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.natural killer cells | NK-DC interactions | TNFSF14 | NK-cell licensing | tumor immunity N atural 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 immunoglobulinlike receptors (KIRs) and CD94/NKG2A heterodimers to regulate activation. In addition, NK cells express CD16, the lowaffinity receptor for IgG, conferring antibody-dependent cellular cytot...

A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice

“…45)), neutrophils (for example, TNF-α46), ILC2 cells (for example, leukotrienes47) and lung structural cells (for example, histamine, leukotrienes and TNF-α4849). Indeed, by being one of the first cells to respond to Ag challenge (via IgE bound to their FcɛRI) and by also being responsive to TNFSF14, which might be produced at sites of developing inflammation by many cells, including various myeloid or lymphoid cells205051 that can be recruited in part in response to MC-derived mediators, MCs might function as powerful local amplifiers of airway responses to Ag.…”

Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment

“…Upon recognition of target cells, NK cells upregulate their cell surface expression of LIGHT. LIGHT-expressing NK cells were able to induce upregulation of CD86 on the surface of autologous DC in a cytokine-independent manner (Holmes et al, 2014). Thus in addition to playing a role in the recruitment of lymphocytes to the TME, LIGHT appears to also have a direct role in priming anti-tumor immune responses, pointing to LIGHT as a potential therapeutic agent to be explored in the clinic.…”

Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells

“…LTab/LTbR and CD40/CD40L interactions appear to be the most relevant, while LIGHT provides a second layer of regulation. 20,21,22,66,67,68 Between LIGHT/LTbR and LIGHT/HVEM, the predominant interaction is the former, because LTbR outcompetes HVEM due its higher affinity for LIGHT. 12 Indirectly, LTbR signaling in stromal cells is also important for maintaining the integrity of lymphoid tissue, which is indispensable for the development of the immune response.…”

“…16,17,18 and from the phenotype of LIGHT-deficient mice, 19,12,17 we postulated that a complete blockade of LIGHT interaction with its receptors would contribute to achieve a more suitable pharmacological control of the allogeneic immune response. LIGHT blockade on T cells would impede its interaction with LTbR or HVEM on dendritic cells, and therefore hinder their maturation, 19,20,21,22 as well as prevent T/T cell collaboration through LIGHT/HVEM interactions that would contribute to maintenance of T cell survival during T cell expansion and differentiation. 23,24,25,26 To confirm this hypothesis, we characterized a set of anti-LIGHT antibodies raised in LIGHT-deficient mice and chose one that fully blocked the binding of soluble LTbR or HVEM to membrane LIGHT.…”