NK-DC Crosstalk in Immunity to Microbial Infection

The interaction between natural killer (NK) cell and dendritic cell (DC), two important cellular components of innate immunity, started to be elucidated in the last years. The crosstalk between NK cells and DC, which leads to NK cell activation, DC maturation, or apoptosis, involves cell-cell contacts and soluble factors. This interaction either in the periphery or in the secondary lymphoid organs acts as a key player linking innate and adaptive immune responses to microbial stimuli. This review focuses on the mechanisms of NK-DC interaction and their relevance in antimicrobial responses. We specifically aim to emphasize the ability of various microbial infections to differently influence NK-DC crosstalk thereby contributing to distinct adaptive immune response.

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NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1

Blood ◽

10.1182/blood-2004-10-3906 ◽

2005 ◽

Vol 106 (2) ◽

pp. 609-616 ◽

Cited By ~ 220

Author(s):

Claudia Semino ◽

Giovanna Angelini ◽

Alessandro Poggi ◽

Anna Rubartelli

Keyword(s):

Nk Cells ◽

Targeted Delivery ◽

Cell Activation ◽

Nk Cell ◽

Adaptive Immune Response ◽

High Mobility ◽

Synaptic Cleft ◽

Immature Dendritic Cells ◽

Underlying Mechanisms ◽

Dc Maturation

Abstract Interaction of natural killer (NK) cells with autologous immature dendritic cells (DCs) results in reciprocal activation; however, the underlying mechanisms are so far elusive. We show here that NK cells trigger immature DCs to polarize and secrete interleukin 18 (IL-18), a cytokine lacking a secretory leader sequence. This occurs through a Ca2+-dependent and tubulin-mediated recruitment of IL-18-containing secretory lysosomes toward the adhering NK cell. Lysosome exocytosis and IL-18 secretion are restricted at the synaptic cleft, thus allowing activation of the interacting NK cells without spreading of the cytokine. In turn, DC-activated NK cells secrete the proinflammatory cytokine high mobility group B1 (HMGB1), which induces DC maturation and protects DCs from lysis. Also HMGB1 is a leaderless cytokine that undergoes regulated secretion. Differently from IL-18, soluble HMGB1 is consistently detected in NK/DC supernatants. These data point to secretion of leaderless cytokines as a key event for the reciprocal activation of NK cells and DCs. DCs initiate NK cell activation by targeted delivery of IL-18, thus instructing NK cells in the absence of adaptive-type cytokines; in turn, activated NK cells release HMGB1, which promotes inflammation and induces DC maturation, thus favoring the onset of the adaptive immune response. (Blood. 2005;106:609-616)

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Antigen mRNA-transfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity

Blood ◽

10.1182/blood-2008-08-176446 ◽

2009 ◽

Vol 113 (18) ◽

pp. 4262-4272 ◽

Cited By ~ 23

Author(s):

Shin-ichiro Fujii ◽

Akira Goto ◽

Kanako Shimizu

Keyword(s):

T Cell ◽

Cell Activation ◽

Nk Cell ◽

Adaptive Immune Response ◽

T Cell Response ◽

Inkt Cell ◽

Inkt Cells ◽

Cell Immunity ◽

Dc Maturation

Abstract The maturation of dendritic cells (DCs) in situ by danger signals plays a central role in linking innate and adaptive immunity. We previously demonstrated that the activation of invariant natural killer T (iNKT) cells by administration of α-galactosylceramide (α-GalCer)–loaded tumor cells can act as a cellular adjuvant through the DC maturation. In the current study, we used allogeneic fibroblasts loaded with α-GalCer and transfected with antigen-encoding mRNA, thus combining the adjuvant effects of iNKT-cell activation with delivery of antigen to DCs in vivo. We found that these cells produce antigen protein and activate NK and iNKT cells. When injected into major histocompatibility complex (MHC)–mismatched mice, they elicited antigen-specific T-cell responses and provided tumor protection, suggesting that these immune responses depend on host DCs. In addition, antigen-expressing fibroblasts loaded with α-GalCer lead to a more potent T-cell response than those expressing NK cell ligands. Thus, glycolipid-loaded, mRNA-transfected allogeneic fibroblasts act as cellular vectors to provide iNKT-cell activation, leading to DC maturation and T-cell immunity. By harnessing the innate immune system and generating an adaptive immune response to a variety of antigens, this unique tool could prove clinically beneficial in the development of immunotherapies against malignant and infectious diseases.

