GITR ligand-costimulation activates effector and regulatory functions of CD4 + T cells
Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25 −CD4 + effector (Teff) and CD25 +CD4 + regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR lig...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2008-05, Vol.369 (4), p.1134-1138 |
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| creator | Igarashi, Hanna Cao, Yujia Iwai, Hideyuki Piao, Jinhua Kamimura, Yosuke Hashiguchi, Masaaki Amagasa, Teruo Azuma, Miyuki |
| description | Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25
−CD4
+ effector (Teff) and CD25
+CD4
+ regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4
+ T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4
+ T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists. |
| doi_str_mv | 10.1016/j.bbrc.2008.03.024 |
| format | Article |
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−CD4
+ effector (Teff) and CD25
+CD4
+ regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4
+ T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4
+ T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1016/j.bbrc.2008.03.024</identifier><identifier>PMID: 18346459</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; Animals ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - pharmacology ; Antigen-Presenting Cells - immunology ; BIOLOGICAL FUNCTIONS ; CD3 Complex - metabolism ; CD4 + T cells ; CD4 Antigens - analysis ; CELL PROLIFERATION ; Coculture Techniques ; Costimulation ; Effector T cells ; Female ; GITR ligand ; GLUCOCORTICOIDS ; Interleukin-10 - metabolism ; Interleukin-2 Receptor alpha Subunit - analysis ; LIGANDS ; Lymphocyte Activation - drug effects ; Mice ; Mice, Inbred BALB C ; PROTEINS ; Regulatory T cells ; STIMULATION ; T-Lymphocytes, Regulatory - drug effects ; T-Lymphocytes, Regulatory - immunology ; Transfection ; Tumor Necrosis Factors - agonists ; Tumor Necrosis Factors - genetics</subject><ispartof>Biochemical and biophysical research communications, 2008-05, Vol.369 (4), p.1134-1138</ispartof><rights>2008 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c382t-5bb77a89a5c2967bb46e360bb3d26cd4a8fab45dbce8ff5de9d08858025137bf3</citedby><cites>FETCH-LOGICAL-c382t-5bb77a89a5c2967bb46e360bb3d26cd4a8fab45dbce8ff5de9d08858025137bf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bbrc.2008.03.024$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3548,27922,27923,45993</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18346459$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/21143684$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Igarashi, Hanna</creatorcontrib><creatorcontrib>Cao, Yujia</creatorcontrib><creatorcontrib>Iwai, Hideyuki</creatorcontrib><creatorcontrib>Piao, Jinhua</creatorcontrib><creatorcontrib>Kamimura, Yosuke</creatorcontrib><creatorcontrib>Hashiguchi, Masaaki</creatorcontrib><creatorcontrib>Amagasa, Teruo</creatorcontrib><creatorcontrib>Azuma, Miyuki</creatorcontrib><title>GITR ligand-costimulation activates effector and regulatory functions of CD4 + T cells</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25
−CD4
+ effector (Teff) and CD25
+CD4
+ regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4
+ T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4
+ T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antigen-Presenting Cells - immunology</subject><subject>BIOLOGICAL FUNCTIONS</subject><subject>CD3 Complex - metabolism</subject><subject>CD4 + T cells</subject><subject>CD4 Antigens - analysis</subject><subject>CELL PROLIFERATION</subject><subject>Coculture Techniques</subject><subject>Costimulation</subject><subject>Effector T cells</subject><subject>Female</subject><subject>GITR ligand</subject><subject>GLUCOCORTICOIDS</subject><subject>Interleukin-10 - metabolism</subject><subject>Interleukin-2 Receptor alpha Subunit - analysis</subject><subject>LIGANDS</subject><subject>Lymphocyte Activation - drug effects</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>PROTEINS</subject><subject>Regulatory T cells</subject><subject>STIMULATION</subject><subject>T-Lymphocytes, Regulatory - drug effects</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Transfection</subject><subject>Tumor Necrosis Factors - agonists</subject><subject>Tumor Necrosis Factors - genetics</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9rFDEYh4NY7Fr9Ah4kIHiRGd_8mUwGvJRV20JBkK14C0kmqVlmJzWZKfTbN2EXvHnK5Xl_PHkQekegJUDE531rTLItBZAtsBYof4E2BAZoKAH-Em0AQDR0IL_P0euc9wCEcDG8QudEMi54N2zQr6ub3U88hXs9j42NeQmHddJLiDPWdgmPenEZO--dXWLCBcLJ3Vcipifs19lWNOPo8fYrx5_wDls3TfkNOvN6yu7t6b1Ad9-_7bbXze2Pq5vt5W1jmaRL0xnT91oOurN0EL0xXDgmwBg2UmFHrqXXhnejsU56341uGEHKTgLtCOuNZxfow3G3mqtsw-LsHxvnufgqWr7LhOSF-nikHlL8u7q8qEPI1VPPLq5Z9cCF4LwvID2CNsWck_PqIYWDTk-KgKrN1V7V5qo2V8BUaV6O3p_WV3Nw47-TU-QCfDkCrpR4DC5VUTdbN4ZUPccY_rf_DLCukjI</recordid><startdate>20080516</startdate><enddate>20080516</enddate><creator>Igarashi, Hanna</creator><creator>Cao, Yujia</creator><creator>Iwai, Hideyuki</creator><creator>Piao, Jinhua</creator><creator>Kamimura, Yosuke</creator><creator>Hashiguchi, Masaaki</creator><creator>Amagasa, Teruo</creator><creator>Azuma, Miyuki</creator><general>Elsevier