Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT

Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK–DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues.Natural killer (NK) cells play an important role in protecting the host against viral infection and cancer. As well as having potent cytotoxic activity, NK cells are endowed with immunoregulatory activity (1, 2). For example, NK cell activation induces the production of chemokines, such as macrophage inflammatory protein-1α (MIP-1α) and IL-8, and proinflammatory cytokines, such as IFN-γ, GM-CSF, and TNF-α. These molecules regulate the recruitment and activity of numerous immune cell types (1, 2). Importantly, NK cells can promote development of T-cell responses via NK–dendritic cell (DC) interactions that favor both DC maturation and NK-cell activation (3–5), with NK cell-derived IFN-γ skewing T-cell differentiation toward the Th1 phenotype (6, 7).Cytotoxic activity and cytokine production are coupled to signaling pathways downstream of a repertoire of activating and inhibitory receptors; signals from activating receptors (including NKG2D, DNAM-1, and 2B4, as well as the natural cytotoxicity receptors NKp30, NKp44, and NKp46) compete with signals from inhibitory receptors such as the killer cell immunoglobulin-like receptors (KIRs) and CD94/NKG2A heterodimers to regulate activation. In addition, NK cells express CD16, the low-affinity receptor for IgG, conferring antibody-dependent cellular cytotoxicity (8–10). Activation thus coordinates the killing of target cells, the induction of inflammation, and the promotion of adaptive immunity. This potent cytotoxicity and proinflammatory activity must be strictly controlled to minimize damage to healthy tissue. Functional competency of unstimulated NK cells is achieved via a process termed “licensing” or “education” (11–14). Licensing ensures that only those NK cells expressing inhibitory receptors for self-MHC class I can respond to target cells and NK cells that lack inhibitory receptors for self-MHC class I molecules are rendered hyporesponsive, preventing them from attacking healthy cells expressing normal levels of MHC class I molecules.We have analyzed the consequences of human NK cell activation by tumor cells. Our results reveal induction of the TNF superfamily member 14 (TNFSF14), also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT) (15). We show that activated NK cells produce TNFSF14 in response to different stimuli, that tumor cells induce TNFSF14 production by licensed NK cells, and that TNFSF14-producing NK cells aid DC maturation during NK–DC cross-talk.