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P04.02 A novel cancer immunotherapy combines rMVA-CD40L with tumor targeting antibodies

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-itoc7.71 ◽

2020 ◽

Vol 8 (Suppl 2) ◽

pp. A37.1-A37

Author(s):

M Hinterberger ◽

J Medina-Echeverz ◽

M Testori ◽

M Geiger ◽

R Giessel ◽

...

Keyword(s):

Immune Responses ◽

Tumor Targeting ◽

Cell Activation ◽

Immune Cell ◽

Nk Cell ◽

Positive Impact ◽

Growth Monitoring ◽

Adaptive Immune ◽

Cell Immunity ◽

Part Time

BackgroundVirus-based vaccines and appropriate costimulation potently enhance antigen-specific T cell immunity against cancer. In the present study, we exploit both innate and adaptive immune responses triggered by a novel recombinant modified vaccinia virus Ankara (rMVA) encoding a Tumor-Associated Antigen (TAA) and the costimulatory CD40L against solid tumors in combination regimes to overcome tumor-induced resistance to immunotherapy.Material and MethodsSubcutaneous murine tumors were induced in C57BL/6 or Balb/c mice using syngeneic tumor cell lines. When tumors were established (60–80 mm3) mice were intravenously injected with rMVA-CD40L. Tumor growth monitoring and immune cell analysis was performed.ResultsTherapeutic treatment with rMVA-CD40L resulted in the control of established tumors in several independent tumor models. This antitumor effect was based on the generation of non-exhausted, systemic tumor-specific cytotoxic CD8+ T cells that was essential for therapeutic efficacy. Strikingly, rMVA-CD40L also induced strong NK cell activation and enhanced cytotoxicity. Moreover, the combination of rMVA-CD40L and tumor targeting antibodies resulted in increased therapeutic antitumor efficacy. This therapeutic combination relied on Fcγ receptor-expressing immune cells as well as on NK cells.ConclusionWe describe a novel and translationally relevant therapeutic synergy between viral vaccination and CD40L costimulation. We show strengthened antitumor immune responses when both rMVA-CD40L-induced innate and adaptive immune mechanisms are exploited by combining immunotherapeutic regimes, such as TAA targeting antibodies. This finding could have a direct positive impact in therapeutic regimens where TAA targeting antibodies could be employed.Disclosure InformationM. Hinterberger: A. Employment (full or part-time); Significant; Bavarian Nordic. J. Medina-Echeverz: A. Employment (full or part-time); Significant; Bavarian Nordic. M. Testori: A. Employment (full or part-time); Significant; Bavarian Nordic. M. Geiger: A. Employment (full or part-time); Significant; Bavarian Nordic. R. Giessel: A. Employment (full or part-time); Significant; Bavarian Nordic. B. Bathke: A. Employment (full or part-time); Significant; Bavarian Nordic. R. Kassub: A. Employment (full or part-time); Significant; Bavarian Nordic. F. Gräbnitz: A. Employment (full or part-time); Significant; Bavarian Nordic. G. Fiore: A. Employment (full or part-time); Significant; Bavarian Nordic. S. Wennier: A. Employment (full or part-time); Significant; Bavarian Nordic. P. Chaplin: A. Employment (full or part-time); Significant; Bavarian Nordic. M. Suter: A. Employment (full or part-time); Significant; Bavarian Nordic. H. Hochrein: A. Employment (full or part-time); Significant; Bavarian Nordic. H. Lauterbach: A. Employment (full or part-time); Significant; Bavarian Nordic.

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Synergistic cancer immunotherapy combines MVA-CD40L induced innate and adaptive immunity with tumor targeting antibodies

Nature Communications ◽

10.1038/s41467-019-12998-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

José Medina-Echeverz ◽

Maria Hinterberger ◽

Marco Testori ◽

Marlene Geiger ◽

Raphael Giessel ◽

...

