1. Academic Validation
  2. Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT

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

  • Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):E5688-96. doi: 10.1073/pnas.1411072112.
Tim D Holmes 1 Erica B Wilson 1 Emma V I Black 1 Andrew V Benest 1 Candida Vaz 2 Betty Tan 2 Vivek M Tanavde 3 Graham P Cook 4
Affiliations

Affiliations

  • 1 Leeds Institute of Cancer and Pathology, University of Leeds School of Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom; and.
  • 2 Bioinformatics Institute and.
  • 3 Bioinformatics Institute and Institute of Medical Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138671.
  • 4 Leeds Institute of Cancer and Pathology, University of Leeds School of Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom; and g.p.cook@leeds.ac.uk.
Abstract

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.

Keywords

NK-cell licensing; NK–DC interactions; TNFSF14; natural killer cells; tumor immunity.

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