Local Modulation of Antigen-Presenting Cell Development after Resolution of Pneumonia Induces Long-Term Susceptibility to Secondary Infections

Roquilly, Antoine; McWilliam, Hamish E G; Jacqueline, Cédric; Tian, Zehua; Cinotti, Raphaël; Rimbert, Marie; Wakim, Linda M.; Caminschi, Irina; Lahoud, Mireille H.; Belz, Gabrielle T.; Kallies, Axel; Mintern, Justine D.; Asehnoune, Karim; Villadangos, José A

doi:10.1016/j.immuni.2017.06.021

Cited by 139 publications

(150 citation statements)

References 62 publications

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“…However, very few studies have investigated the post-acute long-term effects of systemic inflammation on NK cells and their cell intrinsic activities independent of the immune environment. A recent report suggested that NK cell responsiveness was intact 7 days after bacterial and viral pneumonia, but their activation during secondary infection was hampered by the immunosuppressive environment in the lungs (34). These results are similar to what we present here, where 2-9 weeks after endotoxemia, the environment restricts NK cell activation during re-stimulation, independently of their cell-intrinsic functions.…”

Section: Discussionsupporting

confidence: 91%

NK cells acquire epigenetic memory of LPS-induced systemic inflammation

Rasid

Chevalier

Camarasa

et al. 2018

Preprint

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Natural killer cells are unique mediators of innate immunity, and as such, an attractive target for immunotherapy. Following viral infection, NK cells display immune memory properties, defined by heightened responses to re-stimulation, an expansion of specific NK cell sup-populations and a protective role against re-infection. However, similar memory to bacterial infection or systemic inflammation, and the molecular mechanisms behind NK cell memory remain elusive. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory properties as displayed by an amplified production of IFNg upon secondary stimulation. NK cell memory is acquired even under the post-endotoxemic suppressive environment and is detectable for at least 9 weeks. Furthermore, we define an epigenetic mechanism essential for NK cell memory, where an H3K4me1marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erased the enhancer and prevented NK cells from acquiring memory. Thus, NK cells develop memory to LPS during endotoxemia, in a histone methylation-dependent manner, which ensures a heightened response to secondary stimulation and confers protection against bacterial infection.

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Section: Discussionsupporting

confidence: 91%

NK cells acquire epigenetic memory of LPS-induced systemic inflammation

Rasid

Chevalier

Camarasa

et al. 2018

Preprint

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“…However, few studies have investigated the post-acute longterm effects of systemic inflammation on NK cells and their cellintrinsic activities independent of the immune environment. A recent report suggested that NK cell responsiveness was intact 7 days after bacterial and viral pneumonia, but activation during secondary infection was hampered by the immunosuppressive environment in the lungs (Roquilly et al, 2017). These results are similar to what we present here, where 2-9 weeks after endotoxemia, the environment restricts NK cell activation during re-stimulation, independently of their cell-intrinsic functions.…”

Section: Discussionsupporting

confidence: 91%

H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation

et al. 2019

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Graphical Abstract Highlights d NK cells acquire cell-intrinsic memory-like properties after systemic inflammation d Memory-like NK cells uncover a H3K4me1-marked enhancer at À22 kb of the ifng TSS d Memory-like NK cells persist for 9 weeks and can protect from bacterial infection d Memory-like and protective properties are methyltransferase dependent Correspondence orhan.rasid@pasteur.fr (O.R.), melanie.hamon@pasteur.fr (M.A.H.) In Brief Rasid et al. show that sepsis-like systemic inflammation induces a type of long-lasting innate immune memory in NK cells, which can protect from E. coli infection. This is achieved by revealing an enhancer of IFNg through histone monomethylation. 14 days T r a n s f e r T r a n s f e r Naïve NK cells LPS IFNG latent enhancer Memory-like NK cells H3K4me1 IFNG enhancer E.coli Protection bacteria neutrophils Naïve + Memory-like NK cells LPS H3K4me1 IFNG enhancerHigh IFNγ production Naïve + Memory-like NK cells SUMMARY Natural killer (NK) cells are unique players in innate immunity and, as such, an attractive target for immunotherapy. NK cells display immune memory properties in certain models, but the long-term status of NK cells following systemic inflammation is unknown. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memorylike properties, showing increased production of IFNg upon specific secondary stimulation. The NK cell memory response is detectable for at least 9 weeks and contributes to protection from E. coli infection upon adoptive transfer. Importantly, we reveal a mechanism essential for NK cell memory, whereby an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erases the enhancer and abolishes NK cell memory. Thus, NK cell memory develops after endotoxemia in a histone methylationdependent manner, ensuring a heightened response to secondary stimulation.

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“…The protective effect of FLT3L was observed even after the adoptive transfer of DCs treated with FLT3L into the septic animals [189]. Intrapulmonary transfer of bone marrow-derived DCs (BMDCs) also prevented the development of fatal pulmonary aspergillosis in mice recovering from sepsis [190]. Animals recovering from sepsis are more prone to develop severe secondary infections due to prolonged immunosuppression via mechanisms involving transforming growth factor β (TGF-β) secreted by paralyzed DCs causing accumulation of regulatory T cells (Tregs) in lungs and the development of tolerogenic DCs expressing Blimp1 [191].…”

Section: Dendritic Cells (Dcs) and Tlr Expressionmentioning

confidence: 99%

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

Kumar

2018

International Immunopharmacology

529

346

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The immune system is a very diverse system of the host that evolved during evolution to cope with various pathogens present in the vicinity of environmental surroundings inhabited by multicellular organisms ranging from achordates to chordates (including humans). For example, cells of immune system express various pattern recognition receptors (PRRs) that detect danger via recognizing specific pathogen-associated molecular patterns (PAMPs) and mount a specific immune response. Toll-like receptors (TLRs) are one of these PRRs expressed by various immune cells. However, they were first discovered in the Drosophila melanogaster (common fruit fly) as genes/proteins important in embryonic development and dorso-ventral body patterning/polarity. Till date, 13 different types of TLRs (TLR1-TLR13) have been discovered and described in mammals since the first discovery of TLR4 in humans in late 1997. This discovery of TLR4 in humans revolutionized the field of innate immunity and thus the immunology and host-pathogen interaction. Since then TLRs are found to be expressed on various immune cells and have been targeted for therapeutic drug development for various infectious and inflammatory diseases including cancer. Even, Single nucleotide polymorphisms (SNPs) among various TLR genes have been identified among the different human population and their association with susceptibility/resistance to certain infections and other inflammatory diseases. Thus, in the present review the current and future importance of TLRs in immunity, their pattern of expression among various immune cells along with TLR based therapeutic approach is reviewed.

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Local Modulation of Antigen-Presenting Cell Development after Resolution of Pneumonia Induces Long-Term Susceptibility to Secondary Infections

Cited by 139 publications

References 62 publications

NK cells acquire epigenetic memory of LPS-induced systemic inflammation

NK cells acquire epigenetic memory of LPS-induced systemic inflammation

H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

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