Dendritic Cell Editing by Activated Natural Killer Cells Results in a More Protective Cancer-Specific Immune Response

Over the last decade, several studies have extensively reported that activated natural killer (NK) cells can kill autologous immature dendritic cells (DCs) in vitro, whereas they spare fully activated DCs. This led to the proposal that activated NK cells might select a more immunogenic subset of DCs during a protective immune response. However, there is no demonstration that autologous DC killing by NK cells is an event occurring in vivo and, consequently, the functional relevance of this killing remains elusive. Here we report that a significant decrease of CD11c+ DCs was observed in draining lymph nodes of mice inoculated with MHC-devoid cells as NK cell targets able to induce NK cell activation. This in vivo DC editing by NK cells was perforin-dependent and it was functionally relevant, since residual lymph node DCs displayed an improved capability to induce T cell proliferation. In addition, in a model of anti-cancer vaccination, the administration of MHC-devoid cells together with tumor cells increased the number of tumor-specific CTLs and resulted in a significant increase in survival of mice upon challenge with a lethal dose of tumor cells. Depletion of NK cells or the use of perforin knockout mice strongly decreased the tumor-specific CTL expansion and its protective role against tumor cell challenge. As a whole, our data support the hypothesis that NK cell-mediated DC killing takes place in vivo and is able to promote expansion of cancer-specific CTLs. Our results also indicate that cancer vaccines could be improved by strategies aimed at activating NK cells

Heterogeneity of NK Cells and Other Innate Lymphoid Cells in Human and Murine Decidua

Innate lymphoid cells (ILCs) represent a heterogeneous group of cells lacking genetically rearranged antigen receptors that derive from common lymphoid progenitors. Five major groups of ILCs have been defined based on their cytokine production pattern and developmental transcription factor requirements: namely, natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue-inducer (LTi) cells. ILC1s, ILC2s, and ILC3s mirror the corresponding T helper subsets (Th1, Th2, and Th17, respectively) and produce cytokines involved in defense against pathogens, lymphoid organogenesis, and tissue remodeling. During the first trimester of pregnancy, decidual tissues contain high proportion of decidual NK (dNK) cells, representing up to 50% of decidual lymphocytes, and ILC3s. They release peculiar cytokines and chemokines that contribute to successful pregnancy. Recent studies revealed that ILCs display a high degree of plasticity allowing their prompt adaptation to environmental changes. Decidual NK cells may derive from peripheral blood NK cells migrated when pregnancy establishes or from in situ differentiation of hematopoietic precursors. Previous studies showed that human and murine decidua contain dNK cells, tissue resident NK cells, and ILC3s, all characterized by unique phenotypic and functional properties, most likely induced by decidual microenvironment to favor the establishment and the maintenance of pregnancy. Thus, during the early phase of pregnancy, the simultaneous presence of different ILC subsets further underscores the complexity of the cellular components of decidual tissues as well as the role of decidual microenvironment in shaping the plasticity and the function of ILCs

Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein

Hemophagocytic lymphohistiocytosis (HLH) is a life threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-gamma and TN Fu is present in serum. In animal models of the disease, IFN-gamma and INF-alpha have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-gamma, and INF-alpha have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL18 binding protein (IL18BP) resulting in an excess of free IL18 Here we studied whether IL-18B P could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18B P treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-gamma and TNF-alpha production by CD8+ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18B P is beneficial in an animal model of HLH and in combination with anti infectious therapy may be a promising strategy to treat HLH patients

Avances en la estimación del valor bruto de la producción ganadera bovina argentina

El objetivo del presente trabajo fue calcular la producción de carne en pie y el valor bruto de la producción ganadera bovina por provincia a partir del año 2008/09. Es importante destacar que el objetivo específico de este trabajo forma parte de un objetivo más general enmarcado dentro del proyecto nacional “Gestión integral del riesgo agropecuario” de INTA, en el cual se plantea analizar la variabilidad del valor bruto de la producción ganadera bovina y evaluar el efecto del clima sobre la misma. Este primer reporte se focalizó en las provincias de Formosa, Chaco, Corrientes y Entre Ríos y se planea realizar los cálculos a nivel departamento/partido para el resto de las provincias.EEA MercedesFil: Calvi, Mariana. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Mercedes; ArgentinaFil: Pellerano, Liliana Laura. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Colonia Benítez; ArgentinaFil: Rosello Brajovich, José Emilio. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Colonia Benítez; ArgentinaFil: Beribe, Maria Jose. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Pergamino; ArgentinaFil: Chiossone, José Luciano. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Concordia. Agencia de Extensión Rural Colón; ArgentinaFil: Acosta, Fabian Arturo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Corrientes; ArgentinaFil: Cabrini, Silvina María. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Pergamino; ArgentinaFil: Balbuena, Osvaldo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Colonia Benítez; ArgentinaFil: Aguilar, Domingo Emilio. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Mercedes; Argentin

Bringing natural killer cells to the clinic

International audienceCancer is a leading cause of mortality worldwide, with around 10 million deaths every year. Despite huge advances due to immunotherapy, the majority of cancer patients present primary or secondary resistance to these treatments. In this Found in Translation, we focus on the approaches developed to harness the anti-tumor function of NK cells, suggesting promising strategies to complete the therapeutic arsenal of cancer immunotherapies

Nouvelles frontières de la lutte contre le cancer

En un peu plus de 10 ans, les inhibiteurs de points de contrôle immunitaire, en particulier les anti-PD-1/L1, ont révolutionné la prise en charge des patients atteints de cancers. Néanmoins, ils n’affectent qu’une petite partie de la population de patients. Le principal enjeu actuel de l’immuno-oncologie est de surmonter ces résistances en ciblant de nouveaux points de contrôle et d’autres cellules immunitaires, en combinant ces nouvelles immunothérapies entre elles et avec d’autres standards de traitement. Monalizumab est un nouvel anticorps qui stimule simultanément l’action anti-tumorale des cellules NK et T en bloquant l’un de leurs récepteurs inhibiteurs : NKG2A. NKG2A est présent à la surface des deux types de cellules et son ligand, HLA-E, est très fréquemment surexprimé par les tumeurs humaines, ce qui ouvre une large fenêtre thérapeutique au monalizumab

Immune checkpoints on innate lymphoid cells

International audienceIn this issue of JEM, Taylor et al. (https://doi.org/10.1084/jem.20161653) describe PD-1 as a critical negative regulator of group 2 innate lymphoid cells (ILC-2s). PD-1 intrinsically controls proliferation and cytokine production of both mouse and human ILC-2s. PD-1 signaling inhibits STAT5 phosphorylation and the removal of this brake by knocking down PD-1 expression or by using anti-PD-1 blocking antibodies, translated in vivo into better clearance of helminth worm infection in mice

Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more

International audienceAfter many years of research, recent advances have shed new light on the role of the immune system in advanced-stage cancer. Various types of immune cells may be useful for therapeutic purposes, along with chemical molecules and engineered monoclonal antibodies. The immune effectors suitable for manipulation for adoptive transfer or drug targeting in vivo include natural killer (NK) cells. These cells are of particular interest because they are tightly regulated by an array of inhibitory and activating receptors, enabling them to kill tumor cells while sparing normal cells. New therapeutic antibodies blocking the interactions of inhibitory receptors (immune checkpoint inhibitors, ICI) with their ligands have been developed and can potentiate NK cell functions in vivo