IFN‐λ‐mediated IL‐12 production in macrophages induces IFN‐γ production in human NK cells

Abstract

With increasing interest in alternative options to interferon-alpha-based treatments, IFN-λ has shown therapeutic promise in a variety of diseases. Although the antiviral activity of IFN-λ has been extensively studied, there is limited knowledge regarding the immunological functions of IFN-λ and how these differ from those of other classes of IFNs.In this study, we investigated the effects of IFN-λ on primary human NK cells, both in a direct and indirect capacity. We demonstrate that in contrast to interferon-alpha, IFN-λ is unable to directly stimulate NK cells, due to the absence of IFN-λ receptor chain 1 (IFN-λR1) on NK cells. However, IFN-λ, in combination with TLR4 challenge, is able to induce the production of select members of the IL-12 family of cytokines in monocyte-derived macrophages. We further show that through macrophage-mediated IL-12 production, IFN-λ is able to indirectly affect NK cells and ultimately induce IFN-γ production.Keywords: Hepatitis C r IFN-γ r IL-29 r Innate immunity r Macrophages r NK cells Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction NK cells play an important role in the innate immune response, specifically in their ability to recognize and respond to stressed cells, including virus-infected, transformed, and damaged cells. Activated NK cells respond to these stress signals by excretion of cytotoxic factors, including perforin and granzymes, as well as cytokines, such as interferon-γ (IFN-γ) and TNF, that act as a first response to control the source of distress as well as to activate subsequent adaptive immune responses [1,2]. NK cells express an Correspondence: Dr. André Boonstra e-mail: p.a.boonstra@erasmusmc.nl array of activating receptors, such as C-type lectin-like receptors (e.g. NKG2D) and natural cytotoxicity receptors, and inhibiting receptors, C-type lectin-like receptors (e.g. NKG2A) and killer cell immunoglobulin-like receptor. It is currently believed that NK-cell activation or inhibition is governed by a balance of signaling by these receptors, and results after a critical threshold of activation signals exceeds inhibition [3].NK-cell activation ensues after interacting with infected or distressed cells, shifting the balance of inhibitory and activating stimuli delivered via specific surface molecules. These include stressinduced surface markers, including altered MHC expression, as well as soluble factors, of which IL-12 and IL-18 are well described and known triggers of NK-cell effector activity [1,2,4] In line with this, the activity of NK cells can be promoted by exposure to interferon-alpha (IFN-α), e.g. during interaction with IFN-producing activated plasmacytoid DCs leading to enhanced activation and cytolytic activity [9][10][11], and thereby promoting antiviral immunity. In recent years, the type III family of IFNs, comprised IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4, has received increased attention, especially after the discovery of polymorphisms within its gene locus that were a...

IFN-λ Cancer Immunotherapy: New Kid on the Block

“…A direct effect of IFN-λ on NK cells has been suggested following the failure of transferred IFN-λR1-deficient NK cells in suppressing tumor growth in vivo [82]. However, no direct evidence has been reported in vitro, in accordance with our initial report [78] and other studies, demonstrating that IFN-λ was not directly acting on NK cells [88,89]. Innate immunity may also be mediated by macrophages and neutrophils, and there is one report suggesting IFN-λ may influence innate immunity against a fibrosarcoma tumor model through these cells [76].…”

Guarding the frontiers: the biology of type III interferons

“…Similarly, only some subsets of myeloid immune cells, such as human monocyte-derived macrophages 61 , pDCs [60][61][62] and some dendritic cell subsets in humans and in mice 63 , respond directly to type III IFN. For natural killer (NK) cells, reports have come to opposite conclusions about the ability of type III IFNs to influence IFN-γ secretion by NK cells [64][65][66] . However, adoptive transfer experiments in mice using IFN-λR1-deficient (Ifnlr1 −/− ) NK cells Figure 2 Signaling pathway of type I and type III IFNs.…”

Type III Interferons in Hepatitis C Virus Infection

“…Individuals bearing the CC genotype also displayed increased NK cell function measured by IFN-γ production after stimulation irrespective of infectious outcome suggesting that IFN-λ genotype influenced NK cell function but that this was not sufficient to achieve spontaneous HCV clearance (31). Although IFNLR1 mRNA expression could be detected in NK cells (59, 60), they express very low levels of the specific type III IFN receptor (IFN-λR1) on cell surface, even after IFN-α stimulation (31, 61, 62). Treatment of purified NK cells with IFN-λ had no effect on neither NK cytotoxicity nor cytokine production (31, 60, 62, 63).…”

“…Although IFNLR1 mRNA expression could be detected in NK cells (59, 60), they express very low levels of the specific type III IFN receptor (IFN-λR1) on cell surface, even after IFN-α stimulation (31, 61, 62). Treatment of purified NK cells with IFN-λ had no effect on neither NK cytotoxicity nor cytokine production (31, 60, 62, 63). On the other hand, it was reported that the level of expression of IFN-λR1 could be upregulated by IFN-λ treatment (59) and studies in IFN-λR1 −/− mice have demonstrated that this receptor is required for optimal antitumoral in vivo activity of NK cells (64), suggesting that in some activation context, NK cells could become sensitive to type III IFNs.…”

“…Given the lack of activation of NK cells by IFN-λ (31, 60, 62, 63), indirect mechanism were investigated. IFN-λ1 affected NK cells indirectly via the activation of monocyte derived macrophages.…”