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Human NK Cells (human + nk_cell)
Selected AbstractsREVIEW ARTICLE: Human NK Cells in Pregnant Uterus: Why There?AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2008Philippe Le Bouteiller Human Natural Killer (NK) cells are present in great number in pregnant uterine mucosa. They must be there for specialized functions, but which ones? This review discusses important recent observations that further contribute to this fascinating debate. Firstly, an array of corroborating findings indicates that uterine NK cell proliferation is synchronized with the cyclic surge of progesterone. Secondly, uterine NK cells are unlikely to exert a direct control on the embryo implantation. Thirdly, these NK cells influence the uterine vascular remodeling in early pregnancy but might not be the single key element that control trophoblast invasion. Finally, uterine NK cells are likely to be an important component of the local maternal immune response to pathogen infections. [source] Functional role of human NK cell receptor 2B4 (CD244) isoformsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2009Stephen O. Mathew Abstract 2B4 (CD244), a member of the signaling lymphocyte-activation molecule (SLAM/CD150), is expressed on all NK cells, a subpopulation of T cells, monocytes and basophils. Human NK cells express two isoforms of 2B4, h2B4-A and h2B4-B that differ in a small portion of the extracellular domain. In the present investigation, we have studied the functions of h2B4-A and h2B4-B. Our study demonstrated that these two isoforms differ in their binding affinity for CD48, which results in differential cytotoxic activity as well as intracellular calcium release by NK cells upon target cell recognition. Analysis of the predicted 3-D structure of the two isoforms showed conformational differences that could account for their differences in binding affinity to CD48. h2B4-A was able to mediate natural cytotoxicity against CD48-expressing K562 target cells and induce intracellular calcium release, whereas h2B4-B showed no effects. NK-92MI, U937, THP-1, KU812, primary monocytes, basophils and NK cells showed expression of both h2B4-A and h2B4-B whereas YT and IL-2-activated NK cells did not show any h2B4-B expression. Stimulation of NK cells through 2B4 resulted in decreased mRNA levels of both h2B4-A and h2B4-B indicating that down-regulation of 2B4 isoforms may be an important factor in controlling NK cell activation during immune responses. [source] Putting the natural killer cell in its placeIMMUNOLOGY, Issue 1 2006Geraldine M. O'Connor Summary Natural killer (NK) cells were originally described as ,null' lymphocytes, but we have increasing evidence of their role in recognizing pathogen, and our knowledge of NK cell receptors continues to expand exponentially. Human NK cells have many receptors for human leucoctye antigen (HLA) class I. These killer immunoglobulin-like receptors (KIRs) and CD94/NKG2 receptors can signal in both positive and negative ways to regulate NK cell functions. The inhibitory receptors are the best characterized, but even in these cases much of their functional biology remains elusive. In this review, some recent advances in terms of the three-immunoglobulin (3Ig)-domain KIRs are discussed. Natural cytotoxicity receptors (NCRs) are among the activatory receptors found on NK cells. While pathogen ligands for these receptors have been described, endogenous ligands remain elusive. NCRs and NKG2D, a receptor for stress-induced antigens, appear to play complementary functional roles in terms of NK cell activation. More recently described on NK cells are the Toll-like receptors. In particular, these receptors of the innate immune system allow NK cells to directly sense pathogen, and their ligation on accessory cells indirectly activates NK cells through cytokine production. It is becoming clear that none of these receptor systems functions in isolation and that it is the sum of the signals (which will reflect the pathogenic situation), in addition to the cytokine milieu, that will direct NK cell activation. The resulting cytotoxicity, cytokine production and direct cell,cell regulatory interactions with other cells of the immune system, for example dendritic cells, ultimately determine the role of the NK cell in the context of an overall immune response. [source] Human NK cells display major phenotypic and functional changes over the life spanAGING CELL, Issue 4 2010Magali Le Garff-Tavernier Summary Aging is generally associated with an increased predisposition to