Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis
The ultimate goal for the treatment of autoimmunity is to restore immunological tolerance. Regulatory T cells (Treg) play a central role in immune tolerance, and Treg functional abnormalities have been identified in different autoimmune diseases, including rheumatoid arthritis (RA). We have previous...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2008-12, Vol.105 (49), p.19396-19401 |
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| creator | Flores-Borja, Fabian Jury, Elizabeth C Mauri, Claudia Ehrenstein, Michael R |
| description | The ultimate goal for the treatment of autoimmunity is to restore immunological tolerance. Regulatory T cells (Treg) play a central role in immune tolerance, and Treg functional abnormalities have been identified in different autoimmune diseases, including rheumatoid arthritis (RA). We have previously shown that natural Treg from RA patients are competent at suppressing responder T cell proliferation but not cytokine production. Here, we explore the hypothesis that this Treg defect in RA is linked with abnormalities in the expression and function of CTLA-4. We demonstrate that CTLA-4 expression on Treg from RA patients was significantly reduced compared with healthy Treg and is associated with an increased rate of CTLA-4 internalization. Regulation of T cell receptor signaling by CTLA-4 was impaired in RA Treg and associated with delayed recruitment of CTLA-4 to the immunological synapse. Artificial induction of CTLA-4 expression on RA Treg restored their suppressive capacity. Furthermore, CTLA-4 blockade impaired healthy Treg suppression of T cell IFN-γ production, but not proliferation, thereby recapitulating the unique Treg defect in RA. Our results suggest that defects in CTLA-4 could contribute to abnormal Treg function in RA and may represent a target for therapy for inducing long-lasting remission. |
| doi_str_mv | 10.1073/pnas.0806855105 |
| format | Article |
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Regulatory T cells (Treg) play a central role in immune tolerance, and Treg functional abnormalities have been identified in different autoimmune diseases, including rheumatoid arthritis (RA). We have previously shown that natural Treg from RA patients are competent at suppressing responder T cell proliferation but not cytokine production. Here, we explore the hypothesis that this Treg defect in RA is linked with abnormalities in the expression and function of CTLA-4. We demonstrate that CTLA-4 expression on Treg from RA patients was significantly reduced compared with healthy Treg and is associated with an increased rate of CTLA-4 internalization. Regulation of T cell receptor signaling by CTLA-4 was impaired in RA Treg and associated with delayed recruitment of CTLA-4 to the immunological synapse. Artificial induction of CTLA-4 expression on RA Treg restored their suppressive capacity. Furthermore, CTLA-4 blockade impaired healthy Treg suppression of T cell IFN-γ production, but not proliferation, thereby recapitulating the unique Treg defect in RA. Our results suggest that defects in CTLA-4 could contribute to abnormal Treg function in RA and may represent a target for therapy for inducing long-lasting remission.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0806855105</identifier><identifier>PMID: 19036923</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Antibodies ; Antigens, CD - immunology ; Antigens, CD - metabolism ; Arthritis ; Arthritis, Rheumatoid - immunology ; Autoimmune diseases ; Autoimmunity - immunology ; Biological Sciences ; Blood ; CTLA-4 Antigen ; Cytokines ; Forkhead Transcription Factors - immunology ; Forkhead Transcription Factors - metabolism ; Humans ; Immune Tolerance - immunology ; Interleukin-17 - metabolism ; Internalization ; Medical treatment ; Microscopy ; Phosphorylation ; Receptors, Antigen, T-Cell - metabolism ; Rheumatoid arthritis ; Signal Transduction - immunology ; T cell receptors ; T lymphocytes ; T-Lymphocytes, Regulatory - immunology ; T-Lymphocytes, Regulatory - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2008-12, Vol.105 (49), p.19396-19401</ispartof><rights>Copyright 2008 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Dec 9, 2008</rights><rights>2008 by The National Academy of Sciences of the USA</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c554t-28159f901d1db33819b9bed10b1cb7187114a0b7a034c99484c586f6c24ed30f3</citedby><cites>FETCH-LOGICAL-c554t-28159f901d1db33819b9bed10b1cb7187114a0b7a034c99484c586f6c24ed30f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/105/49.