Tbet promotes CXCR6 expression in immature natural killer cells and natural killer cell egress from the bone marrow

Tbet-deficient mice have reduced natural killer (NK) cells in blood and spleen, but increased NK cells in bone marrow and lymph nodes, a phenotype that is thought to be the result of defective migration. Here, we revisit the role of Tbet in NK cell bone marrow egress. We definitively show that the accumulation of NK cells in the bone marrow of Tbet-deficient Tbx21^−/− animals occurs because of a migration defect and identify a module of genes, co-ordinated by Tbet, which affects the localization of NK cells in the bone marrow. Cxcr6 is approximately 125-fold underexpressed in Tbx21^−/−, compared with wild-type, immature NK cells. Immature NK cells accumulate in the bone marrow of CXCR6-deficient mice, and CXCR6-deficient progenitors are less able to reconstitute the peripheral NK cell compartment than their wild-type counterparts. However, the CXCR6 phenotype is largely confined to immature NK cells, whereas the Tbet phenotype is present in both immature and mature NK cells, suggesting that genes identified as being more differentially expressed in mature NK cells, such as S1pr5, Cx3cr1, Sell and Cd69, may be the major drivers of the phenotype.     

Invariant natural killer T cells are phenotypically and functionally altered in Fabry disease

Fabry disease is a lysosomal storage disease belonging to the group of sphingolipidoses.In Fabry disease there is accumulation of mainly globotriaosylceramide due to deficiency of the lysosomal enzyme α-galactosidase A. The lysosome is an important compartment for the activity of invariant natural killer T (iNKT) cells. iNKT cells are lipid-specific T cells that were shown to be important in infection, autoimmunity and tumor surveillance. In several mouse models of lysosomal storage disorders there is a decrease in iNKT cell numbers. Furthermore, alterations on iNKT cell subsets have been recently described in the Fabry disease mouse model. Herein, we analyzed iNKT cells and their subsets in Fabry disease patients. Although there were no differences in the percentage of iNKT cells between Fabry disease patients and control subjects, Fabry disease patients presented a reduction in the iNKT CD4⁺ cells accompanied by an increase in the iNKT DN cells. Since iNKT cell subsets produce different quantities of pro-inflammatory and anti-inflammatory cytokines, we analyzed IFN-γ and IL-4 production by iNKT cells of Fabry disease patients and mice.We found a significant reduction in the production of IL-4 by mice splenic iNKT cells and human iNKT cell subsets, but no significant alterations in the production of IFN-γ. Altogether, our results suggest a bias towards a pro-inflammatory phenotype in Fabry disease iNKT cells.     

Differential responses to interleukin 2 define functionally distinct subsets of human natural killer cells.

Human natural killer (NK) cells can be subdivided into two populations based on the density of cell surface CD56 antigen. The great majority (approximately 90%) of NK cells express CD56 at low levels (the CD56dim phenotype), whereas a small NK cell subset (approximately 10%) exhibits approximately fivefold greater density of surface CD56. Exposure to exogenous interleukin 2 (IL 2) induces tenfold greater proliferation of CD56bright cells compared to CD56dim lymphocytes, even though both subsets constitutively express similar levels of intermediate affinity IL 2 receptor (IL 2R) p75 chains. Incubation with IL 2 alone or irradiated target cells alone could induce expression of the IL 2R p55 chain by both CD56bright and CD56dim NK cells; a combination of both stimuli was most effective. IL 2R p55 induction was evident after co-culture of NK cells with both NK-sensitive and NK-resistant cell lines or with antibody-coated target cells. Activation of NK cells with IL 2 plus target cells resulted in enhanced proliferation compared to activation with IL 2 alone; target cells alone did not induce significant proliferation. Although both NK cell subsets appeared to express high-affinity IL 2R p75/p55 heterodimers after stimulation with target cells and IL 2, proliferation of CD56dim cells remained minimal after such activation; activated CD56dim cells consistently demonstrated less proliferation to IL 2 than did resting CD56bright cells. In contrast, CD56bright NK cells exhibited even greater proliferation after stimulation with target cells. Almost all CD56dim NK cells expressed CD16 (Fc gamma R III) as well as the NK zeta chain, whereas less than 50% of CD56bright cells express either CD16 or zeta. CD56bright and CD56dim lymphocytes, thus, appear to represent distinct subpopulations of NK cells with different functional activities. Unlike CD56bright cells, CD56dim NK cells do not proliferate optimally to IL 2, even after the latter have been stimulated to express both IL 2R p55 and IL 2R p75. Efficient proliferation of CD56dim NK cells may, thus, require additional or alternative signals.     

Lymphokine-activated killer cells, natural killer cells and cytokines

In the past year, natural killer cells have been the subject of much active investigation. The analysis of the effect of cytokines on the generation, proliferation and function of natural killer cells, and the definition of the lymphokines that they produce, have been particularly important areas of research in view of their possible application in adaptive immunotherapy, combined with biological response modifiers.     

