Role of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 on apoptosis‐Prone CD8 T cells in persistent hepatitis B virus infection
An excess of coinhibitory signals has been proposed to drive the T‐cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 (CTLA‐4) to CD8 T cell tolerance in chronic hepatitis B virus (HB...
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| Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2011-05, Vol.53 (5), p.1494-1503 |
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| creator | Schurich, Anna Khanna, Pooja Lopes, A. Ross Han, Ki Jun Peppa, Dimitra Micco, Lorenzo Nebbia, Gaia Kennedy, Patrick T.F. Geretti, Anna‐Maria Dusheiko, Geoffrey Maini, Mala K. |
| description | An excess of coinhibitory signals has been proposed to drive the T‐cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 (CTLA‐4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA‐4 and this correlates with viral load. CTLA‐4 is up‐regulated on those HBV‐specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA‐4‐mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV‐specific CD8 T cells but does not reprogram their CTLA‐4hiBimhi tolerogenic phenotype. Blocking CTLA‐4 is able to increase the expansion of interferon gamma (IFN‐γ)‐producing HBV‐specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti‐HBV responses by either CTLA‐4 or PD‐L1 blockade is nonredundant. Conclusion: CTLA‐4 is expressed by HBV‐specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA‐4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T‐cell exhaustion in this heterogeneous disease. (HEPATOLOGY 2011;) |
| doi_str_mv | 10.1002/hep.24249 |
| format | Article |
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Ross ; Han, Ki Jun ; Peppa, Dimitra ; Micco, Lorenzo ; Nebbia, Gaia ; Kennedy, Patrick T.F. ; Geretti, Anna‐Maria ; Dusheiko, Geoffrey ; Maini, Mala K.</creator><creatorcontrib>Schurich, Anna ; Khanna, Pooja ; Lopes, A. Ross ; Han, Ki Jun ; Peppa, Dimitra ; Micco, Lorenzo ; Nebbia, Gaia ; Kennedy, Patrick T.F. ; Geretti, Anna‐Maria ; Dusheiko, Geoffrey ; Maini, Mala K.</creatorcontrib><description>An excess of coinhibitory signals has been proposed to drive the T‐cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 (CTLA‐4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA‐4 and this correlates with viral load. CTLA‐4 is up‐regulated on those HBV‐specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA‐4‐mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV‐specific CD8 T cells but does not reprogram their CTLA‐4hiBimhi tolerogenic phenotype. Blocking CTLA‐4 is able to increase the expansion of interferon gamma (IFN‐γ)‐producing HBV‐specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti‐HBV responses by either CTLA‐4 or PD‐L1 blockade is nonredundant. Conclusion: CTLA‐4 is expressed by HBV‐specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA‐4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T‐cell exhaustion in this heterogeneous disease. (HEPATOLOGY 2011;)</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.24249</identifier><identifier>PMID: 21360567</identifier><identifier>CODEN: HPTLD9</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adult ; Aged ; Antigens ; Antigens, CD - physiology ; Apoptosis - physiology ; Biological and medical sciences ; CD8-Positive T-Lymphocytes - physiology ; Cells, Cultured ; CTLA-4 Antigen ; Cytotoxicity ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Hepatitis ; Hepatitis B ; Hepatitis B virus ; Hepatitis B, Chronic - immunology ; Hepatology ; Human viral diseases ; Humans ; Infectious diseases ; Interferon ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Lymphocytes ; Male ; Medical sciences ; Middle Aged ; Viral diseases ; Viral hepatitis ; Viral infections ; Young Adult</subject><ispartof>Hepatology (Baltimore, Md.), 2011-05, Vol.53 (5), p.1494-1503</ispartof><rights>Copyright © 2011 American Association for the Study of Liver Diseases</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4509-8bf44a417da50c063886060de3146bb520685951727554250fb0534b2450a5633</citedby><cites>FETCH-LOGICAL-c4509-8bf44a417da50c063886060de3146bb520685951727554250fb0534b2450a5633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.24249$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.24249$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24161870$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21360567$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schurich, Anna</creatorcontrib><creatorcontrib>Khanna, Pooja</creatorcontrib><creatorcontrib>Lopes, A. Ross</creatorcontrib><creatorcontrib>Han, Ki Jun</creatorcontrib><creatorcontrib>Peppa, Dimitra</creatorcontrib><creatorcontrib>Micco, Lorenzo</creatorcontrib><creatorcontrib>Nebbia, Gaia</creatorcontrib><creatorcontrib>Kennedy, Patrick T.F.</creatorcontrib><creatorcontrib>Geretti, Anna‐Maria</creatorcontrib><creatorcontrib>Dusheiko, Geoffrey</creatorcontrib><creatorcontrib>Maini, Mala K.