Human T cells expressing CD56 are capable of tumour cell lysis following activation with interleukin-2 but their role in viral immunity has been less well studied. The work described in this thesis aimed to investigate CD56+ T-cells in relation to cytomegalovirus infection in healthy subjects and kidney transplant patients (KTPs). Proportions of CD56+ T cells were found to be highly significantly increased in healthy cytomegalovirus-seropositive (CMV+) compared to cytomegalovirus-seronegative (CMV-) subjects (8.38% ± 0.33 versus 3.29%± 0.33; P < 0.0001). In donor CMV-/recipient CMV- (D-/R-)- KTPs levels of CD56+ T cells were 1.9% ±0.35 versus 5.42% ±1.01 in D+/R- patients and 5.11% ±0.69 in R+ patients (P 0.0247 and < 0.0001 respectively). CD56+ T cells in both healthy CMV+ subjects and KTPs expressed markers of effector memory-RA T-cells (TEMRA) while in healthy CMV- subjects and D-/R- KTPs the phenotype was predominantly that of naïve T-cells. Other surface markers, CD8, CD4, CD58, CD57, CD94 and NKG2C were expressed by a significantly higher proportion of CD56+ T-cells in healthy CMV+ than CMV- subjects. Functional studies showed levels of pro-inflammatory cytokines IFN-γ and TNF-α, as well as granzyme B and CD107a were significantly higher in CD56+ T-cells from CMV+ than CMV- subjects following stimulation with CMV antigens. This also resulted in higher levels of proliferation in CD56+ T-cells from CMV+ than CMV- subjects. Using class I HLA pentamers, it was found that CD56+ T-cells from CMV+ subjects contained similar proportions of antigen-specific CD8+ T cells to CD56- T cells in healthy donors of several different HLA types. A comprehensive gene expression profile by microarrays of CMV-stimulated sorted CD56+ T-cells was conducted which showed that expression of 106 genes involved in innate and adaptive immune responses was significantly changed, almost all being increased. Some of these changes were validated via RT-PCR and flow cytometry, the latter indicating higher ISG-15 protein expression in response to CMV stimulation in CMV+ than CMV- subjects. Overall, these differences may reflect the expansion and enhanced functional activity of CMV-specific CD56+ memory T cells. In view of the link between CD56 expression and T-cell cytotoxic function, this strongly implicates CD56+ T cells as being an important component of the cytotoxic T-cell response to CMV.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:664371 |
| Date | January 2014 |
| Creators | Almehmadi, Mazen |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://livrepository.liverpool.ac.uk/2008213/ |
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