Keyword(s):

Immune Responses ◽

Tumor Targeting ◽

Cell Activation ◽

Nk Cell ◽

Cancer Therapies ◽

Antitumor Effects ◽

Innate And Adaptive Immunity ◽

Adaptive Immune ◽

Modified Vaccinia Virus Ankara ◽

Cell Immunity

Abstract Virus-based vaccines and appropriate costimulation potently enhance antigen-specific T cell immunity against cancer. Here we report the use of recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against solid tumors. Therapeutic treatment with rMVA-CD40L-expressing tumor-associated antigens results in the control of established tumors. The expansion of tumor-specific cytotoxic CD8+ T cells is essential for the therapeutic antitumor effects. Strikingly, rMVA-CD40L also induces strong natural killer (NK) cell activation and expansion. Moreover, the combination of rMVA-CD40L and tumor-targeting antibodies results in increased therapeutic antitumor efficacy relying on the presence of Fc receptor and NK cells. We describe a translationally relevant therapeutic synergy between systemic viral vaccination and CD40L costimulation. We show strengthened antitumor immune responses when both rMVA-CD40L-induced innate and adaptive immune mechanisms are exploited by combination with tumor-targeting antibodies. This immunotherapeutic approach could translate into clinical cancer therapies where tumor-targeting antibodies are employed.

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Effect of Natural Compounds on NK Cell Activation

Journal of Immunology Research ◽

10.1155/2018/4868417 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Malgorzata Grudzien ◽

Andrzej Rapak

Keyword(s):

Nk Cells ◽

Cell Activation ◽

Nk Cell ◽

Death Receptor ◽

Adaptive Immune Response ◽

The Body ◽

Target Cells ◽

Surface Receptors ◽

Microbial Infections ◽

A Cell

Natural killer (NK) cells are lymphocytes of the innate immune system that survey the body for stressed and abnormal cells. The integration of signals that they receive through various inhibitory and activating cell surface receptors controls their activation and ability to kill target cells and produce cytokines. In this manner, phenotypically and functionally distinct subsets of NK cells help protect against microbial infections and cancer and shape the adaptive immune response. NK cells can use two different mechanisms to kill their targets, either by cytotoxic granule exocytosis or by induction of death receptor-mediated apoptosis. Death ligands belong to the tumor necrosis factor (TNF) family of ligands. Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell through which granzymes and associated molecules can enter and induce apoptosis. NK cells are also involved in antibody-dependent cellular toxicity via the CD16 receptor. In addition to target recognition, NK cells can be also activated by treatment with multiple compounds with stimulatory properties. Apart from interleukins, which belong to the best characterized group of NK cell-stimulating compounds, vitamins and constituents extracted from plants also display the ability to activate NK cells. The current review characterizes several groups of NK cell-activating compounds: vitamins belonging to classes A, B, C, D, and E, polysaccharides, lectins, and a number of phytochemicals used in cancer research, exhibiting stimulatory properties when applied to NK cells. Although in most cases the exact mechanism of action is not known, constituents described in this review seem to be promising candidates for NK cell-stimulating drugs.

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The Impact of Ly49-NK Cell-Dependent Recognition of MCMV Infection on Innate and Adaptive Immune Responses

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/641702 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 14

Author(s):

Michal Pyzik ◽

Eve-Marie Gendron-Pontbriand ◽

Silvia M. Vidal

Keyword(s):

Immune Responses ◽

Nk Cells ◽

Cell Biology ◽

Cell Activation ◽

Nk Cell ◽

Adaptive Immune Responses ◽

Mcmv Infection ◽

Adaptive Immune ◽

Innate Lymphocytes ◽

The Impact

Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in the response against herpesviruses, especially cytomegaloviruses (CMV). Indeed, in mice, NK cells, due to the expression of germline encoded Ly49 receptors, possess multiple mechanisms to recognize CMV infection. Classically, this results in NK cell activation and the destruction of the infected cells. More recently, however, this unique host-pathogen interaction has permitted the discovery of novel aspects of NK cell biology, implicating them in the regulation of adaptive immune responses as well as in the development of immunological memory. Here, we will concisely review the newly acquired evidence pertaining to NK cell Ly49-dependent recognition of MCMV-infected cell and the ensuing NK cell regulatory responses.

