Sabbah, Shereen (2012)
Ph.D. thesis, University of Birmingham.
T cell immunity is important for the control of Kaposi’s sarcoma-associated herpesvirus (KSHV) disease, yet little is known about KSHV-specific immunity in healthy donors. Screening PBMCs from such donors by ELISpot analysis identified weak responses to the KSHV latent antigens; antigens expressed in the virus associated pathologies. We generated T cell clones to the latent proteins LANA and vFLIP and determined whether they recognised target cells. CD8+ clones poorly recognised targets expressing vFLIP or LANA, through mechanisms which reduce target protein synthesis: vFLIP used rare codons in the mRNA encoding this protein, while deleting the acidic repeat of LANA increased its recognition. We then examined whether LANA-specific CD4+ T cells recognised B cells expressing or fed LANA protein. These were recognised, however most KSHV-infected cell lines, in the form of primary effusion lymphoma (PEL) lines, were not. PELs express vIRF3 which inhibits promoter function of the HLA class II transactivator CIITA. Expressing CIITA from a different promoter restored CD4+ T cell recognition of PELs. This study suggests CD8 recognition of the latent antigens tested is inefficient due to the innate properties of the targets but that CD4 T cells can effectively recognise targets if the immune evasion mechanisms are bypassed.
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