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.     

Natural and acquired resistance to Leishmania: cellular activation by Leishmania aethiopica of mononuclear cells from unexposed individuals is through the stimulation of natural killer (NK) cells.

Cells from normal non-Leishmania-exposed individuals could respond in vitro by proliferation and interferon-gamma (IFN-gamma) production to Leishmania aethiopica stimulation. The main cell type that appeared to be activated following such stimulation was CD3-, CD16+/56+, i.e. NK cells. Of the few CD3+ cells responding, an involvement of CD8+ cells was evident in the absence of activation of CD4+ cells in normal individuals, while a different feature was observed when patients' cells were investigated. Cells from patients with L. aethiopica infection did not show this NK response, but rather the CD4+ cells were the prominent responding cells. No evidence of the involvement of superantigens or cells utilizing the gamma delta T cell receptor (gamma delta cells) in the response of unexposed individuals was noted.     

The role of natural killer cells in autoimmune blistering diseases

The major focus of this paper is to describe and evaluate current information on the role of natural killer cells (NK cells) in the pathogenesis of blistering diseases. Until now, only pemphigus vulgaris (PV) has been studied. One co-culture study demonstrated that CD4⁺ T cells from the peripheral blood or perilesional skin of patients with active disease proliferate and secrete cytokines in the presence of major histocompatibility class II-expressing NK cells loaded with antigenic desmoglein self-peptides. Another study showed that NK cells can contribute to a T helper type 2-biased immune response through impaired interleukins (IL)-12 signaling and upregulation of IL, IL-10 and IL-5. Although significant data on other blistering diseases are unavailable at present, some studies implicate NK cells in disease progression. For instance, information on the role of NK cells in psoriasis and their production of tumor necrosis factor-α (TNF-α) will be provided since several TNF-α-inhibitors are used in its treatment. Studies on alopecia areata are also included in this paper because NK cells seem to play a key role in its pathogenesis. This review highlights the potential importance of NK cells and NKT cells as members of the large repertoire of cells and soluble mediators that play a critical role in pathogenesis of blistering diseases and other autoimmune diseases involving the skin. Therefore, the authors advocate a greater focus and interest on the study of the interaction of NK cells and the skin.     

The functional role of natural killer cells early in clinical sepsis

Although much information is available for the function of circulating monocytes when signs of sepsis are apparent, little is known for natural killer (NK) cells. NK cells were isolated from 10 healthy controls and from 103 patients with sepsis within the first 24 h from diagnosis. NK cells were stimulated with lipopolysaccharide for cytokine production. Release of tumor necrosis factor‐alpha and of interleukin (IL)‐6 was below the limit of detection. Release of IL‐23 and of interferon‐gamma (IFNγ) was significantly greater among patients than among healthy volunteers. Release of IFNγ was pronounced in septic shock. Patients were divided into two subgroups based on the ratio of IFNγ to IL‐23 released by the NK cells after stimulation: those with ratio ≤5 and 28‐day survival 13.5%, and those with ratio >5 and 28‐day survival 29.4% (p: 0.048). It is concluded that early after clinical development of sepsis, NK cells remain active for the production of IFNγ. Their activity is associated with the final outcome.     

Functional activity of natural killer cells and killer T cells in mice after ovarian transplantation

Tashkent Postgraduate Medical Institute, Ministry of Health of the USSR. (Presented by Academician of the Academy of Medical Sciences of the USSR N. A. Lopatkin). Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 112, No. 9, pp. 273–275, September, 1991.     

Frequency and phenotype of natural killer cells and natural killer cell subsets in bovine lymphoid compartments and blood

Natural killer (NK) cells are widely distributed in lymphoid and non‐lymphoid tissues, but little is known about the recirculation of NK cells between blood and tissues. This is relevant to understanding recirculation in the steady‐state and also for determining the roles for NK cells in vaccine‐induced immunity and responses to infection. Therefore, the percentage of NK cells and their phenotype across peripheral blood, afferent lymph and lymph nodes in steady‐state conditions was investigated in cattle using the pseudo‐afferent lymphatic cannulation model. CD2⁺ CD25^lo NK cells were the predominant subset of NK cells within the blood. In contrast, CD2⁻ CD25^hi NK cells were the main subset present within the skin‐draining afferent lymphatic vessels and lymph nodes, indicating that CD2⁻ NK cells are the principal NK cell subset trafficking to lymph nodes via the afferent lymphatic vessel. Furthermore, a low percentage of NK cells were present in efferent lymph, which were predominantly of the CD2⁻ subset, indicating that NK cells can egress from lymph nodes and return to circulation in steady‐state conditions. These compartmentalization data indicate that NK cells represent a population of recirculating lymphocytes in steady‐state conditions and therefore may be important during immune responses to vaccination or infection.     

