Showing papers by "Eric Vivier published in 2006"

A novel dendritic cell subset involved in tumor immunosurveillance.

Abstract: The interferon (IFN)-γ–induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice1,2. Here we show that the main source of IFN-γ is not the conventional NK cell but a subset of B220+Ly6C− dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220+NK1.1+ dendritic cells secrete high levels of IFN-γ and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2−/−Il2rg−/− mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.

DAP12 Signaling Directly Augments Proproliferative Cytokine Stimulation of NK Cells during Viral Infections

Abstract: NK cells vigorously proliferate during viral infections. During the course of murine CMV infection, this response becomes dominated by the preferential proliferation of NK cells that express the activation receptor Ly49H. The factors driving such selective NK cell proliferation have not been characterized. In this study, we demonstrate that preferential NK cell proliferation is dependent on DAP12-mediated signaling following the binding of Ly49H to its virally encoded ligand, m157. Ly49H signaling through DAP12 appears to directly augment NK cell sensitivity to low concentrations of proproliferative cytokines such as IL-15. The impact of Ly49H-mediated signaling on NK cell proliferation is masked in the presence of high concentrations of proproliferative cytokines that nonselectively drive all NK cells to proliferate.

Strategies of Natural Killer Cell Recognition and Signaling

Abstract: The participation of natural killer (NK) cells in multiple aspects of innate and adaptive immune responses is supported by the wide array of stimulatory and inhibitory receptors they bear. Here we review the receptor-ligand interactions and subsequent signaling events that culminate in NK effector responses. Whereas some receptor-ligand interactions result in activation of both NK cytotoxicity and cytokine production, others have more subtle effects, selectively activating only one pathway or having distinct context-dependent effects. Recent approaches offer ways to unravel how the integration of complex signaling networks directs the NK response.

DAP12 Signaling Regulates Plasmacytoid Dendritic Cell Homeostasis and Down-Modulates Their Function during Viral Infection

Abstract: DAP12 is an ITAM-containing adaptor molecule conveying activating properties to surface receptors on many cell types. We show here that DAP12 paradoxically down-modulates plasmacytoid dendritic cell (pDC) cytokine production in vivo during murine CMV (MCMV) infection. Higher levels of IFN-αβ and IL-12 were detected upon MCMV infection or CpG treatment in DAP12-deficient (DAP12°) mice as compared with wild-type (WT) mice. This resulted from altered homeostasis and enhanced responsiveness of pDCs in DAP12° animals. Increased numbers of pDCs were observed in the periphery of both naive and MCMV-infected DAP12° mice. A higher proportion of pDCs was activated in infected DAP12° mice, as demonstrated by intracellular staining using an optimized protocol for simultaneous detection of IFN-α and IFN-β. The homeostasis of WT and DAP12° pDCs did not differ in mixed bone marrow chimeric mice. In addition, a similar efficiency of pDC differentiation was observed in vitro in Fms-like tyrosine kinase receptor 3 ligand cultures of WT and DAP12° bone marrow cells. This suggests that DAP12 signaling effects on pDC homeostasis are indirect. In contrast, in response to CpG, DAP12-mediated effects on both IL-12 and IFN-αβ production were intrinsic to the pDCs. However, in response to MCMV, only IL-12 but not IFN-αβ production was affected by pDC-intrinsic DAP12 signaling. Thus, DAP12 signaling in pDCs can mediate different regulatory effects on their functions, depending on the mechanisms of pDC activation. The potential implications of the regulation of pDC functions by DAP12 for promoting health over disease are discussed.

Natural killer cells and malaria.

Abstract: Malaria, caused by the infection with parasites of the germs Plasmodium, is one of the three most important infectious diseases worldwide, along with tuberculosis and infection with human immunodeficiency virus. Natural killer (NK) cells are lymphocytes classically involved in the early defense against viral infections and intracytoplasmic bacterial infections and are also implicated during the course of tumor development and allogeneic transplantation. These cells display important cytotoxic activity and produce high levels of proinflammatory cytokines. In both mouse and human models of malaria, NK cells appear to be a major source of interferon-gamma during the early phase of infection. In humans, indirect signaling through monocytes/macrophages required to optimally stimulate NK cell activity. However, the in vivo functions of NK cells during malaria are still enigmatic, and many issues remain to be dissected, such as the molecular basis of the direct recognition of iRBCs by NK cells.

