CTLA-4 Controls Regulatory T Cell Peripheral Homeostasis and Is Required for Suppression of Pancreatic Islet Autoimmunity
The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan...
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| Veröffentlicht in: | The Journal of immunology (1950) 2009-01, Vol.182 (1), p.274-282 |
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| container_title | The Journal of immunology (1950) |
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| creator | Schmidt, Emily M Wang, Chun Jing Ryan, Gemma A Clough, Louise E Qureshi, Omar S Goodall, Margaret Abbas, Abul K Sharpe, Arlene H Sansom, David M Walker, Lucy S. K |
| description | The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3(+) regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3(+) cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity. |
| doi_str_mv | 10.4049/jimmunol.182.1.274 |
| format | Article |
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We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. 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K</creatorcontrib><title>CTLA-4 Controls Regulatory T Cell Peripheral Homeostasis and Is Required for Suppression of Pancreatic Islet Autoimmunity</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3(+) regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3(+) cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity.</description><subject>Animals</subject><subject>Antigens, CD - genetics</subject><subject>Antigens, CD - metabolism</subject><subject>Antigens, CD - physiology</subject><subject>Autoimmune Diseases - genetics</subject><subject>Autoimmune Diseases - pathology</subject><subject>Autoimmune Diseases - prevention & control</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Differentiation - immunology</subject><subject>Cell Proliferation</subject><subject>CTLA-4 Antigen</subject><subject>Diabetes Mellitus, Type 1 - genetics</subject><subject>Diabetes Mellitus, Type 1 - immunology</subject><subject>Diabetes Mellitus, Type 1 - pathology</subject><subject>Forkhead Transcription Factors - biosynthesis</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Homeostasis - genetics</subject><subject>Homeostasis - immunology</subject><subject>Immunosuppressive Agents - metabolism</subject><subject>Islets of Langerhans - immunology</subject><subject>Islets of Langerhans - metabolism</subject><subject>Islets of Langerhans - pathology</subject><subject>Lymphoproliferative Disorders - genetics</subject><subject>Lymphoproliferative Disorders - immunology</subject><subject>Lymphoproliferative Disorders - mortality</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Receptors, Antigen, T-Cell - biosynthesis</subject><subject>Receptors, Antigen, T-Cell - genetics</subject><subject>Signal Transduction - genetics</subject><subject>Signal Transduction - immunology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>T-Lymphocytes, Regulatory - metabolism</subject><subject>T-Lymphocytes, Regulatory - pathology</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMFO4zAQhi3ECrosL8AB-cQtxXZiOz5WESxIlUC7vVsmnlAjJw62o6pvT7p01dNcvv-fmQ-hG0qWFanU_Yfr-2kIfklrtqRLJqsztKCck0IIIs7RghDGCiqFvEQ_U_oghAjCqgt0SRUlivJ6gfbNZr0qKtyEIcfgE_4D75M3OcQ93uAGvMevEN24hWg8fgo9hJRNcgmbweLnA_85uQgWdyHiv9M4RkjJhQGHDr-aoY1gsmtn0kPGqymHf0e7vP-FfnTGJ7g-ziu0eXzYNE_F-uX3c7NaF20pRS6U7azqyrdacQalAeDKqLZVnawshVKVsm4l54xxIqEyhkhbghUWBJeM0_IK3X3XjjF8TpCy7l1q57_MAGFKWggpFKnJDLJvsI0hpQidHqPrTdxrSvTBt_7vW8--NdWz7zl0e2yf3nqwp8hR8Gn91r1vd7MonXrj_YxTvdvtTk1fOkyNDQ</recordid><startdate>20090101</startdate><enddate>20090101</enddate><creator>Schmidt, Emily M</creator><creator>Wang, Chun Jing</creator><creator>Ryan, Gemma A</creator><creator>Clough, Louise E</creator><creator>Qureshi, Omar S</creator><creator>Goodall, Margaret</creator><creator>Abbas, Abul K</creator><creator>Sharpe, Arlene H</creator><creator>Sansom, David M</creator><creator>Walker, Lucy S. 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K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CTLA-4 Controls Regulatory T Cell Peripheral Homeostasis and Is Required for Suppression of Pancreatic Islet Autoimmunity</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2009-01-01</date><risdate>2009</risdate><volume>182</volume><issue>1</issue><spage>274</spage><epage>282</epage><pages>274-282</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3(+) regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3(+) cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>19109158</pmid><doi>10.4049/jimmunol.182.1.274</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antigens, CD - genetics Antigens, CD - metabolism Antigens, CD - physiology Autoimmune Diseases - genetics Autoimmune Diseases - pathology Autoimmune Diseases - prevention & control Cell Differentiation - genetics Cell Differentiation - immunology Cell Proliferation CTLA-4 Antigen Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology Diabetes Mellitus, Type 1 - pathology Forkhead Transcription Factors - biosynthesis Forkhead Transcription Factors - genetics Homeostasis - genetics Homeostasis - immunology Immunosuppressive Agents - metabolism Islets of Langerhans - immunology Islets of Langerhans - metabolism Islets of Langerhans - pathology Lymphoproliferative Disorders - genetics Lymphoproliferative Disorders - immunology Lymphoproliferative Disorders - mortality Mice Mice, Inbred BALB C Mice, Knockout Mice, Transgenic Receptors, Antigen, T-Cell - biosynthesis Receptors, Antigen, T-Cell - genetics Signal Transduction - genetics Signal Transduction - immunology T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism T-Lymphocytes, Regulatory - pathology |
| title | CTLA-4 Controls Regulatory T Cell Peripheral Homeostasis and Is Required for Suppression of Pancreatic Islet Autoimmunity |
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