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.
Many viral infections target the immune system, making use of the long lived, highly proliferative lymphocytes to propagate and survive within the host. This characteristic has led to an association between some viruses such as Epstein Barr Virus (EBV), Human T cell Lymphotrophic Virus-1 (HTLV-1) and Mareks Disease Virus (MDV) and lymphoid tumors. We employed methods for identifying the T cell receptor repertoire as a molecular bar-code to study the biology of MDV-induced tumors and the anti-tumor response. Each individual contained a small number of large (high frequency) tumor clones alongside some smaller (lower frequency) clones in the CD4+ T cell population. The tumor infiltrating CD8+ T cell response was highly focused with a small number of large clones, with one representing a public CDR3 sequence. This data is consistent with the recognition of a small number of dominant antigens and understanding the relationship between these and protective immunity is important to improve development of new vaccination strategies. Collectively, our results provide insights into the clonal structure of MDV driven tumors and in the responding CD8+ T cell compartment. These studies advance our understanding of MDV biology, an important poultry disease and a natural infection model of virus-induced tumor formation.