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 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. © 2011 mwangi et al.