Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells.
Lymphoid oncogenesis is a life threatening complication associated with a number of persistent viral infections (e.g. EBV and HTLV-1 in humans). With many of these infections it is difficult to study their natural history and the dynamics of tumor formation. Marek's Disease Virus (MDV) is a pre...
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Public Library of Science (PLoS)
2011-05-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001337&type=printable |
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| author | William N Mwangi Lorraine P Smith Susan J Baigent Richard K Beal Venugopal Nair Adrian L Smith |
| author_facet | William N Mwangi Lorraine P Smith Susan J Baigent Richard K Beal Venugopal Nair Adrian L Smith |
| author_sort | William N Mwangi |
| collection | DOAJ |
| description | Lymphoid oncogenesis is a life threatening complication associated with a number of persistent viral infections (e.g. EBV and HTLV-1 in humans). With many of these infections it is difficult to study their natural history and the dynamics of tumor formation. Marek's Disease Virus (MDV) is a prevalent α-herpesvirus of poultry, inducing CD4+ TCRαβ+ T cell tumors in susceptible hosts. The high penetrance and temporal predictability of tumor induction raises issues related to the clonal structure of these lymphomas. Similarly, the clonality of responding CD8 T cells that infiltrate the tumor sites is unknown. Using TCRβ repertoire analysis tools, we demonstrated that MDV driven CD4+ T cell tumors were dominated by one to three large clones within an oligoclonal framework of smaller clones of CD4+ T cells. Individual birds had multiple tumor sites, some the result of metastasis (i.e. shared dominant clones) and others derived from distinct clones of transformed cells. The smaller oligoclonal CD4+ cells may represent an anti-tumor response, although on one occasion a low frequency clone was transformed and expanded after culture. Metastatic tumor clones were detected in the blood early during infection and dominated the circulating T cell repertoire, leading to MDV associated immune suppression. We also demonstrated that the tumor-infiltrating CD8+ T cell response was dominated by large oligoclonal expansions containing both "public" and "private" CDR3 sequences. The frequency of CD8+ T cell CDR3 sequences suggests initial stimulation during the early phases of infection. Collectively, our results indicate that MDV driven tumors are dominated by a highly restricted number of CD4+ clones. Moreover, the responding CD8+ T cell infiltrate is oligoclonal indicating recognition of a limited number of MDV antigens. These studies improve our understanding of the biology of MDV, an important poultry pathogen and a natural infection model of virus-induced tumor formation. |
| format | Article |
| id | doaj-art-d0ade0dec23c438ea374acf69e5bcde1 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2011-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-d0ade0dec23c438ea374acf69e5bcde12025-08-20T02:34:15ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742011-05-0175e100133710.1371/journal.ppat.1001337Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells.William N MwangiLorraine P SmithSusan J BaigentRichard K BealVenugopal NairAdrian L SmithLymphoid oncogenesis is a life threatening complication associated with a number of persistent viral infections (e.g. EBV and HTLV-1 in humans). With many of these infections it is difficult to study their natural history and the dynamics of tumor formation. Marek's Disease Virus (MDV) is a prevalent α-herpesvirus of poultry, inducing CD4+ TCRαβ+ T cell tumors in susceptible hosts. The high penetrance and temporal predictability of tumor induction raises issues related to the clonal structure of these lymphomas. Similarly, the clonality of responding CD8 T cells that infiltrate the tumor sites is unknown. Using TCRβ repertoire analysis tools, we demonstrated that MDV driven CD4+ T cell tumors were dominated by one to three large clones within an oligoclonal framework of smaller clones of CD4+ T cells. Individual birds had multiple tumor sites, some the result of metastasis (i.e. shared dominant clones) and others derived from distinct clones of transformed cells. The smaller oligoclonal CD4+ cells may represent an anti-tumor response, although on one occasion a low frequency clone was transformed and expanded after culture. Metastatic tumor clones were detected in the blood early during infection and dominated the circulating T cell repertoire, leading to MDV associated immune suppression. We also demonstrated that the tumor-infiltrating CD8+ T cell response was dominated by large oligoclonal expansions containing both "public" and "private" CDR3 sequences. The frequency of CD8+ T cell CDR3 sequences suggests initial stimulation during the early phases of infection. Collectively, our results indicate that MDV driven tumors are dominated by a highly restricted number of CD4+ clones. Moreover, the responding CD8+ T cell infiltrate is oligoclonal indicating recognition of a limited number of MDV antigens. These studies improve our understanding of the biology of MDV, an important poultry pathogen and a natural infection model of virus-induced tumor formation.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001337&type=printable |
| spellingShingle | William N Mwangi Lorraine P Smith Susan J Baigent Richard K Beal Venugopal Nair Adrian L Smith Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells. PLoS Pathogens |
| title | Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells. |
| title_full | Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells. |
| title_fullStr | Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells. |
| title_full_unstemmed | Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells. |
| title_short | Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells. |
| title_sort | clonal structure of rapid onset mdv driven cd4 lymphomas and responding cd8 t cells |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001337&type=printable |
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