Differentiation and adaptation of natural killer cells for anti-malarial immunity

Natural killer cells employ a diverse arsenal of effector mechanisms to target intracellular pathogens. Differentiation of natural killer (NK) cell activation pathways occurs along a continuum from reliance on innate pro-inflammatory cytokines and stress-induced host ligands through to interaction with signals derived from acquired immune responses. Importantly, the degree of functional differentiation of the NK cell lineage influences the magnitude and specificity of interactions with host cells infected with viruses, bacteria, fungi, and parasites. Individual humans possess a vast diversity of distinct NK cell clones, each with the capacity to vary along this functional differentiation pathway, which - when combined - results in unique individual responses to different infections. Here we summarize these NK cell differentiation events, review evidence for direct interaction of malaria-infected host cells with NK cells and assess how innate inflammatory signals induced by malaria parasite-associated molecular patterns influence the indirect activation and function of NK cells. Finally, we discuss evidence that anti-malarial immunity develops in parallel with advancing NK differentiation, coincident with a loss of reliance on inflammatory signals, and a refined capacity of NK cells to target malaria parasites more precisely, particularly through antibody-dependent mechanisms.     

Activity of human natural killer cells against target cells differing in sensitivity to interferon

Department of Interferons, N. F. Gameleya Research Institute of Epidemiology and Microbiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 110. No. 10, pp. 406–409, October, 1990.     

Combination chemo-immunotherapy: kinetics of in vivo and in vitro generation of natural killer cells and lymphokine-activated killer cells in the rat.

Rats received a single high dose of cyclophosphamide (Cy) (150 mg/kg), followed 48 h later (on day 0) by immunization with a T cell-dependent soluble antigen, ovalbumin in Freund's complete adjuvant (FCA). The effect of this treatment on lymphoid cell subpopulations in the spleen, natural killer (NK) cell and interleukin-2 (IL-2) induced lymphokine-activated killer (LAK) cell activity was examined. Cy (with and without ovalbumin) caused a large relative increase (by day 14) in splenic OX8+, OX19- cells with NK morphology. A marked relative increase in fresh NK cell activity was noted after Cy + ovalbumin, but not consistently after Cy alone. Elevated NK activity was Cy dose- and time-dependent, was evident within 7 days post Cy/ovalbumin and persisted for at least 28 days. Pooled splenic mononuclear cells (MNC), obtained 14 days after Cy/ovalbumin, lost all cytolytic activity against YAC-1 cells when cultured in the absence of human recombinant IL-2 (rIL-2). In contrast, similarly maintained cells from normal rats displayed NK activity higher than normal 'fresh' levels. Upon culture in medium containing 500 U/ml rIL-2, however, 'augmented' NK activity was equivalent, on a per-cell basis, in both normal and Cy/ovalbumin-pretreated groups. LAK activity generated in vitro (i.e. against NK-resistant target cells) was significantly lower in the latter group, and the overall yield of cells was reduced. By day 21 after Cy/ovalbumin, augmented NK activity was significantly greater than controls, on a per-cell and total culture yield basis. Moreover, LAK activity was now similar between groups. It is concluded that the chemotherapy/immunization protocol which we have used can greatly enhance NK activity in vivo and that these cells are responsive to induction of LAK activity by IL-2 in vitro.     

Dipeptidylpeptidase-4 as a surface marker of human natural killer cells

Institute of Experimental Cardiology, All-Union Cardiologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR V. N. Smirnov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 110, No. 10, pp. 411–413, October, 1990.     

CD11b and CD27 reflect distinct population and functional specialization in human natural killer cells

The identification of developmental stages in natural killer (NK) cells, especially in human NK cells, has lagged for decades. We characterize four novel populations defined by CD11b and CD27, which can represent the distinct stages of human NK cells from different tissues. Nearly all NK cells from peripheral blood are CD11b(+) CD27(-) populations whereas NK cells from cord blood have CD11b(+) CD27(-) and CD11b(+) CD27(+) populations. Interestingly, we have found large CD11b(-) CD27(-) populations of NK cells from deciduas. We also demonstrate that each population could be characterized by unique functional and phenotypic attributes. CD11b(-) CD27(-) NK cells display an immature phenotype and potential for differentiation. CD11b(-) CD27(+) and CD11b(+) CD27(+) NK cells show the best ability to secrete cytokines. CD11b(+) CD27(-) NK cells exhibit high cytolytic function. We demonstrate that human NK cells at different developmental stages have special functions and describe a new model of human NK cell differentiation.     

Activation and self-tolerance of natural killer cells

Summary: Natural killer (NK) cells are regulated by numerous stimulatory and inhibitory receptors that recognize various classes of cell surface ligands, some of which are expressed by normal healthy cells. We review two key issues in NK cell biology. How do NK cells achieve tolerance to healthy self‐cells, despite great potential variability in inhibitory and stimulatory receptor engagement? How is the disease status of unhealthy cells translated into changes in ligand expression and consequent sensitivity to NK cell lysis? Concerning the second question, we review evidence that ligands for one key NK receptor, NKG2D, are induced by the DNA damage response, which is activated in cells exposed to genotoxic stress. Because cancer cells and some infected cells are subject to genotoxic stress, these findings suggest a new concept for how diseased cells are discriminated by the immune system. Second, we review studies that have overturned the prevalent notion that NK cells achieve self‐tolerance by expressing inhibitory receptors specific for self‐major histocompatibility complex class I molecules. A subset of NK cells lacks such receptors. These NK cells are hyporesponsive when stimulatory receptors are engaged, suggesting that alterations in signaling pathways that dampen stimulatory receptor signals contribute to self‐tolerance of NK cells.     

