Characterisation of CD8neg and CD8+ human natural killer cell subsets

NK cells are CD3neg CD56+ lymphocytes that constitute about 10-15% of peripheral blood lymphocytes. They have an innate ability to recognise and kill virus infected cells and tumour cells. Their decision to either kill or not to kill a given target is governed by the balance of signals received from inhibitory and activation receptors. NK cells induce target cell death via production of cytotoxic proteins including perforin and granzymes and death ligands expressed on their cell surface. They can be sub-divided according to their surface expression of CD8 antigens into CD8neg and CD8+ subsets. NK cells express CD8αα homodimer unlike those expressed on cytotoxic T lymphocytes, which are CD8αβ heterodimers. The aim of this study was to compare the phenotype and function of the CD8+ and CD8neg NK cell subsets. The results show that CD8+ NK cells comprise about 50% of human resting peripheral NK cells. This percentage increases following IL-2 and IL-15 activation of NK cells because the CD8neg NK cells upregulate expression of the CD8 antigen. The CD8+ subset is more cytotoxic than the CD8neg subset. This was not due to differential expression of NK cell activation or inhibitory receptors, nor due to differences in the expression of perforin and granzymes. Furthermore, both subsets express comparable levels of IFN-γ and TNF-α and degranulated their cytotoxic granules with similar efficiency. Analysis of NK cells from myeloma patients revealed that the two subsets responded differently in different disease stages. Furthermore, Thalidomide treatment increased the frequency of the CD8+ subset, most likely by inducing T cell production of IL-2, which in turn activates NK cells and promotes CD8neg subset development to the more cytotoxic CD8+ subset that facilitates tumour killing.