific T cells (also CD25(-)) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. 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When wild-type OVA-specific/Rag(-/-) T cells, which are all CD25(-), are transferred into islet antigen-expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4(-/-)/Rag(-/-) OVA-specific T cells (also CD25(-)) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. Further, CTLA-4 and regulatory T cells act cooperatively to maintain tolerance, indicating that the function of CTLA-4 is independent of regulatory cells, and deficiency of both is required to induce pathologic immune responses against the islet self-antigen.</description><subject>Animals</subject><subject>Antigens, CD</subject><subject>Antigens, Differentiation - immunology</subject><subject>Autoantigens - immunology</subject><subject>Autoimmunity</subject><subject>Brief Definitive Report</subject><subject>CTLA-4 Antigen</subject><subject>Diabetes Mellitus, Type 1 - genetics</subject><subject>Diabetes Mellitus, Type 1 - immunology</subject><subject>DNA-Binding Proteins - deficiency</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - immunology</subject><subject>Immune Tolerance - immunology</subject><subject>Islets of Langerhans - immunology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Ovalbumin - immunology</subject><subject>T-Lymphocytes - immunology</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1r20AQxZeSUrtpbzmHPeUUpTOrWWl9CQSRNAVDLy70tqzWI0dG1jq7csD_feXGzcepp5nh_XjM4wlxhnCFYOjbmjdXCoAAFX0QU9QE2Uzn5kRMAZTKEKCciM8prQGQSBefxAS1QijJTMXvKoQtRze0Tyxj6DjJ0MhqMb_JSLp-KSOvdp0bQtzLhfTcdUm2vRxGMrre87iNmGxTx8NfebyGdsX9F_GxcV3ir8d5Kn7d3S6q-2z-8_uP6maeeUIcMgPGkPJYas49Ut2Y2uc4YwVaKT1zhAoorxtcutrkUGguSwZuvGsQSDf5qbh-9t3u6g0vPfdDdJ3dxnbj4t4G19r3St8-2FV4skqhMgijwcXRIIbHHafBbtp0SOJ6Drtki6IgpAL_C2JZkjLmAF4-gz6GlCI3L98g2ENnduzM_utsxM_fJniFjyXlfwBWUpHJ</recordid><startdate>20040621</startdate><enddate>20040621</enddate><creator>Eggena, Mark P</creator><creator>Walker, Lucy S K</creator><creator>Nagabhushanam, Vijaya</creator><creator>Barron, Luke</creator><creator>Chodos, Anna</creator><creator>Abbas, Abul K</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>7T5</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20040621</creationdate><title>Cooperative roles of CTLA-4 and regulatory T cells in tolerance to an islet cell antigen</title><author>Eggena, Mark P ; Walker, Lucy S K ; Nagabhushanam, Vijaya ; Barron, Luke ; Chodos, Anna ; Abbas, Abul K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-808842c175e3c14bf8bc319e2052259a412043bf1dab83065e77e0efcaf1045f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Antigens, CD</topic><topic>Antigens, Differentiation - immunology</topic><topic>Autoantigens - immunology</topic><topic>Autoimmunity</topic><topic>Brief Definitive Report</topic><topic>CTLA-4 Antigen</topic><topic>Diabetes Mellitus, Type 1 - genetics</topic><topic>Diabetes Mellitus, Type 1 - immunology</topic><topic>DNA-Binding Proteins - deficiency</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - immunology</topic><topic>Immune Tolerance - immunology</topic><topic>Islets of Langerhans - immunology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Ovalbumin - immunology</topic><topic>T-Lymphocytes - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Eggena, Mark P</creatorcontrib><creatorcontrib>Walker, Lucy S K</creatorcontrib><creatorcontrib>Nagabhushanam, Vijaya</creatorcontrib><creatorcontrib>Barron, Luke</creatorcontrib><creatorcontrib>Chodos, Anna</creatorcontrib><creatorcontrib>Abbas, Abul K</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</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>Eggena, Mark P</au><au>Walker, Lucy S K</au><au>Nagabhushanam, Vijaya</au><au>Barron, Luke</au><au>Chodos, Anna</au><au>Abbas, Abul K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cooperative roles of CTLA-4 and regulatory T cells in tolerance to an islet cell antigen</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2004-06-21</date><risdate>2004</risdate><volume>199</volume><issue>12</issue><spage>1725</spage><epage>1730</epage><pages>1725-1730</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><abstract>Adoptive transfer of ovalbumin (OVA)-specific T cells from the DO.11 TCR transgenic mouse on a Rag(-/-) background into mice expressing OVA in pancreatic islet cells induces acute insulitis and diabetes only if endogenous lymphocytes, including regulatory T cells, are removed. When wild-type OVA-specific/Rag(-/-) T cells, which are all CD25(-), are transferred into islet antigen-expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4(-/-)/Rag(-/-) OVA-specific T cells (also CD25(-)) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. 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| subjects | Animals Antigens, CD Antigens, Differentiation - immunology Autoantigens - immunology Autoimmunity Brief Definitive Report CTLA-4 Antigen Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology DNA-Binding Proteins - deficiency DNA-Binding Proteins - genetics DNA-Binding Proteins - immunology Immune Tolerance - immunology Islets of Langerhans - immunology Mice Mice, Knockout Mice, Transgenic Ovalbumin - immunology T-Lymphocytes - immunology |
| title | Cooperative roles of CTLA-4 and regulatory T cells in tolerance to an islet cell antigen |
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