Controlling the activation and inhibition of human natural killer cells

Natural Killer (NK) cells are innate lymphocytes that play an essential role in host defence against viral infection and tumours. The activation and function of NK cells is regulated by cytokines, in particular IL-15, which promotes their differentiation, survival and activation. IL-10 is a potent immunosuppressive cytokine; however, some studies report immunostimulatory activity towards NK cells. The aim of this study was to investigate the immunomodulatory effects of IL-10 on NK cell activity. Using an in vitro system of primary human NK cells, the effect of IL-10 stimulation on key NK cell activating pathways, such as cytotoxicity, receptor expression and proliferation was explored. IL-10 stimulation of NK cells enhanced granzyme B expression and NK cell cytotoxicity in a STAT3-dependent manner. Unlike the prototypical NK cell activator, IL-15, IL-10 stimulation did not alter the expression of NK cell activating receptors, induce proliferation or activate the mTOR pathway. The immunosuppressive cytokine TGF-β inhibits IL-15-mediated NK cell activation by inhibiting mTOR signalling. Interestingly, although this study does not show IL-10 activation of mTOR signalling, IL-10 mediated NK cell activation was susceptible to TGF-β-mediated inhibition. Moreover, this TGF-β mediated inhibition was independent of STAT3 signalling, suggesting the involvement of other, as yet undefined pathways. This study highlights distinct pathways of NK cell activation by IL-15 and IL-10, and defines an IL-10 mediated, mTOR-independent, activation pathway. Observations in this study suggest that the complex mechanisms leading to activation of NK cells can be induced independently of one another, providing further insight into immune cell regulation.