Elucidating the immunomodulatory mechanisms of the KSHV protein vOX2

Misstear, Karen (2010). Elucidating the immunomodulatory mechanisms of the KSHV protein vOX2. University of Birmingham. Ph.D.

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Abstract

CD200 is a transmembrane protein with known immunoregulatory activities exerted via its receptor, CD200R. The Kaposi’s sarcoma associated-herpesvirus (KSHV) ORF K14 lytic cycle gene product, vOX2, shares 36% protein identity with cellular CD200. Both vOX2 and CD200 ligate CD200R with similar affinity. The main aim of this project was to determine whether vOX2 and CD200 regulate the function of human leukocytes. Thus, vOX2, CD200 and an inactive KSHV protein KCPmut were fused to the Fc region of human IgG1. vOX2:Fc and CD200:Fc exerted no effect upon isolated neutrophils, but suppressed granulocyte oxidative activity in whole blood by up to 25%. B lymphoblastoid cells were engineered to express full-length vOX2 or CD200 and utilized as antigen-presenting cells for Epstein Barr Virus-specific human T cell clones. vOX2 and CD200 suppressed IFNγ production by up to 50% in seven CD8\(^+\) CD200R\(^+\) T cell clones and one CD4\(^+\) CD200R\(^+\) clone. Mechanistically, vOX2 and CD200 suppressed the phosphorylation of ERK1/2, p38 and Akt kinases. This is the first evidence of a role for both cellular CD200 and KSHV vOX2 in negatively modulating antigen-specific T cell activity. The negative regulation of T cells by vOX2 probably contributes to KSHV evasion of antigen-specific T cell responses during lytic replication.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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