Familial NK Cell Deficiency Associated with Impaired IL-2- and IL-15-Dependent Survival of Lymphocytes

Abstract: We previously reported the clinical phenotype of two siblings with a novel inherited developmental and immunodeficiency syndrome consisting of severe intrauterine growth retardation and the impaired development of specific lymphoid lineages, including transient CD8 αβ T lymphopenia and a persistent lack of blood NK cells. We describe here the elucidation of a plausible underlying pathogenic mechanism, with a cellular phenotype of impaired survival of both fresh and herpesvirus saimiri-transformed T cells, in the surviving child. Clearly, NK cells could not be studied. However, peripheral blood T lymphocytes displayed excessive apoptosis ex vivo. Moreover, the survival rates of CD4 and CD8 αβ T cell blasts generated in vitro, and herpesvirus saimiri-transformed T cells cultured in vitro, were low, but not nil, following treatment with IL-2 and IL-15. In contrast, Fas-mediated activation-induced cell death was not enhanced, indicating a selective excess of cytokine deprivation-mediated apoptosis. In keeping with the known roles of IL-2 and IL-15 in the development of NK and CD8 T cells in the mouse model, these data suggest that an impaired, but not abolished, survival response to IL-2 and IL-15 accounts for the persistent lack of NK cells and the transient CD8 αβ T lymphopenia documented in vivo. Impaired cytokine-mediated lymphocyte survival is likely to be the pathogenic mechanism underlying this novel form of inherited and selective NK deficiency in humans.

Distribution of killer-cell immunoglobulin-like receptor (KIR) in Comoros and Southeast France.

Abstract: Killer-cell immunoglobulin-like receptors (KIRs) expressed by natural killer cells are cell surface molecules able to recognize groups of HLA class I alleles. The number and distribution of KIR genes vary among individuals and populations. The aim of this study is to analyse the KIR gene content in a Comorian population in order to investigate genetic relationships with other populations and to reconstruct past migration events. The Comorian population consisted of 54 unrelated immigrants living in France and a control population consisted of 38 individuals from Southeast France. We investigated the presence or absence of 15 KIR genes, two pseudogenes expressed and non-expressed forms of KIR2DL5 and the two major subtype full-length and deleted forms of KIR2DS4. All individuals were typed positive for the framework genes, i.e. KIR2DL4, KIR3DL2 and KIR3DL3, and the two pseudogenes KIR3DP1 and KIR2DP1. The frequencies of full-length KIR2DS4 (*00101/00102/002) were lower in the French population (F = 29%) than in the Comorian population (F = 72%) (P(c) < 0.05). No significant differences were found for other KIR genes. A total of 11 genotypes were identified in the Southeast French population and 22 genotypes in the Comorian population. The most common genotype (2DL1, 2DL3, 2DL4, 3DL1, 3DL2, 3DL3 and 2DS4) accounted for 41% in the Comorian population and 34% in the Southeast French population. Principal component analysis using KIR gene data from 20 populations was performed to determine genetic differences and relations between populations. The Comorian population exhibited closest kinship with Africans and Asians. As KIR gene content is heterogeneous among ethnic groups, it can probably be used to assess the genetic relationships among populations from different geographic areas.

NK cell development: gas matters.

Abstract: The mechanisms governing natural killer cell development are not well understood. Activation of the tyrosine kinase receptors Tyro3, Axl and Mer on pre–natural killer cells by stromal cell–produced ligands now seems to be critical.

NK cells and innate immunity to malaria

Abstract: Innate immune response against Plasmodium falciparum (Pf), a causative agent of human malaria, is the result of several thousand years of co-evolution between the parasite and his host An early IFN-gamma production during infection is associated with a better evolution of the disease Natural killer (NK) cells are among the first cells in peripheral blood to produce IFN-gamma in response to Pf-infected erythrocytes (Pf-E) NK cells are found in blood, in secondary lymphoid organs as well as in peripheral non-lymphoid tissues They participate in host innate responses that occur upon viral and intracytoplasmic bacterial infections, but also during the course of tumor development and allogeneic transplantation These lymphocytes are not only important players of innate effector responses, but also participate in the initiation and development of adaptive immune responses In addition, direct sensing of Pf infection by NK cells induces their production of the proinflammatory chemokine IL-8, suggesting a role for NK cells in the recruitment and the activation of other cells during malaria infection Several other cell subsets are involved in the innate immune response to Pf Dendritic cells, macrophages, gamma delta T cells, NKT cells are able to sense the presence of the parasite Along this line, the presence of IL-12 is necessary to NK cell IFN-gamma production and a functional cooperation takes place between macrophages and NK cells in the context of this parasitic infection In particular, IL-18 produced by macrophages is a key factor for this NK response However, the molecular basis of Pf-E recognition by NK cells as well as the functional role of NK cell responses during the course of the disease remain to be adressed

