Soluble factors produced by activated CD4⁺ T cells modulate EBV latency
Following infection with Epstein-Barr virus (EBV), the virus is carried for life in the memory B-cell compartment in a silent state (latency 1/0). These cells do not resemble the proliferating lymphoblastoid cells (LCLs) (latency III) that are generated after infection. It is of fundamental signific...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2012-01, Vol.109 (5), p.1512-1517 |
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| creator | Nagy, Noémi Ádori, Mónika Rasul, Abu Heuts, Frank Salamon, Daniel Ujvári, Dorina Madapura, Harsha S. Leveau, Benjamin Klein, George Klein, Eva |
| description | Following infection with Epstein-Barr virus (EBV), the virus is carried for life in the memory B-cell compartment in a silent state (latency 1/0). These cells do not resemble the proliferating lymphoblastoid cells (LCLs) (latency III) that are generated after infection. It is of fundamental significance to identify how the different EBV expression patterns are established in the latently infected cell. In view of the prompt activatability of CD4⁺ T cells in primary EBV infection, and their role in B-cell differentiation, we studied the involvement of CD4⁺ T cells in the regulation of EBV latency. Lymphoblastoid cell lines (LCLs) were cocultured with autologous or allogeneic CD4⁺ T cells. Activated T cells influenced the expression of two key viral proteins that determine the fate of the infected B cell. EBNA2 was down-regulated, whereas LMP1 was unregulated and the cells proliferated less. This was paralleled by the downregulation of the latency III promoter (Cp). Experiments performed in the transwell system showed that this change does not require cell contact, but it is mediated by soluble factors. Neutralizing experiments proved that the up-regulation of LMP1 is, to some extent, mediated by IL21, but this cytokine was not responsible for EBNA2 down-regulation. This effect was partly mediated by soluble CD40L. We detected similar regulatory functions of T cells in in vitro-infected lymphocyte populations. In conclusion, our results revealed an additional mechanism by which CD4⁺ T cells can control the EBV-induced B-cell proliferation. |
| doi_str_mv | 10.1073/pnas.1120587109 |
| format | Article |
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These cells do not resemble the proliferating lymphoblastoid cells (LCLs) (latency III) that are generated after infection. It is of fundamental significance to identify how the different EBV expression patterns are established in the latently infected cell. In view of the prompt activatability of CD4⁺ T cells in primary EBV infection, and their role in B-cell differentiation, we studied the involvement of CD4⁺ T cells in the regulation of EBV latency. Lymphoblastoid cell lines (LCLs) were cocultured with autologous or allogeneic CD4⁺ T cells. Activated T cells influenced the expression of two key viral proteins that determine the fate of the infected B cell. EBNA2 was down-regulated, whereas LMP1 was unregulated and the cells proliferated less. This was paralleled by the downregulation of the latency III promoter (Cp). Experiments performed in the transwell system showed that this change does not require cell contact, but it is mediated by soluble factors. Neutralizing experiments proved that the up-regulation of LMP1 is, to some extent, mediated by IL21, but this cytokine was not responsible for EBNA2 down-regulation. This effect was partly mediated by soluble CD40L. We detected similar regulatory functions of T cells in in vitro-infected lymphocyte populations. In conclusion, our results revealed an additional mechanism by which CD4⁺ T cells can control the EBV-induced B-cell proliferation.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1120587109</identifier><identifier>PMID: 22307606</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Antibodies ; Biological Sciences ; CD4-positive T-lymphocytes ; CD4-Positive T-Lymphocytes - cytology ; CD4-Positive T-Lymphocytes - metabolism ; Cell lines ; coculture ; Coculture Techniques ; Cultured cells ; Cytokines ; Down regulation ; Epstein Barr virus infections ; Epstein-Barr virus ; Gene expression ; Herpesvirus 4, Human - physiology ; Humans ; Infections ; Lymphocyte Activation ; Messenger RNA ; neutralization ; Proteins ; Solubility ; T cell receptors ; T lymphocytes ; viral proteins ; Virus Latency ; Viruses</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2012-01, Vol.109 (5), p.1512-1517</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jan 31, 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c568t-5794af8b20ec2efa6e75850b1afb3de5b67a076ceb3caedaad805208704f9a863</citedby><cites>FETCH-LOGICAL-c568t-5794af8b20ec2efa6e75850b1afb3de5b67a076ceb3caedaad805208704f9a863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/109/5.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41477130$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41477130$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,550,723,776,780,799,881,27903,27904,53770,53772,57996,58229</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22307606$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:124698512$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Nagy, Noémi</creatorcontrib><creatorcontrib>Ádori, Mónika</creatorcontrib><creatorcontrib>Rasul, Abu</creatorcontrib><creatorcontrib>Heuts, Frank</creatorcontrib><creatorcontrib>Salamon, Daniel</creatorcontrib><creatorcontrib>Ujvári, Dorina</creatorcontrib><creatorcontrib>Madapura, Harsha S.