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T cell immunity to Kaposi’s sarcoma-associated herpesvirus latent proteins

Sabbah, Shereen (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

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.

Type of Work:Ph.D. thesis.
Supervisor(s):Hislop, Andrew and Rickinson, Alan
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Cancer Studies
Subjects:QR180 Immunology
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:3273
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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