Marashi, S.M.; (2011) Functional competence of CD8+ T cell responses specific to human cytomegalovirus in common variable immunodeficiency. Doctoral thesis , UCL (University College London).

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Abstract

This PhD investigated the role of human cytomegalovirus (HCMV) in inflammatory disease associated with common variable immunodeficiency (CVID) by examining the functional competence of HCMV specific CD8+ T cell responses. The project was based on the hypothesis that HCMV is a major factor driving the expansion of CD8+ T cells that contribute to the inflammatory pathology. HCMV specific CD8+ T cell frequencies were significantly elevated in inflammatory patients compared to non-inflammatory patients or healthy subjects. The frequency of EBV (GLC) epitope specific CD8+ T cells did not differ between patient groups. HCMV CD8+ T cells from inflammatory patients displayed a distinct cytokine expression profile with the majority of cells producing IFN-γ only or IFN-γ and TNF-α in response to antigen stimulation. These cells did not show evidence of exhaustion, with low PD-1 expression; rather, they showed high functionality, high TCR avidity and high proliferative potential. CD8+ T cells from inflammatory patients but not non-inflammatory patients or healthy donors expressed high levels of Ki-67 and proliferated in response to antigen stimulation in vitro without co-stimulation. Further phenotypic analysis revealed striking correlations between the frequencies of HCMV specific CD8+ T cells expressing PD-1 or granzyme B and the overall frequency of CD8+ CD27-CD28- T cells. Consistent with their hypothesized role in the inflammatory disease, the CD8+ T cells from inflammatory patients expressed reduced levels of the anti-inflammatory marker CD73. Further support for the involvement of HCMV in driving the inflammatory pathology came from collaborative work in which viral antigen was detected at the sites of inflammation. The results support the hypothesis that HCMV and HCMV-specific T cells are key factors in CVID associated inflammation. They explain previously reported T cell ‘abnormalities’ seen in CVID and provide an evidence base for clinical trials of anti-TNF therapy and/or antiviral therapy in these patients.

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