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

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.

• Authors: Tim D Holmes, Erica B Wilson, Emma V I Black, Andrew V Benest, Candida Vaz, Betty Tan, Vivek M Tanavde, Graham P Cook
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 52 Pg. E5688-96 (Dec 30 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25512551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FCGR3B protein, human
• GPI-Linked Proteins
• IL15 protein, human
• IL2 protein, human
• Interleukin-15
• Interleukin-2
• Receptors, IgG
• TNFSF14 protein, human
• Tumor Necrosis Factor Ligand Superfamily Member 14

Topics

• Cell Communication (immunology)
• Coculture Techniques
• Dendritic Cells (cytology, immunology)
• Female
• GPI-Linked Proteins (immunology)
• Humans
• Immunologic Surveillance
• Interleukin-15 (immunology)
• Interleukin-2 (immunology)
• K562 Cells
• Killer Cells, Natural (cytology, immunology)
• Lymphocyte Activation
• Male
• Neoplasms (immunology)
• Receptors, IgG (immunology)
• Tumor Necrosis Factor Ligand Superfamily Member 14 (immunology)