Journal Article

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

Tim D. Holmes, Candida Vaz, Erica B. Wilson, Emma V. I. Black, Vivek M. Tanavde, Andrew V. Benest, Graham P. Cook, Betty Tan

2014

Overview

Significance As well as having potent cytotoxic activity, natural killer (NK) cells have a regulatory role and interactions between NK cells and dendritic cells (DCs) aid DC maturation and adaptive immunity. However, the mechanisms underpinning NK–DC cross-talk are poorly defined. We show that tumor cells induce rapid production of the cytokine TNF superfamily member 14 (TNFSF14) in human NK cells and that these NK cells induce DC maturation in a TNFSF14-dependent manner. The synergistic activity of NK cell activation receptors in licensed NK cells couples the release of cytotoxic granules to TNFSF14 production. Thus, NK cell activation by tumor cells is linked to the initiation of adaptive immunity via TNFSF14-mediated NK–DC cross-talk. 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adaptive immunity / Biological Sciences / Cell Communication - immunology / Coculture Techniques / Cytokines / cytotoxicity / dendritic cells / Dendritic Cells - cytology / Dendritic Cells - immunology / Female / Gene expression / Glycoproteins / GPI-Linked Proteins - immunology / granules / Humans / Immunologic Surveillance / Interleukin-15 - immunology / Interleukin-2 - immunology / K562 Cells / Killer Cells, Natural - cytology / Killer Cells, Natural - immunology / Licensing / Lymphocyte Activation / Lymphocytes / Male / Molecules / natural killer cells / neoplasm cells / Neoplasms - immunology / PNAS Plus / receptors / Receptors, IgG - immunology / T cell receptors / Tumor Necrosis Factor Ligand Superfamily Member 14 - immunology / tumor necrosis factors / Tumors