Alteration of T cells and natural killer cells during chickenpox in infancy

To determine the reasons for the low immune response and the mild morbidity of chickenpox in infancy, we investigated alteration of T cells and natural killer (NK) cells during chickenpox in children <1 year and 2 years old using flow cytometry. The CD4/CD8 ratio decreased only in the <1-year-old group from the acute to the convalescent phase (P<0.05). The CD3–CD16+CD56+ and CD57–CD16+ counts increased in the <1-year-old group, but those in the 2-year-old group did not increase from the acute to the convalescent phase. The CD3–CD16+CD56+ counts and the CD57-CD16+ counts and percentage were larger in the <1-year-old group than those in the 2-year-old group (P=0.001,P=0.002, andP<0.05) in the convalescent phase. These results seem to indicate that the low immune response in infancy after chickenpox are related to the small number of CD8 in contrast with CD4 and that increased subsets of NK cells during chickenpox may correlate to the mild morbidity of chickenpox in infancy.     

Control of Mycobacterium tuberculosis growth by activated natural killer cells

We characterized the underlying mechanisms by which glutathione (GSH)‐enhanced natural killer (NK) cells inhibit the growth of Mycobacterium tuberculosis (M. tb) inside human monocytes. We observed that in healthy individuals, treatment of NK cells with N‐acetyl cysteine (NAC), a GSH prodrug in conjunction with cytokines such as interleukin (IL)‐2 + IL‐12, resulted in enhanced expression of NK cytotoxic ligands (FasL and CD40L) with concomitant stasis in the intracellular growth of M. tb. Neutralization of FasL and CD40L in IL‐2 + IL‐12 + NAC‐treated NK cells resulted in abrogation in the growth inhibition of M. tb inside monocytes. Importantly, we observed that the levels of GSH are decreased significantly in NK cells derived from individuals with HIV infection compared to healthy subjects, and this decrease correlated with a several‐fold increase in the growth of M. tb inside monocytes. This study describes a novel innate defence mechanism adopted by NK cells to control M. tb infection.     

Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study.

Endometrial natural killer (NK) cells were compared in luteal-phase endometrial samples from women with recurrent miscarriage and from normal subjects. Cryostat sections were labelled using a monoclonal antibody to CD56 using an avidin-biotin complex method and a morphometric study performed. Increased mean numbers of CD56+ cells were documented in the endometrium of women with recurrent early miscarriage only. These findings suggest a possible role for NK cells in the pathogenesis of recurrent early pregnancy loss.     

Lung natural killer cells in mice: phenotype and response to respiratory infection

Natural killer (NK) cells have a specialized function in peripheral organs, which is determined by the organ-specific niches. We have attempted to explore whether lung NK cells display a particular phenotype according to their function in the unique pulmonary environment in health or during respiratory infection in mice. In healthy mice, higher frequencies of NK cells among lymphocytes were detected in the lung than in other tissues (lymph node, bone marrow, spleen, blood and liver), and lung NK cells maintained a more mature phenotype, implying that lung NK cells were critical for the pulmonary immune response. However, lung NK cells expressed higher levels of inhibitory receptors and lower levels of activating receptors, migration/adhesion-associated molecules and co-stimulatory molecules than splenic NK cells, implying that lung NK cells were quiescent, and the activation of lung NK cells was tightly regulated by the pulmonary environment in health. During respiratory infection, lung NK cells could be activated and express functional molecules (CD107a and interferon-γ) to take part in the response to infection quickly. These results suggested that the unique pulmonary environment promotes the development of NK cells with a lung-specific phenotype.     

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.     

The biology of natural killer cells during sepsis

Natural killer (NK) cells are large granular lymphocytes largely recognized for their importance in tumour surveillance and the host response to viral infections. However, as the major innate lymphocyte population, NK cells also coordinate early responses to bacterial infections by amplifying the antimicrobial functions of myeloid cells, especially macrophages, by production of interferon‐γ (IFN‐γ). Alternatively, excessive NK cell activation and IFN‐γ production can amplify the systemic inflammatory response during sepsis resulting in increased physiological dysfunction and organ injury. Our understanding of NK cell biology during bacterial infections and sepsis is mostly derived from studies performed in mice. Human studies have demonstrated a correlation between altered NK cell functions and outcomes during sepsis. However, mechanistic understanding of NK cell function during human sepsis is limited. In this review, we will review the current understanding of NK cell biology during sepsis and discuss the challenges associated with modulating NK cell function during sepsis for therapeutic benefit.