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Licensed Human Natural Killer Cells Aid Dendritic Cell Maturation Via TNFSF14/LIGHT

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Licensed Human Natural Killer Cells Aid Dendritic Cell Maturation Via TNFSF14/LIGHT Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT Tim D. Holmesa,1, Erica B. Wilsona, Emma V. I. Blacka, Andrew V. Benesta,2, Candida Vazb, Betty Tanb, Vivek M. Tanavdeb,c, and Graham P. Cooka,3 aLeeds Institute of Cancer and Pathology, University of Leeds School of Medicine, St. James’s University Hospital, Leeds LS9 7TF, United Kingdom; and bBioinformatics Institute and cInstitute of Medical Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138671 Edited by Wayne M. Yokoyama, Washington University School of Medicine, St. Louis, MO, and approved November 19, 2014 (received for review June 13, 2014) Interactions between natural killer (NK) cells and dendritic cells adaptive immunity. This potent cytotoxicity and proinflammatory (DCs) aid DC maturation and promote T-cell responses. Here, we activity must be strictly controlled to minimize damage to healthy have analyzed the response of human NK cells to tumor cells, and tissue. Functional competency of unstimulated NK cells is – we identify a pathway by which NK DC interactions occur. Gene achieved via a process termed “licensing” or “education” (11– expression profiling of tumor-responsive NK cells identified the very 14). Licensing ensures that only those NK cells expressing in- rapid induction of TNF superfamily member 14 [TNFSF14; also hibitory receptors for self-MHC class I can respond to target cells known as homologous to lymphotoxins, exhibits inducible expres- sion, and competes with HSV glycoprotein D for HVEM, a receptor and NK cells that lack inhibitory receptors for self-MHC class I expressed by T lymphocytes (LIGHT)], a cytokine implicated in the molecules are rendered hyporesponsive, preventing them from enhancement of antitumor responses. TNFSF14 protein expression attacking healthy cells expressing normal levels of MHC class was induced by three primary mechanisms of NK cell activation, I molecules. namely, via the engagement of CD16, by the synergistic activity We have analyzed the consequences of human NK cell activa- of multiple target cell-sensing NK-cell activation receptors, and by tion by tumor cells. Our results reveal induction of the TNF su- the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was perfamily member 14 (TNFSF14), also known as homologous preferentially produced by the licensed NK-cell population, defined to lymphotoxins, exhibits inducible expression, and competes by the expression of inhibitory receptors specific for self-MHC class I with HSV glycoprotein D for HVEM, a receptor expressed by T molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 lymphocytes (LIGHT) (15). We show that activated NK cells production by both licensed and unlicensed NK cells, reflecting the produce TNFSF14 in response to different stimuli, that tumor ability of proinflammatory conditions to override the licensing cells induce TNFSF14 production by licensed NK cells, and that mechanism. Importantly, both tumor- and cytokine-activated NK – cells induced DC maturation in a TNFSF14-dependent manner. The TNFSF14-producing NK cells aid DC maturation during NK coupling of TNFSF14 production to tumor-sensing NK-cell activation DC cross-talk. receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation Significance by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues. As well as having potent cytotoxic activity, natural killer (NK) cells have a regulatory role and interactions between NK cells natural killer cells | NK–DC interactions | TNFSF14 | and dendritic cells (DCs) aid DC maturation and adaptive immu- NK-cell licensing | tumor immunity nity. However, the mechanisms underpinning NK–DC cross-talk are poorly defined. We show that tumor cells induce rapid pro- atural killer (NK) cells play an important role in protecting duction of the cytokine TNF superfamily member 14 (TNFSF14) in Nthe host against viral infection and cancer. As well as having human NK cells and that these NK cells induce DC maturation in potent cytotoxic activity, NK cells are endowed with immunoreg- a TNFSF14-dependent manner. The synergistic activity of NK cell ulatory activity (1, 2). For example, NK cell activation induces the activation receptors in licensed NK cells couples the release of production of chemokines, such as macrophage inflammatory cytotoxic granules to TNFSF14 production. Thus, NK cell activa- protein-1α (MIP-1α) and IL-8, and proinflammatory cytokines, tion by tumor cells is linked to the initiation of adaptive immu- such as IFN-γ, GM-CSF, and TNF-α. These molecules regulate nity via TNFSF14-mediated NK–DC cross-talk. the recruitment and activity of numerous immune cell types (1, 2). Importantly, NK cells can promote development of T-cell respon- Author contributions: T.D.H., E.B.W., and G.P.C. designed research; T.D.H., E.B.W., E.V.I.B., – A.V.B., C.V., B.T., and