Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells. PLoS Pathog 7(5):e1001337

Freie Universitaet Berlin, Germany
PLoS Pathogens (Impact Factor: 7.56). 05/2011; 7(5):e1001337. DOI: 10.1371/journal.ppat.1001337
Source: PubMed


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.

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Available from: Susan Jean Baigent, Oct 04, 2015
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    • "After replicating in B lymphocytes, MDV infects activated T lymphocytes, mainly CD4+ cells. It is believed that only a few T lymphocytes undergo transformation and are at the origin of the T lymphoma, which may be either monoclonal or oligoclonal [13]. This lymphoma is mostly localized in visceral organs (kidneys, spleen, liver, gonads, and proventriculus), peripheral nerves, skin, and muscles. "
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    ABSTRACT: : Marek's disease virus (MDV) is a highly contagious herpesvirus which induces T-cell lymphoma in the chicken. This virus is still spreading in flocks despite forty years of vaccination, with important economical losses worldwide. The feather follicles, which anchor feathers into the skin and allow their morphogenesis, are considered as the unique source of MDV excretion, causing environmental contamination and disease transmission. Epithelial cells from the feather follicles are the only known cells in which high levels of infectious mature virions have been observed by transmission electron microscopy and from which cell-free infectious virions have been purified. Finally, feathers harvested on animals and dust are today considered excellent materials to monitor vaccination, spread of pathogenic viruses, and environmental contamination. This article reviews the current knowledge on MDV-skin interactions and discusses new approaches that could solve important issues in the future.
    Veterinary Research 04/2014; 45(1):36. DOI:10.1186/1297-9716-45-36 · 2.82 Impact Factor
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    • "Moreover, MDV-driven tumors are dominated by a highly restricted number of CD4 + clones. Further, the responding CD8 + T cell infiltrate is oligoclonal, indicating recognition of a limited number of MDV antigens (Mwangi et al., 2011). These early cytolytic events result in atrophic changes in the bursa of Fabricius and thymus, leading to severe debilitation of the immune system and marked immunosuppression. "
    Herpesviridae - A Look Into This Unique Family of Viruses, 03/2012; , ISBN: 978-953-51-0186-4
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    ABSTRACT: Lymphoblastoid cell lines 265(L) and 990(O) are monoclonal lymphomas, derived respectively from liver and ovarian tumours, generated in inbred P-line (MHC B(19)/B(19)) chickens infected with RB-1B strain of Marek's disease virus (MDV) and pRB-1B5 BAC clone respectively. These were inoculated into inbred, MDV-susceptible, P-line chickens by intra-venous or intra-abdominal routes. Additional groups of birds were vaccinated using 1000 plaque-forming units of CVI988 vaccine 8 days prior to inoculation of the cell lines. Non-vaccinated birds developed visceral Marek's disease tumours with an increased rate 30 to 60 days post inoculation. Vaccination prevented tumour and disease development in challenged birds. TCRβ repertoire analysis by spectratyping and sequencing of the inoculum was used to track tumour identity in primary tumours and tumour cell lines derived from inoculated birds. These data revealed that the tumours were a consequence of de novo virus infection and not metastasis and expansion of the inoculated tumour cells. Moreover, the data showed that the two MDV-derived cell lines were not transplantable even in syngeneic P-line birds. The data also demonstrated the application of spectratyping as a tool to track tumour identity in lymphoma transplantation studies.
    Avian Pathology 12/2012; 41(6):589-98. DOI:10.1080/03079457.2012.740159 · 1.64 Impact Factor
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