1,720,959 research outputs found
THE ROLE OF NATURAL CYTOTOXICITY RECEPTORS IN THE HOMEOSTASIS AND FUNCTION OF A NEWLY DISCOVERED SUBSET OF HUMAN GAMMA DELTA T CELLS
No full textNatural Cytotoxicity Receptors (NCRs) were originally identified as specific natural killer cell activating receptors that, upon binding to their endogenous ligands, trigger the killing of tumor cell targets. Here we describe a population of Vδ1 + T cells from human peripheral blood that can differentiate in vitro to express the NCRs NKp30, NKp44 and NKp46. Moreover, we show that the expression of NKp30 endows Vδ1 + T cells with the ability to suppress HIV-1 viral replication and lyse hematologic tumor cells in vitro, through the production of CC chemokines and cytolytic granules, respectively. These experiments were also accompanied by the finding that a substantial population of Vδ1 + T cells within the intestinal epithelium expresses all three NCRs, with NKp46 being predominant. While the role for the NCR on expanded populations of γδ T cells from the peripheral blood grants γδ T cells with potent effector functions, we provide evidence that the NCR, and in particular NKp46, is a marker of hyporesponsive γδ T cells in the intestinal epithelium. These data suggest two opposing roles for the NCR on γδ T cells depending on the environment: 1) NCRs which can be induced in vitro are able to impart cytotoxic effector functions on the γδ T cells and 2) NCRs present in physiological conditions in the healthy intestine may function to regulate the γδ T cell. Our findings open exciting new avenues for the understanding of γδ IEL T cell function. Moreover, the induction of NCRs on peripheral γδ T cells in vitro may have direct implications in the development of adoptive cell therapies for the treatment of various diseases including cancer and HIV-1 infection
Pathologic natural killer cell subset redistribution in HIV-1 infection: new insights in pathophysiology and clinical outcomes
No full textSeveral lines of evidence indicate that the interaction of HIV-1 with NK cells markedly affects host immune responses and leads to a defective control of the virus. Until recently, it was generally believed that the absolute number of total circulating NK cells was decreased during the course of chronic and active phases of HIV-1 infection and that this explained, at least in part, the defective NK cell antiviral activities. However, scientific advances made over recent years have changed this concept and have clarified that HIV-1 viremia is associated with a pathologic redistribution rather than an absolute decrease in the number of circulating NK cells. In particular, the expansion of dysfunctional Siglec-7neg and/or CD56neg NK cell subsets expressing an aberrant repertoire of activating and inhibitory receptors has been associated with functional impairments of NK cells and with clinical outcomes of HIV-1 disease. Indeed, these pathologic NK cell populations often comprise the majority of NK cells in the presence of high levels of chronic HIV-1 viremia. The reasons for these NK cell aberrancies remain unknown, as freshly purified CD4neg NK cells are not productively infected by HIV-1. Disclosing the cellular and molecular mechanisms underlying such dysfunctions represents an important challenge of biomedical research, also considering that the presence of a rare KIR3DS1pos NK cell population represents a protective factor against HIV-1 disease progression. In this review, we will summarize the recent updates regarding NK cell pathophysiology during the course of HIV-1 infection
Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection
No full textBackground: The HIV-1-induced expansion of highly dysfunctional natural killer (NK) cell subsets represents a strategy to evade NK cell antiviral functions. In this context, the loss of NKG2A NK cells in chronic viremic HIV-1-infected individuals has also been associated with a dramatic expansion of NKG2C NK cells. The viral trigger associated with high frequencies of NK cell subsets expressing NKG2C is still being debated. Objective: To confirm that human cytomegalovirus (HCMV) infection is necessary for the expansion of NKG2C NK cells and to assess whether this phenomenon affects NKG2A/NKG2C ratio on NK cells in patients coinfected with HIV-1 and HCMV. Design: We measured the expression of NKG2A and NKG2C on NK cells from 70 healthy donors, 21 early, 96 chronic and 27 long-term nonprogressor's (LTNPs) HIV-1-infected patients using a multicolor flow cytometric approach. HCMV infection was detected by titrating the serum levels of specific circulating antibodies. Results: A significant expansion of NKG2C NK cells could be detected only in HCMV-infected patients. This phenotypic feature, together with the HIV-1-mediated downmodulation of NKG2A, pathologically reverses the ratio of NKG2A/NKG2C uniquely on NK cells from chronic viremic HIV-1-infected patients with a concomitant HCMV infection. The normalization of NKG2A/NKG2C ratio to values more than one occurred only after 24 months of suppression of HIV-1 replication following antiretroviral therapy. Conclusion: The inversion of NKG2A/NKG2C ratio characterizes advanced stages of HIV-1 disease in patients showing a concomitant HCMV infection. This NK cell immune parameter renders this cohort of patients distinguishable from LTNPs and early HIV-1-infected individuals
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Differentiation of human peripheral blood Vδ1 T cells expressing Natural Cytotoxicity Receptors : implications for immunotherapies and the understanding of γδ T cell function
No full textNatural Cytotoxicity Receptors (NCRs) were originally identified as specific natural killer cell activating receptors that, upon binding to their endogenous ligands, trigger the killing of tumor cell targets. Here we describe a population of Vδ1+ T cells from human peripheral blood that can differentiate in vitro to express the NCRs NKp30, NKp44 and NKp46. We show that the expression of NKp30 endows Vδ1+ T cells with the ability to lyse, in vitro, both hematologic tumor cell lines as well as chronic lymphocytic leukemia cells isolated from patients. Moreover, we found that these cells are also able to produce CC chemokines upon the triggering of NKp30, which suppresses HIV-1 viral replication in CD4+ T cells in vitro. This evidence not only further discloses the key role of NK cell receptors in certain γδ T cell functions, but also suggests that Vδ1+ T cells specifically harbor a powerful therapeutic potential through the induction of NCRs, whose function can be manipulated for the treatment of various diseases
Engagement of Siglec-7 receptor induces a pro-inflammatory response selectively in monocytes.
Full text linkSialic acid binding immunoglobulin-like lectin-7 (Siglec-7) is a trans-membrane receptor carrying immunoreceptor tyrosine based inhibitory motifs (ITIMs) and delivering inhibitory signals upon ligation with sialylated glycans. This inhibitory function can be also targeted by several pathogens that have evolved to express sialic acids on their surface to escape host immune responses. Here, we demonstrate that cross-linking of Siglec-7 by a specific monoclonal antibody (mAb) induces a remarkably high production of IL-6, IL-1α, CCL4/MIP-1β, IL-8 and TNF-α. Among the three immune cell subsets known to constitutively express Siglec-7, the production of these pro-inflammatory cytokines and chemokines selectively occurs in monocytes and not in Natural Killer or T lymphocytes. This Siglec-7-mediated activating function is associated with the phosphorylation of the extracellular signal-regulated kinase (ERK) pathway. The present study also shows that sialic acid-free Zymosan yeast particles are able to bind Siglec-7 on monocytes and that this interaction mimics the ability of the anti Siglec-7 mAb to induce the production of pro-inflammatory mediators. Indeed, blocking or silencing Siglec-7 in primary monocytes greatly reduced the production of inflammatory cytokines and chemokines in response to Zymosan, thus confirming that Siglec-7 participates in generating a monocyte-mediated inflammatory outcome following pathogen recognition. The presence of an activating form of Siglec-7 in monocytes provides the host with a new and alternative mechanism to encounter pathogens not expressing sialylated glycans
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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