infectious diseases and cancers, related in part to the development of immune senescence, a process that affects all cell compartments of the immune system. Although many studies have investigated the effects of age on natural killer (NK) cells, their conclusions remain controversial because the diverse health status of study subjects resulted in discordant findings. To clarify this situation, we conducted the first extensive phenotypic and functional analysis of NK cells from healthy subjects, comparing NK cells derived from newborn (cord blood), middle-aged (18,60 years), old (60,80 years), and very old (80,100 years) subjects. We found that NK cells in cord blood displayed specific features associated with immaturity, including poor expression of KIR and LIR-1/ILT-2 and high expression of both NKG2A and IFN-,. NK cells from older subjects, on the other hand, preserved their major phenotypic and functional characteristics, but with their mature features accentuated. These include a profound decline of the CD56bright subset, a specific increase in LIR-1/ILT-2, and a perfect recovering of NK-cell function following IL2-activation in very old subjects. We conclude that the preservation of NK cell features until very advanced age may contribute to longevity and successful aging. [source] Both CD133+ and CD133, medulloblastoma cell lines express ligands for triggering NK receptors and are susceptible to NK-mediated cytotoxicityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2007Roberta Castriconi Abstract Adoptive cellular immunotherapy has been proposed as an additional treatment of medulloblastoma, an intracranial tumor characterized by a particularly poor prognosis. However, little is known on the ability of the immune system to effectively attack this tumor. In this study, we show that activated human NK cells efficiently kill medulloblastoma cell lines in vitro. NK-mediated killing involved different activating receptors (including NKp46, NKp30, DNAM-1 and NKG2D) and correlated with the presence of their specific ligands on tumor cells. In contrast, the absence of major adhesion interactions, such as LFA-1/ICAM did not impair the NK-mediated cytotoxicity. Medulloblastoma expressed a number of tumor-associated molecules including CD146 and CD133, considered a marker for cancer stem cells. Remarkably, both CD133-positive and CD133-negative cell lines were susceptible to lysis. Tumor cells also expressed molecules that are currently used as diagnostic tools for neuroblastoma cell identification. In particular, B7 homolog 3 (B7-H3) was expressed by all the medulloblastoma cell lines analyzed, while the presence of GD2 and NB84 was restricted to given cell lines and/or marked a defined tumor cell subset. [source] Modulation of 2B4 (CD244) activity and regulated SAP expression in human NK cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2007Johanna Endt Abstract The adapter protein SAP is important for the signal transduction of the family of SLAM-related receptors (SRR), which have important immune-modulating functions. The importance of SAP and SRR for a functional immune reaction becomes obvious in patients suffering from X-linked lymphoproliferative disease, which is characterized by non-functional SAP. Here we investigate the regulation of SAP expression in human NK cells. We demonstrate that SAP mRNA expression and protein levels are low in freshly isolated resting NK cells. IL-2 stimulation leads to an up-regulation of SAP expression, which can be enhanced by IL-12, the stimulation of TLR3 by polyinosinic-polycytidylic acid (poly(I:C))and to a lesser extent by IFN-,. EAT-2, a SAP-related adapter protein, is already detectable in resting NK cells and does not change its expression after IL-2 stimulation. The regulation of SAP has functional consequences for the stimulation of NK cell cytotoxicity by 2B4. In resting NK cells, 2B4 stimulation can only enhance NK cell lysis when co-triggered with other activating NK cell receptors. In IL-2-activated NK cells with high SAP expression the triggering of 2B4 alone is sufficient to induce NK cell cytotoxicity, demonstrating a correlation between the regulated SAP expression and the function of 2B4. [source] Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirusEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2006Andrea Sáez-Borderías Abstract The human NKG2D killer lectin-like receptor (KLR) is coupled by the DAP10 adapter to phosphoinositide 3-kinase (PI3,K) and specifically interacts with different stress-inducible molecules (i.e. MICA, MICB, ULBP) displayed by some