title: Clonal structure of rapid-onset MDV-driven CD4+ lymphomas and responding CD8+ T cells.
abstract: 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.
authors.affiliation: Avian Infectious Disease Programme, Institute for Animal Health, Compton, Berkshire, United Kingdom.
authors.forename: William N
authors.initials: WN
authors.lastname: Mwangi
authors.forename: Lorraine P
authors.initials: LP
authors.lastname: Smith
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Baigent
authors.forename: Richard K
authors.initials: RK
authors.lastname: Beal
authors.forename: Venugopal
authors.initials: V
authors.lastname: Nair
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Smith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002645:Chickens; D022801:Complementarity Determining Regions; D008381:Herpesvirus 2, Gallid / Q000276:immunology* / Q000472:pathogenicity*; D007107:Immune System; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008223:Lymphoma / Q000473:pathology / Q000821:virology; D008380:Marek Disease / Q000276:immunology* / Q000821:virology; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D022801:Complementarity Determining Regions; D016693:Receptors, Antigen, T-Cell, alpha-beta