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25465655$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25465655$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19036923$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Flores-Borja, Fabian</creatorcontrib><creatorcontrib>Jury, Elizabeth C</creatorcontrib><creatorcontrib>Mauri, Claudia</creatorcontrib><creatorcontrib>Ehrenstein, Michael R</creatorcontrib><title>Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The ultimate goal for the treatment of autoimmunity is to restore immunological tolerance. Regulatory T cells (Treg) play a central role in immune tolerance, and Treg functional abnormalities have been identified in different autoimmune diseases, including rheumatoid arthritis (RA). We have previously shown that natural Treg from RA patients are competent at suppressing responder T cell proliferation but not cytokine production. Here, we explore the hypothesis that this Treg defect in RA is linked with abnormalities in the expression and function of CTLA-4. We demonstrate that CTLA-4 expression on Treg from RA patients was significantly reduced compared with healthy Treg and is associated with an increased rate of CTLA-4 internalization. Regulation of T cell receptor signaling by CTLA-4 was impaired in RA Treg and associated with delayed recruitment of CTLA-4 to the immunological synapse. Artificial induction of CTLA-4 expression on RA Treg restored their suppressive capacity. Furthermore, CTLA-4 blockade impaired healthy Treg suppression of T cell IFN-γ production, but not proliferation, thereby recapitulating the unique Treg defect in RA. Our results suggest that defects in CTLA-4 could contribute to abnormal Treg function in RA and may represent a target for therapy for inducing long-lasting remission.</description><subject>Antibodies</subject><subject>Antigens, CD - immunology</subject><subject>Antigens, CD - metabolism</subject><subject>Arthritis</subject><subject>Arthritis, Rheumatoid - immunology</subject><subject>Autoimmune diseases</subject><subject>Autoimmunity - immunology</subject><subject>Biological Sciences</subject><subject>Blood</subject><subject>CTLA-4 Antigen</subject><subject>Cytokines</subject><subject>Forkhead Transcription Factors - immunology</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Humans</subject><subject>Immune Tolerance - immunology</subject><subject>Interleukin-17 - metabolism</subject><subject>Internalization</subject><subject>Medical treatment</subject><subject>Microscopy</subject><subject>Phosphorylation</subject><subject>Receptors, Antigen, T-Cell - metabolism</subject><subject>Rheumatoid arthritis</subject><subject>Signal Transduction - immunology</subject><subject>T cell receptors</subject><subject>T lymphocytes</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>T-Lymphocytes, Regulatory - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0c1v0zAYBvAIgVgZnDkB1g5IHLK9jj9iXyZN5VOqxIHubDmO07pK4mI7sP33OGq1ApedfHh_fuTXT1G8xnCJoSZX-1HHSxDABWMY2JNigUHiklMJT4sFQFWXglb0rHgR4w4AJBPwvDjDEgiXFVkU-qPtrEkRuREt16ubkiIdLNIxeuN0si367dIW6Wb0YdA9CnYz9Tr5cI_WyNi-R900muT8OCeErZ2GPHVtTknb4JKLL4tnne6jfXU8z4vbz5_Wy6_l6vuXb8ubVWkYo6msBGayk4Bb3DaECCwb2dgWQ4NNU2NRY0w1NLUGQo2UVFDDBO-4qahtCXTkvLg-5O6nZrCtsWMKulf74AYd7pXXTv07Gd1WbfwvVXFM67rKAe-PAcH_nGxManBxXlGP1k9RcSlqKgR_FFZQEUIlzvDiP7jzUxjzL2SDSS04h4yuDsgEH2Ow3cOTMai5ZDWXrE4l5xtv_9705I-tZvDhCOabpzimqMyKSK66qe-TvUvZokdsJm8OZBdz8Q-mYpQzzub3vDvMO-2V3gQX1e2PeUHAjEuWE_4A9a3ONQ</recordid><startdate>20081209</startdate><enddate>20081209</enddate><creator>Flores-Borja, Fabian</creator><creator>Jury, Elizabeth C</creator><creator>Mauri, Claudia</creator><creator>Ehrenstein, Michael