</creatorcontrib><title>Role of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 on apoptosis‐Prone CD8 T cells in persistent hepatitis B virus infection</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>An excess of coinhibitory signals has been proposed to drive the T‐cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 (CTLA‐4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA‐4 and this correlates with viral load. CTLA‐4 is up‐regulated on those HBV‐specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA‐4‐mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV‐specific CD8 T cells but does not reprogram their CTLA‐4hiBimhi tolerogenic phenotype. Blocking CTLA‐4 is able to increase the expansion of interferon gamma (IFN‐γ)‐producing HBV‐specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti‐HBV responses by either CTLA‐4 or PD‐L1 blockade is nonredundant. Conclusion: CTLA‐4 is expressed by HBV‐specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA‐4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T‐cell exhaustion in this heterogeneous disease. (HEPATOLOGY 2011;)</description><subject>Adult</subject><subject>Aged</subject><subject>Antigens</subject><subject>Antigens, CD - physiology</subject><subject>Apoptosis - physiology</subject><subject>Biological and medical sciences</subject><subject>CD8-Positive T-Lymphocytes - physiology</subject><subject>Cells, Cultured</subject><subject>CTLA-4 Antigen</subject><subject>Cytotoxicity</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>Hepatitis B virus</subject><subject>Hepatitis B, Chronic - immunology</subject><subject>Hepatology</subject><subject>Human viral diseases</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Interferon</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Lymphocytes</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Viral diseases</subject><subject>Viral hepatitis</subject><subject>Viral infections</subject><subject>Young Adult</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90c1u1DAQAGALgehSOPACyBJCwCHt-DfOEZZCkSpRoXKOHK_DusrawXaA3HgDeEaeBC9ZQEKCky3PN2N7BqH7BE4IAD3d2vGEcsqbG2hFBK0rxgTcRCugNVQNYc0RupPSNQA0nKrb6IgSJkHIeoW-vg2DxaHHeWuxCc5vXedyiDOO1tix7LCZc8jhszP4Cg_zbtyGcmKx9tm9t_77l28cB4_1GIpOLpWDyxi8xesXqmQYOwwJO49HG0s0W59xea_OLruEn-OPLk77eG9NdsHfRbd6PSR777Aeo3cvz67W59XFm1ev188uKsMFNJXqes41J_VGCzAgmVISJGwsI1x2naAglWgEqWktBKcC-g4E4x0t2VpIxo7R46XuGMOHyabc7lzav1V7G6bUKslqqUrvinzyX0nqWkpJGaGFPvyLXocp-vKPoqRUlC3q6aJMDClF27djdDsd55ZAu59nW_rT_pxnsQ8OFaduZze_5a8BFvDoAHQyeuij9salP44TSVQNxZ0u7pMb7PzvG9vzs8vl6h_mVrcy</recordid><startdate>201105</startdate><enddate>201105</enddate><creator>Schurich, Anna</creator><creator>Khanna, Pooja</creator><creator>Lopes, A. 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Abdomen</topic><topic>Hepatitis</topic><topic>Hepatitis B</topic><topic>Hepatitis B virus</topic><topic>Hepatitis B, Chronic - immunology</topic><topic>Hepatology</topic><topic>Human viral diseases</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Interferon</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Lymphocytes</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Viral diseases</topic><topic>Viral hepatitis</topic><topic>Viral infections</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schurich, Anna</creatorcontrib><creatorcontrib>Khanna, Pooja</creatorcontrib><creatorcontrib>Lopes, A. Ross</creatorcontrib><creatorcontrib>Han, Ki Jun</creatorcontrib><creatorcontrib>Peppa, Dimitra</creatorcontrib><creatorcontrib>Micco, Lorenzo</creatorcontrib><creatorcontrib>Nebbia, Gaia</creatorcontrib><creatorcontrib>Kennedy, Patrick T.F.</creatorcontrib><creatorcontrib>Geretti, Anna‐Maria</creatorcontrib><creatorcontrib>Dusheiko, Geoffrey</creatorcontrib><creatorcontrib>Maini, Mala K.</creatorcontrib><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>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schurich, Anna</au><au>Khanna, Pooja</au><au>Lopes, A. Ross</au><au>Han, Ki Jun</au><au>Peppa, Dimitra</au><au>Micco, Lorenzo</au><au>Nebbia, Gaia</au><au>Kennedy, Patrick T.F.</au><au>Geretti, Anna‐Maria</au><au>Dusheiko, Geoffrey</au><au>Maini, Mala K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 on apoptosis‐Prone CD8 T cells in persistent hepatitis B virus infection</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2011-05</date><risdate>2011</risdate><volume>53</volume><issue>5</issue><spage>1494</spage><epage>1503</epage><pages>1494-1503</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><abstract>An excess of coinhibitory signals has been proposed to drive the T‐cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 (CTLA‐4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA‐4 and this correlates with viral load. CTLA‐4 is up‐regulated on those HBV‐specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA‐4‐mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV‐specific CD8 T cells but does not reprogram their CTLA‐4hiBimhi tolerogenic phenotype. Blocking CTLA‐4 is able to increase the expansion of interferon gamma (IFN‐γ)‐producing HBV‐specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti‐HBV responses by either CTLA‐4 or PD‐L1 blockade is nonredundant. Conclusion: CTLA‐4 is expressed by HBV‐specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA‐4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T‐cell exhaustion in this heterogeneous disease. (HEPATOLOGY 2011;)</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>21360567</pmid><doi>10.1002/hep.24249</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Antigens Antigens, CD - physiology Apoptosis - physiology Biological and medical sciences CD8-Positive T-Lymphocytes - physiology Cells, Cultured CTLA-4 Antigen Cytotoxicity Female Gastroenterology. Liver. Pancreas. Abdomen Hepatitis Hepatitis B Hepatitis B virus Hepatitis B, Chronic - immunology Hepatology Human viral diseases Humans Infectious diseases Interferon Liver. Biliary tract. Portal circulation. Exocrine pancreas Lymphocytes Male Medical sciences Middle Aged Viral diseases Viral hepatitis Viral infections Young Adult |
| title | Role of the coinhibitory receptor cytotoxic T lymphocyte antigen‐4 on apoptosis‐Prone CD8 T cells in persistent hepatitis B virus infection |
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