tumour and virus-infected cells. This KLR is commonly expressed by human NK cells as well as TCR,,+ and TCR,,+CD8+ T lymphocytes, but it has been also detected in CD4+ T cells from rheumatoid arthritis and cancer patients. In the present study, we analysed NKG2D expression in human cytomegalovirus (HCMV)-specific CD4+ T lymphocytes. In vitro stimulation of peripheral blood mononuclear cells (PBMC) from healthy seropositive individuals with HCMV promoted variable expansion of CD4+NKG2D+ T lymphocytes that coexpressed perforin. NKG2D was detected in CD28, and CD28dull subsets and was not systematically associated with the expression of other NK cell receptors (i.e. KIR, CD94/NKG2 and ILT2). Engagement of NKG2D with specific mAb synergized with TCR-dependent activation of CD4+ T cells, triggering proliferation and cytokine production (i.e. IFN-, and TNF-,). Altogether, the data support the notion that NKG2D functions as a prototypic costimulatory receptor in a subset of HCMV-specific CD4+ T lymphocytes and thus may have a role in the response against infected HLA class II+ cells displaying NKG2D ligands. [source] Structural and functional differences between the promoters of independently expressed killer cell Ig-like receptorsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2005Bergen, Jeroen van Abstract Killer Ig-like receptors (KIR) are important for the recognition and elimination of diseased cells by human NK cells. Myeloid leukemia patients given a hematopoietic stem cell transplantation, for example, benefit from KIR-mediated NK alloreactivity directed against the leukemia cells. To establish an effective NK cell repertoire, most KIR genes are expressed stochastically, independently of the others. However, the sequences upstream of the coding regions of these KIR genes are highly homologous to the recently identified KIR3DL1 promoter (91.1,99.6% sequence identity), suggesting that they are regulated by similar if not identical mechanisms of transcriptional activation. We investigated the effects of small sequence differences between the KIR3DL1 promoter and other KIR promoters on transcription factor binding and promoter activity. Surprisingly, electrophoretic mobility shift assays and promoter-reporter assays revealed significant structural and functional differences in the cis-acting elements of these highly homologous KIR promoters, suggesting a key role for transcription factors in independent control of expression of specific KIR loci. Thus, the KIR repertoire may be shaped by a combination of both gene-specific and stochastic mechanisms. [source] Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec-7-dependent and -independent mechanismsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2003Gavin Nicoll Abstract Siglec-7 is a sialic acid binding receptor with inhibitory potential, expressed on human NK cells and monocytes. It has an unusual binding preference for ,2,8-linked disialic acids, such as those displayed by ganglioside GD3. Here we have investigated whether siglec-7-GD3 interactions are able to modulate NK cell cytotoxicity. Using synthetic polyacrylamide glycoprobes, siglec-7 was found to be masked at the NK cell surface but it could be unmasked by sialidase treatment of NK cells. GD3 synthase-transfected P815 target cells expressed high levels of GD3 and bound strongly to recombinant siglec-7-Fc protein. Surprisingly, GD3 synthase-transfected P815 cells were killed more effectively by untreated cells in a siglec-7-independent manner. However, following sialidase treatment of NK cells, a siglec-7-dependent inhibition of killing was observed. These findings have important implications for NK cell cytotoxicity against tumor cells like melanoma that express high levels of GD3 ganglioside. [source] Do functional subsets of leukocytes arise by divergent or linear differentiation?IMMUNOLOGY, Issue 4 2002Alistair Noble Summary The T helper type 1 (Th1)/Th2 paradigm has been extended to a wide variety of leukocyte lineages since its inception, including innate immune cells such as dendritic cells and natural killer (NK) cells. Recently, studies of human NK cells have led to the proposition of a new model of linear differentiation in which cell phenotype is controlled by regulation of proliferation versus differentiation, rather than by divergent differentiation programmes. It was suggested that this model might also apply to T cells. Here we discuss the relevance of each model to different leukocyte lineages and argue that the linear differentiation model does not apply to ,, T cells. [source] | ||||||||||