Vaccinating for natural killer cell effector functions

Wagstaffe, Helen R; Mooney, Jason P.; Riley, Eleanor M.; Goodier, Martin R.

doi:10.1002/cti2.1010

Cited by 28 publications

(26 citation statements)

References 112 publications

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“…Our finding that expression of PRV gB triggers NK cell cytotoxicity increases our understanding of the interaction of alphaherpesviruses with this particularly important immune cell population and may lead to clinical applications. Indeed, activation of NK cells has been proposed as a valuable strategy in the design of alphaherpesvirus vaccines (25)(26)(27)(28)(29)(30)(31). In addition, NK cell-mediated elimination of virus-infected cells has been reported to interfere with efficient tumor cell lysis by HSV-based oncolytic vectors in a mouse model of glioblastoma (32).…”

Section: Discussionmentioning

confidence: 99%

Expression of the Pseudorabies Virus gB Glycoprotein Triggers NK Cell Cytotoxicity and Increases Binding of the Activating NK Cell Receptor PILRβ

Pelsmaeker

Dierick

Klupp

et al. 2019

J Virol

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Natural killer (NK) cells are components of the innate immunity and are key players in the defense against virus-infected and malignant cells. NK cells are particularly important in the innate defense against herpesviruses, including alphaherpesviruses. Aggravated and life-threatening alphaherpesvirus-induced disease has been reported in patients with NK cell deficiencies. NK cells are regulated by a diversity of activating and inhibitory cell surface receptors that recognize specific ligands on the plasma membrane of virus-infected or malignant target cells. Although alphaherpesviruses have developed several evasion strategies against NK cell-mediated attack, alphaherpesvirus-infected cells are still readily recognized and killed by NK cells. However, the (viral) factors that trigger NK cell activation against alphaherpesvirus-infected cells are largely unknown. In this study, we show that expression of the gB glycoprotein of the alphaherpesvirus pseudorabies virus (PRV) triggers NK cell-mediated cytotoxicity, both in PRV-infected and in gB-transfected cells. In addition, we report that, like their human and murine counterpart, porcine NK cells express the activating receptor paired immunoglobulin-like type 2 receptor beta (PILRβ), and we show that gB expression triggers increased binding of recombinant porcine PILRβ to the surfaces of PRV-infected cells and gB-transfected cells. IMPORTANCE Natural killer (NK) cells display a prominent cytolytic activity against virus-infected cells and are indispensable in the innate antiviral response, particularly against herpesviruses. Despite their importance in the control of alphaherpesvirus infections, relatively little is known about the mechanisms that trigger NK cell cytotoxicity against alphaherpesvirus-infected cells. Here, using the porcine alphaherpesvirus pseudorabies virus (PRV), we found that the conserved alphaherpesvirus glycoprotein gB triggers NK cell-mediated cytotoxicity, both in virus-infected and in gB-transfected cells. In addition, we report that gB expression results in increased cell surface binding of porcine paired immunoglobulin-like type 2 receptor beta (PILRβ), an activating NK cell receptor. The interaction between PILRβ and viral gB may have consequences that stretch beyond the interaction with NK cells, including virus entry into host cells. The identification of gB as an NK cell-activating viral protein may be of importance in the construction of future vaccines and therapeutics requiring optimized interactions of alphaherpesviruses with NK cells.

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Section: Discussionmentioning

confidence: 99%

Expression of the Pseudorabies Virus gB Glycoprotein Triggers NK Cell Cytotoxicity and Increases Binding of the Activating NK Cell Receptor PILRβ

Pelsmaeker

Dierick

Klupp

et al. 2019

J Virol

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“…CIML NK cells have been described in a number of different in vitro models and postinfection and vaccination (reviewed in Ref. 22,23). Similarly to in vitro priming with cytokines, in vitro priming with inactivated H1N1 virus and TIV vaccination led to enhanced NK cell responses to cytokines alone (9), suggesting that antiviral cytokine stimulation is sufficient to generate CIML NK cells.…”

Section: Discussionmentioning

confidence: 99%

Influenza Vaccination Primes Human Myeloid Cell Cytokine Secretion and NK Cell Function

