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Memory and Memory-Like NK Cell Responses to Microbial Pathogens.

ABSTRACT: NK cells are cytotoxic lymphocytes that provide systemic defense against pathogens and malignancy. Although historically considered cells of the innate immune system, NK cells are now known to be capable of memory or memory-like immune responses in certain settings. Memory NK responses were initially reported over a decade ago in studies involving mouse models of cytomegalovirus infection and delayed-type hypersensitivity reactions to chemical haptens and viral antigens. Since then, a growing body of literature suggests that memory or memory-like NK cell responses may occur in a broader range of immunological settings, including in response to various viral and bacterial infections, and some immunization protocols. Memory-like NK cell responses have also now been reported in humans and non-human primates. Here, we summarize recent studies demonstrating memory or memory-like responses by NK cells in settings of infection and immunization against infectious agents.

SUBMITTER: Brillantes M

PROVIDER: S-EPMC7109401 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Memory and Memory-Like NK Cell Responses to Microbial Pathogens.

Brillantes Marc M Beaulieu Aimee M AM

Frontiers in cellular and infection microbiology 20200325

NK cells are cytotoxic lymphocytes that provide systemic defense against pathogens and malignancy. Although historically considered cells of the innate immune system, NK cells are now known to be capable of memory or memory-like immune responses in certain settings. Memory NK responses were initially reported over a decade ago in studies involving mouse models of cytomegalovirus infection and delayed-type hypersensitivity reactions to chemical haptens and viral antigens. Since then, a growing bo ...[more]

PMID: 32269968

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Project description:Human blood V?9/V?2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that V?9/V?2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, V?9/V?2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-? and tumor necrosis factor (TNF)-?. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of V?9/V?2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-? dependent proliferation of V?9/V?2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting ?? T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis--characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity--show a selective activation of local V?9/V?2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The ?? T cell-driven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of ?? T cells and TNF-? and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive ?? T cells in early infection and suggest novel diagnostic and therapeutic approaches.

Project description:BackgroundCytokine-induced memory-like natural killer (CIML NK) cells have been found to possess potent antitumor responses and induce complete remissions in patients with leukemia. However, the poor infiltration of transferred NK cells is a major obstacle in developing adoptive cell immunotherapy for solid tumors. In our study, we explored the potential of using the tumor-penetrating peptide iRGD to deliver activated CIML NK cells deep into tumor tissues.MethodsAfter being briefly stimulated with interleukin-12 (IL-12), IL-15, and IL-18, CIML NK cells were assessed for their phenotype and function with flow cytometry. The penetrating and killing capability of iRGD-modified CIML NK cells in tumor spheroids was revealed by confocal microscopy. The anti-tumor efficacy of these modified CIML NK cells was tested in hepatocellular carcinoma (HCC) xenograft mouse models.ResultsTreating NK cells with cytokines led to a substantial activation, which was evidenced by the upregulation of CD25 and CD137. After a resting period of six days, CIML NK cells were still able to display strong activation when targeting HepG2 and SK-Hep-1 HCC cell lines. Additionally, CIML NK cells produced increased amounts of cytokines (interferon-gamma and tumor necrosis factor alpha) and exhibited heightened cytotoxicity towards HCC cell lines. The iRGD modification enabled CIML NK cells to infiltrate multicellular spheroids (MCSs) and, consequently, to induce cytotoxicity against the target cancer cells. Moreover, the CIML NK cells modified with iRGD significantly decreased tumor growth in a HCC xenograft mouse model.ConclusionOur findings demonstrate that CIML NK cells possess augmented potency and durability against HCC cell lines in vitro. Additionally, we have seen that the incorporation of iRGD to CIML NK cells facilitates enhanced infiltration and targeted destruction of MCSs. Moreover, the application of iRGD-modified CIML NK cells reveal remarkable anti-tumor efficacy against HCC in vivo.

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Dataset Information

Memory and Memory-Like NK Cell Responses to Microbial Pathogens.

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Memory and Memory-Like NK Cell Responses to Microbial Pathogens.

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