Immunobiology of Natural Killer Cell Receptors

Abstract: Preface.- Strategies of NK cell receptor recognition and signaling.- Signal Transduction in Natural Killer Cells Alexander.- Transcriptional Regulation of NK Cell Receptors.- Extending Missing-Self? Functional Interactions Between Lectin-Like Nkrp1 Receptors on NK Cells with Lectin-Like Ligands.-Immunobiology of Human NKG2D and its Ligands.- NKG2 receptor-mediated regulation of effector CTL functions in the human tissue microenvironment.- The Dendritic Cell/NK Cell Cross -Talk: Regulation and Physiopathology.- NK cell activating receptors and tumor recognition in human.- NK cell recognition of mouse cytomegalovirus-infected cells.- NK cell receptors involved in the response to human cytomegalovirus infection.- The Impact of Variation at the KIR Gene Cluster on Human Disease.- NK cells in autoimmune disease.- Subject index

Les cellules natural killer : acquisitions récentes et implication en pathologie humaine

Abstract: Resume Introduction – Les cellules NK sont des lymphocytes impliques dans les defenses immunitaires, participant principalement a la reponse immunitaire innee De nombreuses avancees ces dix dernieres annees, ont fait progresser la comprehension de leurs fonctions et des mecanismes qui les controlent Notre propos est de faire une mise au point sur ces avancees et les implications reconnues ou potentielles en pathologie chez l'homme Actualites et points forts – Deux points importants ont ouvert le champ d'exploration des cellules NK : les mecanismes de controle de leur activation et de leur inhibition et la mise en evidence de familles de recepteurs multigeniques et multialleliques reconnaissant des molecules du CMH de classe I La mise en evidence recente d'une interaction avec les cellules dendritiques pourrait representer un point de controle, exerce par les cellules NK, sur la reponse immunitaire acquise Perspectives et projets – Ces acquisitions ont permis l'exploration et une meilleure comprehension de l'importance du compartiment NK dans les domaines de l'oncologie, des maladies infectieuses, des deficits immunitaires mais aussi des maladies auto-immunes et de certaines pathologies obstetricales Il s'agit d'un champ de recherche fondamental et clinique en pleine expansion qui devra preciser dans les annees a venir l'interet en pratique clinique de l'evaluation du compartiment NK et/ou des genotypes en recepteurs NK

Expression Vectors and Methods for Obtaining Nk Cell Specific Expression

Abstract: The present invention relates to expression constructs and methods of specifically marking NK cells in nonhuman mammals. Specifically, methods are presented that allow, the specific expression of foreign genes in the NK cells of a nonhuman mammal. Such methods are useful for the generation of animal models for disorders involving NK cells, and for the evaluation of genes or compounds with respect to their effects on NK cells.

Cellules natural killer et immunité innée contre le paludisme

Abstract: La reponse immunitaire dirigee contre Plasmodium falciparum (Pf), agent responsable du paludisme chez l’homme, est le resultat de plusieurs milliers d’annees de co-evolution entre le parasite et son hote. La production rapide d’IFNγ (interferon γ) est importante pour le pronostic evolutif de la pathologie. Des etudes recentes suggerent que les cellules natural killer (NK) pourraient etre l’une des sources de cette production precoce d’IFNγ. Plus connues pour leur role dans l’immunite antitumorale et antivirale, les cellules NK seraient egalement capables de reconnaitre directement des hematies infectees par Pf. A la suite de ce contact, leur secretion de la chimiokine IL-8 (interleukine 8) pourrait permettre le recrutement d’autres types cellulaires dans des lieux strategiques. L’activation des cellules NK doit etre replacee dans le contexte d’une reponse immunitaire complexe impliquant d’autres acteurs. Une collaboration entre cellules NK et macrophages serait notamment requise pour une reponse NK optimale. Les fondements moleculaires de l’activation des cellules NK, ainsi que leur role dans le controle initial du stade sanguin de l’infection font aujourd’hui l’objet d’intenses recherches.