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Assessment of the pulmonary adaptive immune response to Cladosporium cladosporioides infection using an experimental mouse model

Scientific Reports ◽

10.1038/s41598-020-79642-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaoping Ma ◽

Jing Hu ◽

Yan Yu ◽

Chengdong Wang ◽

Yu Gu ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Adaptive Immune Response ◽

Pulmonary Hemorrhage ◽

Cladosporium Cladosporioides ◽

Th2 Cells ◽

Intercellular Adhesion Molecule ◽

Post Inoculation ◽

Adaptive Immune ◽

Systemic Infections

AbstractCladosporium cladosporioides causes asthma and superficial and deep infections, mostly in immunodeficient individuals and animals. This study aimed to investigate whether C. cladosporioides spores can enter the lungs through pulmonary circulation and influence pulmonary immune response. We intravenously injected mice with C. cladosporioides spore suspension and conducted several assays on the lungs. Pulmonary hemorrhage symptoms and congestion were most severe on days 1, 2, and 3 post-inoculation (PI). Extensive inflammatory cell infiltration occurred throughout the period of infection. More spores and hyphae colonizing the lungs were detected on days 1, 2, and 3 PI, and fewer spores and hyphae were observed within 21 d of infection. Numerous macrophages, dendritic cells, and neutrophils were observed on day 5 PI, along with upregulation of CD54, an intercellular adhesion molecule. Th1 and Th2 cells increased after infection; specifically, Th2 cells increased considerably on day 5 PI. These results suggest that days 2 and 5 PI represent the inflammatory peak in the lungs and that the Th2 and Th1 signaling pathways are potentially involved in pulmonary immune responses. In conclusion, the further adaptive immune responses played important roles in establishing effective pulmonary immunity against C. cladosporioides systemic infections based on innate immune responses.

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Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1815716116 ◽

2018 ◽

Vol 116 (3) ◽

pp. 988-996 ◽

Cited By ~ 3

Author(s):

Han Wang ◽

Jianxun Qi ◽

Shuijun Zhang ◽

Yan Li ◽

Shuguang Tan ◽

...

Keyword(s):

Nk Cells ◽

Cell Activation ◽

Nk Cell ◽

Complex Structure ◽

Binding Mode ◽

Adaptive Immune ◽

Binding Interface ◽

Nk Cell Receptors ◽

D2 Domain ◽

Hybrid Complex

Natural killer (NK) cells are important component of innate immunity and also contribute to activating and reshaping the adaptive immune responses. The functions of NK cells are modulated by multiple inhibitory and stimulatory receptors. Among these receptors, the activating receptor CD226 (DNAM-1) mediates NK cell activation via binding to its nectin-like (Necl) family ligand, CD155 (Necl-5). Here, we present a unique side-by-side arrangement pattern of two tandem immunoglobulin V-set (IgV) domains deriving from the ectodomains of both human CD226 (hCD226-ecto) and mouse CD226 (mCD226-ecto), which is substantially different from the conventional head-to-tail arrangement of other multiple Ig-like domain molecules. The hybrid complex structure of mCD226-ecto binding to the first domain of human CD155 (hCD155-D1) reveals a conserved binding interface with the first domain of CD226 (D1), whereas the second domain of CD226 (D2) both provides structural supports for the unique architecture of CD226 and forms direct interactions with CD155. In the absence of the D2 domain, CD226-D1 exhibited substantially reduced binding efficacy to CD155. Collectively, these findings would broaden our knowledge of the interaction between NK cell receptors and the nectin/Necl family ligands, as well as provide molecular basis for the development of CD226-targeted antitumor immunotherapeutics.

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Murine myeloid cell MCPIP1 suppresses autoimmunity by regulating B-cell expansion and differentiation

Disease Models & Mechanisms ◽

10.1242/dmm.047589 ◽

2021 ◽

Vol 14 (3) ◽

pp. dmm047589

Author(s):

Ewelina Dobosz ◽

Georg Lorenz ◽

Andrea Ribeiro ◽

Vivian Würf ◽

Marta Wadowska ◽

...

Keyword(s):