</creatorcontrib><creatorcontrib>Leveau, Benjamin</creatorcontrib><creatorcontrib>Klein, George</creatorcontrib><creatorcontrib>Klein, Eva</creatorcontrib><title>Soluble factors produced by activated CD4⁺ T cells modulate EBV latency</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Following infection with Epstein-Barr virus (EBV), the virus is carried for life in the memory B-cell compartment in a silent state (latency 1/0). These cells do not resemble the proliferating lymphoblastoid cells (LCLs) (latency III) that are generated after infection. It is of fundamental significance to identify how the different EBV expression patterns are established in the latently infected cell. In view of the prompt activatability of CD4⁺ T cells in primary EBV infection, and their role in B-cell differentiation, we studied the involvement of CD4⁺ T cells in the regulation of EBV latency. Lymphoblastoid cell lines (LCLs) were cocultured with autologous or allogeneic CD4⁺ T cells. Activated T cells influenced the expression of two key viral proteins that determine the fate of the infected B cell. EBNA2 was down-regulated, whereas LMP1 was unregulated and the cells proliferated less. This was paralleled by the downregulation of the latency III promoter (Cp). Experiments performed in the transwell system showed that this change does not require cell contact, but it is mediated by soluble factors. Neutralizing experiments proved that the up-regulation of LMP1 is, to some extent, mediated by IL21, but this cytokine was not responsible for EBNA2 down-regulation. This effect was partly mediated by soluble CD40L. We detected similar regulatory functions of T cells in in vitro-infected lymphocyte populations. In conclusion, our results revealed an additional mechanism by which CD4⁺ T cells can control the EBV-induced B-cell proliferation.</description><subject>Antibodies</subject><subject>Biological Sciences</subject><subject>CD4-positive T-lymphocytes</subject><subject>CD4-Positive T-Lymphocytes - cytology</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>Cell lines</subject><subject>coculture</subject><subject>Coculture Techniques</subject><subject>Cultured cells</subject><subject>Cytokines</subject><subject>Down regulation</subject><subject>Epstein Barr virus infections</subject><subject>Epstein-Barr virus</subject><subject>Gene expression</subject><subject>Herpesvirus 4, Human - physiology</subject><subject>Humans</subject><subject>Infections</subject><subject>Lymphocyte Activation</subject><subject>Messenger RNA</subject><subject>neutralization</subject><subject>Proteins</subject><subject>Solubility</subject><subject>T cell receptors</subject><subject>T lymphocytes</subject><subject>viral proteins</subject><subject>Virus Latency</subject><subject>Viruses</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqFks9u1DAQxi1ERZeFMyeQxQUuacf_7QsSLG2pVIkDhavlOA5kySZbOynaI6_F4_AkdbTLtuUAF3s885tPntGH0DMCRwQUO153Lh0RQkFoRcA8QLN8kkJyAw_RDICqQnPKD9HjlJYAYISGR-iQUgZKgpyh8099O5ZtwLXzQx8TXse-Gn2ocLnBOdVcuyE_Fu_575-_8CX2oW0TXmWmzQV88u4LnoLOb56gg9q1KTzd3XP0-fTkcvGhuPh4dr54e1F4IfVQCGW4q3VJIXgaaieDElpASVxdsiqIUiqX_-ZDybwLlXOVBkFBK-C1cVqyOSq2uulHWI-lXcdm5eLG9q6xu9T3HAUrmCHKZP7Nls-VVah86Ibo2ntt9ytd881-7a8to0oRKbLAq51A7K_GkAa7atK0B9eFfkzWUKBUG0Ez-fqfJDVaclBKyv-iBEBrzjRhGX35F7rsx9jlHVtDjJRmAufoeAv52KcUQ70fkICdrGInq9hbq-SOF3f3suf_eOMOMHXeyhkrLBFkGvf5FlimbJ09wQnPi2PAbgAYH86Y</recordid><startdate>20120131</startdate><enddate>20120131</enddate><creator>Nagy, Noémi</creator><creator>Ádori, Mónika</creator><creator>Rasul, Abu</creator><creator>Heuts, Frank</creator><creator>Salamon, Daniel</creator><creator>Ujvári, Dorina</creator><creator>Madapura, Harsha S.</creator><creator>Leveau, Benjamin</creator><creator>Klein, George</creator><creator>Klein, Eva</creator><general>National Academy of Sciences</general><general>National Acad Sciences</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>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>7S9</scope><scope>L.6</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20120131</creationdate><title>Soluble factors produced by activated CD4⁺ T cells modulate EBV latency</title><author>Nagy, Noémi ; 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| source | MEDLINE; SWEPUB Freely available online; Jstor Complete Legacy; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Antibodies Biological Sciences CD4-positive T-lymphocytes CD4-Positive T-Lymphocytes - cytology CD4-Positive T-Lymphocytes - metabolism Cell lines coculture Coculture Techniques Cultured cells Cytokines Down regulation Epstein Barr virus infections Epstein-Barr virus Gene expression Herpesvirus 4, Human - physiology Humans Infections Lymphocyte Activation Messenger RNA neutralization Proteins Solubility T cell receptors T lymphocytes viral proteins Virus Latency Viruses |
| title | Soluble factors produced by activated CD4⁺ T cells modulate EBV latency |
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