Wagstaffe

Pickering

Houghton

et al. 2019

The Journal of Immunology

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Cytokine-induced memory-like (CIML) NK cells generated in response to proinflammatory cytokines in vitro and in vivo can also be generated by vaccination, exhibiting heightened responses to cytokine stimulation months after their initial induction. Our previous study demonstrated that in vitro human NK cell responses to inactivated influenza virus were also indirectly augmented by very low doses of IL-15, which increased induction of myeloid cell-derived cytokine secretion. These findings led us to hypothesize that IL-15 stimulation could reveal a similar effect for active influenza vaccination and influence CIML NK cell effector functions. In this study, 51 healthy adults were vaccinated with seasonal influenza vaccine, and PBMC were collected before and up to 30 d after vaccination. Myeloid and lymphoid cell cytokine secretion was measured after in vitro PBMC restimulation with low-dose IL-15, alone or in combination with inactivated H3N2 virus; the associated NK cell response was assessed by flow cytometry. PBMC collected 30 d postvaccination showed heightened cytokine production in response to IL-15 compared with PBMC collected at baseline; these responses were further enhanced when IL-15 was combined with H3N2. NK cell activation in response to IL-15 alone (CD25) and H3N2 plus IL-15 (CD25 and IFN-g) was enhanced postvaccination. We also observed proliferation of lessdifferentiated NK cells with downregulation of cytokine receptors as early as 3 d after vaccination, suggesting cytokine stimulation in vivo. We conclude that vaccination-induced "training" of accessory cells combines with the generation of CIML NK cells to enhance the overall NK cell response postvaccination.

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“…46 Furthermore, following infection or vaccination, NK cells themselves can develop into long-lived memory cells capable of more robust cytotoxic responses and higher IFN-c production upon rechallengein some cases in an antigen-specific mannercompared with naive NK cells. 47,48 Most interestingly, NKp46 and NKp30, two key NK cell cytotoxicity receptors, were reported to act as fungicidal PRRs for Cryptococcus and Candida, 30,31,49 posing the exciting possibility that pathogen-specific NK cell memory, the existence of which has already been demonstrated for viruses, 47 could develop against fungi. IL-12, IL-15 and IL-18) alone were found to be capable of supporting splenic NK cell memory properties in the absence of antigen; these cytokine-induced memory-like NK cells can be induced by vaccination in response to CD4 + T-cellderived IL-2 and myeloid cell-derived IL-12 and type I interferons, and have been implicated in the enhancement of NK cell function ex vivo.…”

Section: Discussionmentioning

confidence: 99%

“…IL-12, IL-15 and IL-18) alone were found to be capable of supporting splenic NK cell memory properties in the absence of antigen; these cytokine-induced memory-like NK cells can be induced by vaccination in response to CD4 + T-cellderived IL-2 and myeloid cell-derived IL-12 and type I interferons, and have been implicated in the enhancement of NK cell function ex vivo. 47,48 Most interestingly, NKp46 and NKp30, two key NK cell cytotoxicity receptors, were reported to act as fungicidal PRRs for Cryptococcus and Candida, 30,31,49 posing the exciting possibility that pathogen-specific NK cell memory, the existence of which has already been demonstrated for viruses, 47 could develop against fungi. Given our own work developing an anti-Sporothrix vaccine, 50,51 the above underlines the huge clinical value of a better understanding of the NK-Sporothrix relationship.…”

Section: Discussionmentioning

confidence: 99%

Natural killer cells are pivotal for in vivo protection following systemic infection by Sporothrix schenckii

et al. 2018

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Natural killer (NK) cells are one of the first cell types to enter inflammation sites and have been historically known as key effector cells against tumours and viruses; now, accumulating evidence shows that NK cells are also capable of direct in vitro activity and play a protective role against clinically important fungi in vivo. However, our understanding of NK cell development, maturation and activation in the setting of fungal infections is preliminary at best. Sporotrichosis is an emerging worldwide-distributed subcutaneous mycosis endemic in many countries, affecting humans and other animals and caused by various related thermodimorphic Sporothrix species, whose prototypical member is Sporothrix schenckii. We show that following systemic infection of BALB/c mice with S. schenckii sensu stricto, NK cells displayed a more mature phenotype as early as 5 days post-infection as judged by CD11b/CD27 expression. At 10 days post-infection, NK cells had increased expression of CD62 ligand (CD62L) and killer cell lectin-like receptor subfamily G member 1 (KLRG1), but not of CD25 or CD69. Depletion of NK cells with anti-asialo GM1 drastically impaired fungal clearance, leading to a more than eightfold increase in splenic fungal load accompanied by heightened systemic inflammation, as shown by augmented production of the pro-inflammatory cytokines tumour necrosis factor-α, interferon-γ and interleukin-6, but not interleukin-17A, in the spleen and serum. Our study is, to the best of our knowledge, the first to demonstrate that a fungal infection can drive NK cell maturation in vivo and that such cells are pivotal for in vivo protection against S. schenckii.

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Vaccinating for natural killer cell effector functions

Cited by 28 publications

References 112 publications

Expression of the Pseudorabies Virus gB Glycoprotein Triggers NK Cell Cytotoxicity and Increases Binding of the Activating NK Cell Receptor PILRβ

Expression of the Pseudorabies Virus gB Glycoprotein Triggers NK Cell Cytotoxicity and Increases Binding of the Activating NK Cell Receptor PILRβ

Influenza Vaccination Primes Human Myeloid Cell Cytokine Secretion and NK Cell Function

Natural killer cells are pivotal for in vivo protection following systemic infection by Sporothrix schenckii

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