Cellules natural killer et immunité innée contre le paludisme

La réponse immunitaire dirigée contre Plasmodium falciparum (Pf), agent responsable du paludisme chez l’homme, est le résultat de plusieurs milliers d’années de co-évolution entre le parasite et son hôte. La production rapide d’IFNγ (interféron γ) est importante pour le pronostic évolutif de la pathologie. Des études récentes suggèrent que les cellules natural killer (NK) pourraient être l’une des sources de cette production précoce d’IFNγ. Plus connues pour leur rôle dans l’immunité antitumorale et antivirale, les cellules NK seraient également capables de reconnaître directement des hématies infectées par Pf. À la suite de ce contact, leur sécrétion de la chimiokine IL-8 (interleukine 8) pourrait permettre le recrutement d’autres types cellulaires dans des lieux stratégiques. L’activation des cellules NK doit être replacée dans le contexte d’une réponse immunitaire complexe impliquant d’autres acteurs. Une collaboration entre cellules NK et macrophages serait notamment requise pour une réponse NK optimale. Les fondements moléculaires de l’activation des cellules NK, ainsi que leur rôle dans le contrôle initial du stade sanguin de l’infection font aujourd’hui l’objet d’intenses recherches.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-γ 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-γ 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, γδT 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-γ 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

CD4+ T Cell Polarization in Mice Is Modulated by Strain-specific Major Histocompatibility Complex–independent Differences within Dendritic Cells

Resistance and susceptibility to Leishmania major in mice are determined by multiple genes and correlate with the preferential development of Th1 and Th2 responses, respectively. Here, we found that CD11b+ dendritic cells (DCs) prime parasite-specific CD4+ T cells in both susceptible BALB/c (H2-d) and resistant B10.D2 (H2-d) mice. However, BALB/c and B10.D2 DCs from L. major–infected mice differ in their ability to polarize naive T cells into Th1 or Th2 effector cells. This difference is cell-intrinsic, is not restricted to H2-d mice, and is observed with both parasite-specific and allospecific CD4+ T cells. Thus, strain-specific differences within CD11b+ DCs influence the ability of inbred mice to mount polarized CD4+ T cell responses

Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis

Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea–induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60–million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans

Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis Development.

RATIONALE: Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunities are involved. Although several studies have evaluated the functions of natural killer (NK) cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or proatherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss or gain of function of NK cells. OBJECTIVES: We used 2 selective genetic approaches to investigate the role of NK cells in atherosclerosis: (1) Ncr1iCre/+R26lsl-DTA/+ mice in which NK cells were depleted and (2) Noé mice in which NK cells are hyperresponsive. METHODS AND RESULTS: No difference in atherosclerotic lesion size was found in Ldlr-/- (low-density lipoprotein receptor null) mice transplanted with bone marrow (BM) cells from Ncr1iCreR26Rlsl-DTA , Noé, or wild-type mice. Also, no difference was observed in plaque composition in terms of collagen content, macrophage infiltration, or the immune profile, although Noé chimera had more IFN (interferon)-γ-producing NK cells, compared with wild-type mice. Then, we investigated the NK-cell selectivity of anti-asialoganglioside M1 antiserum, which was previously used to conclude the proatherogenicity of NK cells. Anti-asialoganglioside M1 treatment decreased atherosclerosis in both Ldlr-/- mice transplanted with Ncr1iCreR26Rlsl-DTA or wild-type bone marrow, indicating that its antiatherogenic effects are unrelated to NK-cell depletion, but to CD8+ T and NKT cells. Finally, to determine whether NK cells could contribute to the disease in conditions of pathological NK-cell overactivation, we treated irradiated Ldlr-/- mice reconstituted with either wild-type or Ncr1iCreR26Rlsl-DTA bone marrow with the viral mimic polyinosinic:polycytidylic acid and found a significant reduction of plaque size in NK-cell-deficient chimeric mice. CONCLUSIONS: Our findings, using state-of-the-art mouse models, demonstrate that NK cells have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis, but may play a role when an additional systemic NK-cell overactivation occurs

Innate or adaptive immunity, The example of natural killer cells.

Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity endowed with constitutive cytolytic functions. More recently, a more nuanced view of NK cells has emerged. NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development. Moreover, NK cells do not react in an invariant manner but rather adapt to their environment. Finally, recent studies have unveiled that NK cells can also mount a form of antigen-specific immunologic memory. NK cells thus exert sophisticated biological functions that are attributes of both innate and adaptive immunity, blurring the functional borders between these two arms of the immune response

Dissection of the Role of PfEMP1 and ICAM-1 in the Sensing of Plasmodium falciparum-Infected Erythrocytes by Natural Killer Cells