R</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20081209</creationdate><title>Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis</title><author>Flores-Borja, Fabian ; Jury, Elizabeth C ; Mauri, Claudia ; Ehrenstein, Michael R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c554t-28159f901d1db33819b9bed10b1cb7187114a0b7a034c99484c586f6c24ed30f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Antibodies</topic><topic>Antigens, CD - immunology</topic><topic>Antigens, CD - metabolism</topic><topic>Arthritis</topic><topic>Arthritis, Rheumatoid - immunology</topic><topic>Autoimmune diseases</topic><topic>Autoimmunity - immunology</topic><topic>Biological Sciences</topic><topic>Blood</topic><topic>CTLA-4 Antigen</topic><topic>Cytokines</topic><topic>Forkhead Transcription Factors - immunology</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Humans</topic><topic>Immune Tolerance - immunology</topic><topic>Interleukin-17 - metabolism</topic><topic>Internalization</topic><topic>Medical treatment</topic><topic>Microscopy</topic><topic>Phosphorylation</topic><topic>Receptors, Antigen, T-Cell - metabolism</topic><topic>Rheumatoid arthritis</topic><topic>Signal Transduction - immunology</topic><topic>T cell receptors</topic><topic>T lymphocytes</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>T-Lymphocytes, Regulatory - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Flores-Borja, Fabian</creatorcontrib><creatorcontrib>Jury, Elizabeth C</creatorcontrib><creatorcontrib>Mauri, Claudia</creatorcontrib><creatorcontrib>Ehrenstein, Michael R</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flores-Borja, Fabian</au><au>Jury, Elizabeth C</au><au>Mauri, Claudia</au><au>Ehrenstein, Michael R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2008-12-09</date><risdate>2008</risdate><volume>105</volume><issue>49</issue><spage>19396</spage><epage>19401</epage><pages>19396-19401</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The ultimate goal for the treatment of autoimmunity is to restore immunological tolerance. Regulatory T cells (Treg) play a central role in immune tolerance, and Treg functional abnormalities have been identified in different autoimmune diseases, including rheumatoid arthritis (RA). We have previously shown that natural Treg from RA patients are competent at suppressing responder T cell proliferation but not cytokine production. Here, we explore the hypothesis that this Treg defect in RA is linked with abnormalities in the expression and function of CTLA-4. We demonstrate that CTLA-4 expression on Treg from RA patients was significantly reduced compared with healthy Treg and is associated with an increased rate of CTLA-4 internalization. Regulation of T cell receptor signaling by CTLA-4 was impaired in RA Treg and associated with delayed recruitment of CTLA-4 to the immunological synapse. Artificial induction of CTLA-4 expression on RA Treg restored their suppressive capacity. Furthermore, CTLA-4 blockade impaired healthy Treg suppression of T cell IFN-γ production, but not proliferation, thereby recapitulating the unique Treg defect in RA. Our results suggest that defects in CTLA-4 could contribute to abnormal Treg function in RA and may represent a target for therapy for inducing long-lasting remission.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>19036923</pmid><doi>10.1073/pnas.0806855105</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antibodies Antigens, CD - immunology Antigens, CD - metabolism Arthritis Arthritis, Rheumatoid - immunology Autoimmune diseases Autoimmunity - immunology Biological Sciences Blood CTLA-4 Antigen Cytokines Forkhead Transcription Factors - immunology Forkhead Transcription Factors - metabolism Humans Immune Tolerance - immunology Interleukin-17 - metabolism Internalization Medical treatment Microscopy Phosphorylation Receptors, Antigen, T-Cell - metabolism Rheumatoid arthritis Signal Transduction - immunology T cell receptors T lymphocytes T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism |
| title | Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis |
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