Chronic myeloid leukemia and allogeneic natural killer cells: a surprising dialogue

Chronic myeloid leukemia (CML) is a clonal multilineage myeloproliferative disease of stem cell origin characterized by the presence of the Bcr/Abl oncoprotein, a constitutively active tyrosine kinase. The actual treatment of CML patients in chronic phase is the specific abl kinase inhibitor imatinib mesylate that induces 90% of cytogenetic responses in early-phase patients. However, resistance in long-term treated patients occurs and the allogeneic stem cell transplantation remains the only curative treatment in resistant patients. Despite recent reports outlining the role of allogeneic natural killer (NK) cells as potent antileukemic effectors, the mechanisms controlling the leukemic target recognition and lysis by activated NK cells have not been well identified. The authors’ experimental data obtained on appropriate cellular models identify diverse mechanisms that could explain the increased NK-cell susceptibility of Bcr/Abl targets to NK-mediated lysis. They further delineate unexpected effects of the inhibition of the tyrosine kinase activity on the cross-talk between NK and CML leukemic cells. The consequences of such discoveries are discussed in the context of combined treatments with antikinases as well as adoptive cellular therapy approaches in myeloid leukemia patients.     

Functions of natural killer cells

Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Recent research highlights the fact that NK cells are also regulatory cells engaged in reciprocal interactions with dendritic cells, macrophages, T cells and endothelial cells. NK cells can thus limit or exacerbate immune responses. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.     

Memory-like responses of natural killer cells

Summary: Natural killer (NK) cells are lymphocytes with the capacity to produce cytokines and kill target cells upon activation. NK cells have long been categorized as members of the innate immune system and as such have been thought to follow the ‘rules’ of innate immunity, including the principle that they have no immunologic memory, a property thought to be strictly limited to adaptive immunity. However, recent studies have suggested that NK cells have the capacity to alter their behavior based on prior activation. This property is analogous to adaptive immune memory; however, some NK cell memory-like functions are not strictly antigen dependent and can be demonstrated following cytokine stimulation. Here, we discuss the recent evidence that NK cells can exhibit properties of immunologic memory, focusing on the ability of cytokines to non-specifically induce memory-like NK cells with enhanced responses to restimulation.     

The trafficking of natural killer cells

Summary: Natural killer (NK) cells are large granular lymphocytes of the innate immune system that participate in the early control of microbial infections and cancer. NK cells can induce the death of autologous cells undergoing various forms of stress, recognizing and providing non-microbial 'danger' signals to the immune system. NK cells are widely distributed in lymphoid and non-lymphoid organs. NK cell precursors originate from the bone marrow and go through a complex maturation process that leads to the acquisition of their effector functions, to changes in their expression of integrins and chemotactic receptors, and to their redistribution from the bone marrow and lymph nodes to blood, spleen, liver, and lung. Here, we describe the tissue localization of NK cells, using NKp46 as an NK cell marker, and review the current knowledge on the mechanisms that govern their trafficking in humans and in mice.     

自然杀伤细胞的抗病毒活性

自然杀伤细胞是一类不同于T、B淋巴细胞的多功能淋巴细胞，在抗病毒免疫中发挥着重要作用。目前关于自然杀伤细胞参与抗病毒反应的研究主要集中于以下3点：①自然杀伤细胞介导抗病毒反应的路径；②自然杀伤细胞受体的功能；③自然杀伤细胞及自然杀伤T细胞在抗病毒反应中的激活和作用机理。尽管其中仍然存在许多悬而未决的问题，但大量的研究从分子水平揭示了自然杀伤细胞在病毒感染过程中的功能和反应。     

Compartmentalization of human natural killer cells

Human natural killer (NK) cells are bone marrow-derived cells that are found in the bloodstream, but can extravasate into various tissue sites upon inflammation. NK cells that migrate toward inflamed sites must be activated prior to their extravasation. However, the factors responsible for NK cell compartmentalization are not clearly defined. Resting human NK cells (CD16(-) and CD16(+)) express constitutive chemokine receptors, as well as receptors that have both constitutive and inflammatory functions. Upon activation, NK cells up-regulate the expression of the inflammatory chemokine receptors which facilitate their distribution into inflammatory sites. However, chemokines are not expected to play any role in maintaining resting NK cells in the blood circulation. In contrast, members of the lysolipids which are abundant in the bloodstream may be the major factors responsible for maintaining resting NK cells in the bloodstream, and also for facilitating their extravasation into inflamed tissues. Both resting and activated NK cells express receptors for various lysolipids. Hence, chemoattractants which include chemokines and lysolipids have important roles in determining the compartmentalization of NK cells where resting NK cells are found in the blood circulation, and activated NK cells extravasate into inflamed sites.     

