THE NK/DC COMPLOT

Abstract

Different NK cell subsets exist that display major functional differences in their cytolytic activity, cytokine production, and homing capabilities. In particular, CD56high CD16− NK cells, which largely predominate in lymph nodes, have little cytolytic activity but release high levels of cytokines; whereas CD56low CD16+ NK cells, which predominate in peripheral blood and inflamed tissues, display lower cytokine production but potent cytotoxicity. 1 Various cell types that are resident within peripheral tissues as well as circulating cells that have been recruited in response to chemokine gradients into inflamed sites are equipped with receptors for pathogen-associated products that induce cytokine release upon engagement by their specific ligands. These cytokines directly influence the ability of NK cells to modulate both innate and adaptive immune responses. 2 For example, innate cytokines such as IL12 and IL18, produced by antigen presenting cells (APCs) including monocyte-derived dendritic cells (DCs), by acting on NK cells at early stages of immune response, promote two distinct pathways of T cell priming each characterized by a sharp polarization toward Th1 priming. 3 On the contrary, exposure of NK cells to an IL4-rich milieu, resulting from the release of this cytokine by other innate immune cells such as mastocytes and eosinophils, leads to a deviation from Th1 responses toward nonpolarized T cell priming. 4 The polarizing effects of NK cells are exerted at two different stages: the first, taking place in peripheral inflamed tissues, is based on the “editing” process by which optimal maturation of DC is achieved, 5 while the second one takes place in secondary lymphoid tissues where NK cells upon release of IFN-gamma directly influence T cell polarization toward Th1 responses. 6