V.M.T. performed research; T.D.H., E.B.W., C.V., B.T., V.M.T., and ses via NK dendritic cell (DC) interactions that favor both DC G.P.C. analyzed data; and T.D.H., E.B.W., E.V.I.B., A.V.B., V.M.T., and G.P.C. wrote maturation and NK-cell activation (3–5), with NK cell-derived the paper. γ IFN- skewing T-cell differentiation toward the Th1 phenotype The authors declare no conflict of interest. (6, 7). This article is a PNAS Direct Submission. Cytotoxic activity and cytokine production are coupled to Freely available online through the PNAS open access option. signaling pathways downstream of a repertoire of activating and Data deposition: Microarray-based gene expression profiling data reported in this paper inhibitory receptors; signals from activating receptors (including have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih. NKG2D, DNAM-1, and 2B4, as well as the natural cytotoxicity gov/geo (accession no. GSE55977). receptors NKp30, NKp44, and NKp46) compete with signals 1Present address: Centre for Infectious Medicine, Karolinska Institute, Karolinska Univer- from inhibitory receptors such as the killer cell immunoglobulin- sity Hospital, Stockholm S14186, Sweden. 2 like receptors (KIRs) and CD94/NKG2A heterodimers to reg- Present address: Tumour Vascular Biology Group, Cancer Biology and Stem Cells, School of Medicine, University of Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, ulate activation. In addition, NK cells express CD16, the low- United Kingdom. affinity receptor for IgG, conferring antibody-dependent cellular 3To whom correspondence should be addressed. Email: [email protected]. – cytotoxicity (8 10). Activation thus coordinates the killing of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. target cells, the induction of inflammation, and the promotion of 1073/pnas.1411072112/-/DCSupplemental. E5688–E5696 | PNAS | Published online December 15, 2014 www.pnas.org/cgi/doi/10.1073/pnas.1411072112 Downloaded by guest on September 26, 2021 PNAS PLUS INFLAMMATION IMMUNOLOGY AND Fig. 1. Gene expression profiling of tumor-stimulated human NK cells. (A) Primary human NK cells (isolated from healthy donors) were cocultured for 4 h with K562 tumor cells, and the R-NK and NR-NK cell populations were identified by staining for cell surface expression of CD56 (as a marker of NK cells) and CD107 (as a marker of NK cell degranulation). The R-NK and NR-NK populations were purified by FACS and used as a source of mRNA for cDNA synthesis and gene expression profiling using Illumina arrays. (Inset) CD107 display (x axis) vs. CD56 expression (y axis) on NK cells in the absence of tumor targets. (B) Venn diagram of the number of genes exhibiting a significant difference in expression between the R-NK and NR-NK populations (greater than 1.5-fold change; P < 0.05) of samples from a single donor and three pooled donors. A list of the 541 genes differentially expressed in both the single donor and pooled donor datasets is provided in Dataset S1. The array data are available from the Gene Expression Omnibus (ncbi.nlm.nih.gov/geo), under accession number GSE55977. The graph shows validation (using quantitative RT-PCR) of a selection of genes exhibiting differential expression in the array analysis (in order of increasing expression in the R-NK population, as determined by the array analysis). (C) Summary of differential expression between the R-NK and NR-NK samples. Selected genes exhibiting >1.5 fold upregulation (P < 0.05) in the R-NK cell fraction are shown according to the broad function of their encoded products. Functional details along with the gene identification number and supporting references are provided in Table S1. Genes with a defined AU rich element (ARE) in the 3’ untranslated region (52, 53, 65, 66) are indicated (*), as are genes encoding molecules in the HVEM regulatory axis (**); TNFSF6 (FASL) has an ARE (67) and it is linked to the HVEM axis via its binding to DcR3(***). (D) The HVEM regulatory axis. Ligands (Top) include TNF superfamily (TNFSF) molecules (TNFSF2, TNFSF14, TNFSF15 and TNFSF6) as well as the immunoglobulin superfamily molecule CD160. Alternative names are also shown. The receptor molecules (Middle) all belong to the TNF receptor superfamily (TNFRSF). Soluble decoy receptor 3 (sDcR3; also known as TNFRSF6B) interacts with TNFSF14, TNFSF15 and TNFSF6 as shown, antagonizing their action. Both TNF (TNFSF2) and TNFSF14 (LIGHT) activate the transcription factor NF-κB (circled). This panel is based on information presented in published reviews (20, 21). Results have responded to a tumor target (R-NK) to be separated from Gene Expression Profiling of Tumor-Stimulated NK Cells Identifies nonresponding (NR-NK) cells using fluorescence-activated cell Induction of a Putative Immunomodulatory Pathway. Gene expres- sorting (FACS). We purified human peripheral blood NK cells, sion profiling has provided great insight into NK-cell function cocultured them (in the absence of exogenous cytokines) for 4 h (16–18).
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