Inc</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>7X8</scope><scope>OTOTI</scope></search><sort><creationdate>20080516</creationdate><title>GITR ligand-costimulation activates effector and regulatory functions of CD4 + T cells</title><author>Igarashi, Hanna ; Cao, Yujia ; Iwai, Hideyuki ; Piao, Jinhua ; Kamimura, Yosuke ; Hashiguchi, Masaaki ; Amagasa, Teruo ; Azuma, Miyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c382t-5bb77a89a5c2967bb46e360bb3d26cd4a8fab45dbce8ff5de9d08858025137bf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antigen-Presenting Cells - immunology</topic><topic>BIOLOGICAL FUNCTIONS</topic><topic>CD3 Complex - metabolism</topic><topic>CD4 + T cells</topic><topic>CD4 Antigens - analysis</topic><topic>CELL PROLIFERATION</topic><topic>Coculture Techniques</topic><topic>Costimulation</topic><topic>Effector T cells</topic><topic>Female</topic><topic>GITR ligand</topic><topic>GLUCOCORTICOIDS</topic><topic>Interleukin-10 - metabolism</topic><topic>Interleukin-2 Receptor alpha Subunit - analysis</topic><topic>LIGANDS</topic><topic>Lymphocyte Activation - drug effects</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>PROTEINS</topic><topic>Regulatory T cells</topic><topic>STIMULATION</topic><topic>T-Lymphocytes, Regulatory - drug effects</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Transfection</topic><topic>Tumor Necrosis Factors - agonists</topic><topic>Tumor Necrosis Factors - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Igarashi, Hanna</creatorcontrib><creatorcontrib>Cao, Yujia</creatorcontrib><creatorcontrib>Iwai, Hideyuki</creatorcontrib><creatorcontrib>Piao, Jinhua</creatorcontrib><creatorcontrib>Kamimura, Yosuke</creatorcontrib><creatorcontrib>Hashiguchi, Masaaki</creatorcontrib><creatorcontrib>Amagasa, Teruo</creatorcontrib><creatorcontrib>Azuma, Miyuki</creatorcontrib><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><collection>OSTI.GOV</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Igarashi, Hanna</au><au>Cao, Yujia</au><au>Iwai, Hideyuki</au><au>Piao, Jinhua</au><au>Kamimura, Yosuke</au><au>Hashiguchi, Masaaki</au><au>Amagasa, Teruo</au><au>Azuma, Miyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GITR ligand-costimulation activates effector and regulatory functions of CD4 + T cells</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2008-05-16</date><risdate>2008</risdate><volume>369</volume><issue>4</issue><spage>1134</spage><epage>1138</epage><pages>1134-1138</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>Engagement of glucocorticoid-induced TNFR-related protein (GITR) enables the costimulation of both CD25
−CD4
+ effector (Teff) and CD25
+CD4
+ regulatory (Treg) cells; however, the effects of GITR-costimulation on Treg function remain controversial. In this study, we examined the effects of GITR ligand (GITRL) binding on the respective functions of CD4
+ T cells. GITRL-P815 transfectants efficiently augmented anti-CD3-induced proliferation and cytokine production by Teff cells. Proliferation and IL-10 production in Treg were also enhanced by GITRL transfectants when exogenous IL-2 and stronger CD3 stimulation was provided. Concomitant GITRL-costimulation of Teff and Treg converted the anergic state of Treg into a proliferating state, maintaining and augmenting their function. Thus, GITRL-costimulation augments both effector and regulatory functions of CD4
+ T cells. Our results suggest that highly activated and increased ratios of Treg reverse the immune-enhancing effects of GITRL-costimulation in Teff, which may be problematic for therapeutic applications using strong GITR agonists.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18346459</pmid><doi>10.1016/j.bbrc.2008.03.024</doi><tpages>5</tpages></addata></record> |
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| ispartof | Biochemical and biophysical research communications, 2008-05, Vol.369 (4), p.1134-1138 |
| issn | 0006-291X 1090-2104 |
| language | eng |
| recordid | cdi_osti_scitechconnect_21143684 |
| source | Elsevier ScienceDirect Journals Complete - AutoHoldings; MEDLINE |
| subjects | 60 APPLIED LIFE SCIENCES Animals Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacology Antigen-Presenting Cells - immunology BIOLOGICAL FUNCTIONS CD3 Complex - metabolism CD4 + T cells CD4 Antigens - analysis CELL PROLIFERATION Coculture Techniques Costimulation Effector T cells Female GITR ligand GLUCOCORTICOIDS Interleukin-10 - metabolism Interleukin-2 Receptor alpha Subunit - analysis LIGANDS Lymphocyte Activation - drug effects Mice Mice, Inbred BALB C PROTEINS Regulatory T cells STIMULATION T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - immunology Transfection Tumor Necrosis Factors - agonists Tumor Necrosis Factors - genetics |
| title | GITR ligand-costimulation activates effector and regulatory functions of CD4 + T cells |
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