Fletcher, Jean Margaret; (2000) The effect of cytomegalovirus infection on the susceptibility of target cells to lysis by natural killer cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Natural killer (NK) cells are important in the early host defence against viral infection; however, the mechanisms by which they can recognise and kill virus- infected cells are unclear. Early studies showed that in contrast to tumour cells, an extended cytotoxicity assay was necessary to measure the NK lysis of cells infected with cytomegalovirus (CMV). In the current study, the necessity for an extended cytotoxicity assay was shown to be due to the need for an activation phase in addition to a lytic phase. The activation of NK cells by CMV was mediated via interferon-a, which was produced by DR+ accessory cells in response to cell surface interactions with virus particles. Fibroblasts infected with some strains of CMV were found to be refractory to lysis by NK cells, whilst those infected with other strains were susceptible. All of the strains tested were able to activate NK cells, however fibroblasts infected with the "resistant" strains were not lysed by activated NK cells, indicating that the resistance lay at the level of target cell recognition and lysis. All of the viral strains down- regulated human leukocyte antigen (HLA) class I to a similar extent, providing no evidence for any correlation between the latter and susceptibility to NK lysis. In contrast, there was a strong correlation between NK killing of CMV-infected cells and cell surface levels of the adhesion molecule lymphocyte function associated antigen (LFA) -3. Fibroblasts infected with the "resistant" strains of CMV down- regulated LFA-3, whilst those infected with the "susceptible" CMV strains up- regulated LFA-3. Astrocytoma cells that expressed constitutively high levels of LFA- 3 were sensitive to lysis when infected with any of the strains of CMV. In addition, it was demonstrated that fibroblasts infected with the NK "resistant" strains expressed a ganciclovir sensitive CMV late gene product that delivered an inhibitory signal to NK cells. These results suggested that the NK lysis of CMV-infected cells results from a balance between positive signals, including the LFA-3-cluster of differentiation (CD) 2 interaction, and an undefined inhibitory signal that results from the expression of a CMV late gene.

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