Viral evasion of natural killer cells

Viruses have evolved mechanisms to avoid the host immune system, including means of escaping detection by both the innate and adaptive immune responses. Natural killer (NK) cells are a central component of the innate immune system and are crucial in defense against certain viruses. To attain a state of chronic infection, some successful viruses have developed specific mechanisms to evade detection by and activation of NK cells. These NK cell-specific evasion mechanisms fall into distinct mechanistic categories used in numerous virus families.     

An angiocentric orbital lesion with an immature natural killer cell immunophenotype

In this report, a unique case of a large unilateral orbital tumor occurring in a 5-year-old white girl is described. The lesion, which was associated with no systemic clinical symptoms, waxed and waned in size over 12 months and eventually spontaneously resolved. Multiple biopsies were performed, which showed an angiocentric and angioinvasive infiltrate composed of a monotonous population of atypical, immature-appearing, large lymphocytes. Extensive molecular and immunophenotypic studies led to the diagnosis of an Epstein-Barr virus-negative angiocentric lymphoproliferative disorder with an immature natural killer (NK) cell immunophenotype (CD16+CD56-), specifically an immunophenotype expressed by normal cord blood NK cells. HUM PATHOL 32:339-342.     

Memory responses of natural killer cells

Natural killer (NK) cells have traditionally been classified as a cellular component of the innate immune system, given their ability to rapidly produce effector cytokines and kill infected or transformed cells without prior exposure. More recently, NK cells have been shown to possess features of adaptive immunity such as clonal expansion, longevity, and robust recall responses. NK cell memory can be broadly divided into two categories: antigen-specific and antigen-independent. In the first case, exposure to certain viral or hapten stimuli endows NK cells with antigen-specific immunological memory, similar to T and B cells. In the second case, exposure of NK cells to specific cytokine milieus can imprint long-lasting changes on effector functions, resulting in antigen-independent memory-like NK cells. In this review, we discuss the various conditions that promote generation of these two categories of memory NK cells, and the mechanistic requirements underlying these processes.     

Recognition of infected cells by natural killer cells

Under the influence of cytokines associated with innate immunity, natural killer (NK) cells rapidly become activated and migrate to sites of infection. Upon contact with infected parenchyma they proliferate, release cytokines and/or kill cells harboring pathogens. Multiple stimulatory and inhibitory receptors can provide the integrated signals that trigger this contact-mediated NK-cell function. Recent work has begun to define the ligands for these receptors in the context of infection by certain well-studied viruses. These results, in addition to future work involving other pathogens, will provide an understanding of the molecules present on parasitized cells that mark them as targets of innate immunity.     

Adipose invariant natural killer T cells

Adipose tissue is a dynamic organ that makes up a substantial proportion of the body; in severe obesity it can account for 50% of body mass. Details of the unique immune system resident in human and murine adipose tissue are only recently emerging, and so it has remained a largely unexplored and unappreciated immune site until now. Adipose tissue harbours a unique collection of immune cells, which often display unusual functions compared with their counterparts elsewhere in the body. These resident immune cells are key to maintaining tissue and immune homeostasis, yet in obesity their chronic aberrant stimulation can contribute to the inflammation and pathogenesis associated with obesity. Anti‐inflammatory adipose‐resident lymphocytes are often depleted in obesity, whereas pro‐inflammatory immune cells accumulate, leading to an overall inflammatory state, which is a key step in the development of obesity‐induced metabolic disease. A good example is invariant natural killer T (iNKT) cells, which make up a large proportion of lymphocytes in human and murine adipose tissue. Here, they are unusually poised to produce anti‐inflammatory or regulatory cytokines, however in obesity, iNKT cells are greatly reduced. As iNKT cells are potent transactivaors of other immune cells, and can act as a bridge between innate and adaptive immunity, their loss in obesity represents the loss of a major regulatory population. Restoring iNKT cells, or activating them in obese mice leads to improved glucose handling, insulin sensitivity, and even weight loss, and hence represents an exciting therapeutic avenue to be explored for restoring homeostasis in obese adipose tissue.     

Viral- and tumor-reactive natural killer cells

When we can understand what natural killer (NK) cells recognize during an encounter with an infectious pathogen or a tumor cell, and when we can understand how the NK cell responds to that encounter, we can then begin to understand the role of NK cells in human health and how to improve upon their role for the prevention and treatment of human disease. In the quest to understand how these cells function in antiviral and antitumoral immunity, there have been previously described mechanisms established for NK cells to participate in clearing viral infections and tumors, including classical NK cell antibody dependent cellular cytotoxicity (ADCC) as well as recognition and elimination of transformed malignant cells through direct ligand interactions. However, it is now clear that there are additional mechanisms by which NK cells can participate in these critical immune tasks. Here we review two recently described types of NK cell recognition and response: the first is to primary infection with herpes virus, recognized and responded to by non-specific Fc bridged cellular cytotoxicity (FcBCC), and the second describes a novel phenotypic and functional response when a subset of NK cells recognize myeloid leukemia.