Autoimmune Disease ◽

Immune Responses ◽

Cell Activation ◽

Plasma Cells ◽

Myeloid Cell ◽

Skin Inflammation ◽

Adaptive Immune ◽

Systemic Autoimmunity ◽

Key Factor ◽

Old Mice

ABSTRACTMyeloid-derived cells, in particular macrophages, are increasingly recognized as critical regulators of the balance of immunity and tolerance. However, whether they initiate autoimmune disease or perpetuate disease progression in terms of epiphenomena remains undefined.Here, we show that depletion of MCPIP1 in macrophages and granulocytes (Mcpip1fl/fl-LysMcre+ C57BL/6 mice) is sufficient to trigger severe autoimmune disease. This was evidenced by the expansion of B cells and plasma cells and spontaneous production of autoantibodies, including anti-dsDNA, anti-Smith and anti-histone antibodies. Consequently, we document evidence of severe skin inflammation, pneumonitis and histopathologic evidence of glomerular IgG deposits alongside mesangioproliferative nephritis in 6-month-old mice. These phenomena are related to systemic autoinflammation, which secondarily induces a set of cytokines such as Baff, Il5, Il9 and Cd40L, affecting adaptive immune responses. Therefore, abnormal macrophage activation is a key factor involved in the loss of immune tolerance.Overall, we demonstrate that deficiency of MCPIP1 solely in myeloid cells triggers systemic lupus-like autoimmunity and that the control of myeloid cell activation is a crucial checkpoint in the development of systemic autoimmunity.

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SARS-CoV-2 Serology Status Detected by Commercialized Platforms Distinguishes Previous Infection and Vaccination Adaptive Immune Responses

10.1101/2021.03.10.21253299 ◽

2021 ◽

Author(s):

Raymond T. Suhandynata ◽

Nicholas J. Bevins ◽

Jenny T. Tran ◽

Deli Huang ◽

Melissa A. Hoffman ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Natural Infection ◽

Adaptive Immune Response ◽

Antibody Assay ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Previous Infection ◽

A Cell

AbstractBackgroundThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 110 million individuals and led to 2.5 million deaths worldwide. As more individuals are vaccinated, the clinical performance and utility of SARS-CoV-2 serology platforms needs to be evaluated.MethodsThe ability of four commercial SARS-CoV-2 serology platforms to detect previous infection or vaccination were evaluated using a cohort of 53 SARS-CoV-2 PCR-positive patients, 89 SARS-CoV-2-vaccinated healthcare workers (Pfizer or Moderna), and 127 SARS-CoV-2 negative patients. Serology results were compared to a cell based SARS-CoV-2 pseudovirus (PSV) neutralizing antibodies assay.ResultsThe Roche S-(spike) antibody and Diazyme neutralizing antibodies (NAbs) assays detected adaptive immune response in 100.0% and 90.1% of vaccinated individuals who received two-doses of vaccine (initial and booster), respectively. The Roche N-(nucleocapsid) antibody assay and Diazyme IgG assay did not detect adaptive immune response in vaccinated individuals. The Diazyme Nabs assay correlated with the PSV SARS-CoV-2 ID50 neutralization titers (R2= 0.70), while correlation of the Roche S-antibody assay was weaker (R2= 0.39). Median PSV SARS-CoV-2 ID50 titers more than doubled in vaccinated individuals who received two-doses of the Moderna vaccine (ID50: 597) compared to individuals that received a single dose (ID50: 284).ConclusionsThe Roche S-antibody and Diazyme NAbs assays robustly detected adaptive immune responses in SARS-CoV-2 vaccinated individuals and SARS-CoV-2 infected individuals. The Diazyme NAbs assay strongly correlates with the PSV SARS-CoV-2 NAbs in vaccinated individuals. Understanding the reactivity of commercially available serology platforms is important when distinguishing vaccination response versus natural infection.SummaryThe Roche S (spike protein)-antibody and Diazyme neutralizing-antibodies (NAbs) assays were evaluated for their clinical utility in the detection of SARS-CoV-2 related adaptive immune responses by testing SARS-CoV-2 PCR-confirmed patients, SARS-CoV-2-vaccinated individuals, and SARS-CoV-2-negative individuals. Commercial serology results were compared to results generated using a cell-based SARS-CoV-2 pseudovirus (PSV) NAbs assay and previously validated SARS-CoV-2 commercial serology assays (Roche N (nucleocapsid protein) antibody and Diazyme IgG). We demonstrate that the Roche S-antibody and Diazyme NAbs assays detected adaptive immune response in SARS-CoV-2 vaccinated individuals and the presence of SARS-CoV-2 PSV NAbs. The Roche S-antibody assay had an observed positive percent agreement (PPA) of 100% for individuals who received two doses of the Pfizer or Moderna vaccine. By contrast, the Roche N assay and Diazyme IgG assay did not detect vaccine adaptive immune responses. Our findings also indicate that the Diazyme NAbs assay correlates strongly with the levels of SARS-CoV-2 ID50 neutralization titers using the PSV Nab assay in vaccinated individuals.

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