BACKGROUND: Host innate immunity contributes to malaria clinical outcome by providing protective inflammatory cytokines such as interferon-γ, and by shaping the adaptive immune response. Plasmodium falciparum (Pf) is the etiologic agent of the most severe forms of human malaria. Natural Killer (NK) cells are lymphocytes of the innate immune system that are the first effectors to produce interferon-γ in response to Pf. However, the molecular bases of Pf-NK cell recognition events are unknown. Our study focuses on the role of Pf erythrocyte membrane protein 1 (PfEMP1), a major Pf virulence factor. PfEMP1 is expressed on parasitized-erythrocytes and participates to vascular obstruction through the binding to several host receptors. PfEMP1 is also a pivotal target for host antibody response to Pf infection. METHODOLOGY/PRINCIPAL FINDINGS: Using genetically-engineered parasite mutant strains, a human genetic deficiency, and blocking antibodies, we identified two receptor-ligand pairs involved in two uncoupled events occurring during the sensing of Pf infection by NK cells. First, PfEMP1 interaction with one of its host receptor, chondroitin sulfate A, mediates the cytoadhesion of Pf-infected erythrocytes to human NK cell lines, but is not required for primary NK cell activation. Second, intercellular adhesion molecule-1 (ICAM-1), another host receptor for PfEMP1, is mandatory for NK cell interferon-γ response. In this case, ICAM-1 acts via its engagement with its host ligand, LFA-1, and not with PfEMP1, consistent with the obligatory cross-talk of NK cells with macrophages for their production of interferon-γ. CONCLUSION/SIGNIFICANCE: PfEMP1-independent but ICAM-1/LFA-1-dependent events occurring during NK cell activation by Pf highlight the fundamental role of cellular cooperation during innate immune response to malaria

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Grecs et indigènes de la Catalogne à la mer Noire

Le programme de travail qui aboutit à ce livre s’inscrit dans le cadre du réseau d’excellence européen Ramses2, initié par la Maison méditerranéenne des sciences de l’homme. Une demi-douzaine de tables rondes ont réuni entre 2006 et 2008, d’un bout à l’autre de la Méditerranée (à Empúries, Aix-en-Provence, Palerme, Naples, Athènes), quelque soixante-dix chercheurs essentiellement français, italiens et espagnols, mais aussi anglais, grecs, bulgares, roumains, canadiens et russes. Il s’agissait d’étudier les rapports d’acculturation entre colons grecs et populations indigènes, en tenant compte des différences géographiques et chronologiques mais aussi de l’historiographie et des habitudes de recherche des diverses institutions. Les nombreuses communications qui ont jalonné les six tables rondes sont ici la plupart du temps précédées de textes introductifs. Une première partie, consacrée aux approches régionales, permet d’illustrer l’état de la recherche dans quelques régions choisies (autour d’Empuries, d’Himère, de Marseille, de Vélia, en Thrace et en mer Noire). La seconde partie, thématique, aborde un certain nombre de thèmes de recherche dans les régions précédentes, mais aussi dans d’autres régions du monde de la colonisation grecque. Le point de vue adopté dans ce livre est d’abord celui de la culture matérielle ; l’approche en est essentiellement archéologique. On se demandera par exemple quels sont les indices archéologiques qui permettent de dire si un site est habité par des Grecs, par des indigènes ou par une population “mixte”, et comment ces indices ont été appréciés selon les périodes et selon les régions. Beaucoup de communications présentent des synthèses régionales ou thématiques, mais une large place est faite également à des sites inédits, pour lesquels on n’a pas hésité à livrer une abondante documentation (plans, matériel de fouille). C’est en effet par le renouvellement de la documentation archéologique que nous pouvons espérer avancer dans la compréhension des rapports d’acculturation entre les colons grecs et les populations locales

Contacts et acculturations en Méditerranée occidentale

La question des contacts entre les différents peuples qui bordent les rives de la Méditerranée nord occidentale est l’un des sujets phares de la recherche archéologique de ces trente dernières années. Que l’on parle d’époque archaïque et classique ou de Protohistoire et d’âge du Fer, les échanges et les processus d’acculturation de ces peuples qui entrèrent alors en contact les uns avec les autres : Grecs, Celtes, Phéniciens, Ibères, Ligures, Étrusques, ont retenu l’attention des chercheurs travaillant sur l’expansion grecque dans ces régions, sur les trafics commerciaux, sur les échanges culturels. L’œuvre de Michel Bats (Directeur de recherche honoraire du CNRS) traverse toutes ces thématiques : la présence des Phocéens et des Étrusques dans le bassin occidental de la Méditerranée, l’acculturation et les identités ethno-culturelles, les recherches sur la céramique et ses usages dans une perspective anthropologique, l’appropriation de l’écriture par les sociétés protohistoriques. Ses collègues et amis, en organisant ce colloque et en participant à ces actes, entendent lui témoigner leur amitié et leur dette intellectuelle. Ce volume réunit des articles des meilleurs spécialistes, actuels de la question - des chercheurs de toute la Méditerranée - autour des quatre grands thèmes que nous venons d’évoquer afin tout à la fois de dresser un bilan et de définir de nouvelles perspectives. Cet ouvrage présente donc aussi bien des synthèses - sur la présence grecque en Espagne, sur l’origine de l’écriture, sur les pratiques funéraires, sur les identités culturelles et ethniques - que des découvertes récentes concernant la thématique des contacts et de l’acculturation en Méditerranée nord occidentale : l’agglomération du Premier âge du Fer de La Cougourlude (Lattes, Hérault) fouillée durant l’été 2010 ; le sanctuaire hellénistique de Cumes et les fouilles récentes de Fratte en Italie ; les ateliers de potiers de Rosas en Espagne ; les dernières découvertes d’Olbia de Provence