The two‐pore domain K2P channel TASK2 drives human NK‐cell proliferation and cytolytic function

Natural killer (NK) cells are a subset of cytotoxic lymphocytes that recognize and kill tumor‐ and virus‐infected cells without prior stimulation. Killing of target cells is a multistep process including adhesion to target cells, formation of an immunological synapse, and polarization and release of cytolytic granules. The role of distinct potassium channels in this orchestrated process is still poorly understood. The current study reveals that in addition to the voltage‐gated K_V1.3 and the calcium‐activated K_Ca3.1 channels, human NK cells also express the two‐pore domain K₂P channel TASK2 (TWIK‐related acid‐sensitive potassium channel). Expression of Task2 varies among NK‐cell subsets and depends on their differentiation and activation state. Despite its different expression in TASK2^highCD56^brightCD16^? and TASK2^lowCD56^dimCD16⁺ NK cells, TASK2 is involved in cytokine‐induced proliferation and cytolytic function of both subsets. TASK2 is crucial for leukocyte functional antigen (LFA‐1) mediated adhesion of both resting and cytokine‐activated NK cells to target cells, an early step in killing of target cells. With regard to the following mechanism, TASK2 plays a role in release of cytotoxic granules by resting, but not IL‐15‐induced NK cells. Taken together, our data exhibit two‐pore potassium channels as important players in NK‐cell activation and effector function.     

IL‐15 dependent induction of IL‐18 secretion as a feedback mechanism controlling human MAIT‐cell effector functions

Mucosal‐associated invariant T (MAIT) cells are characterized by an invariant TCRVα7.2 chain recognizing microbial vitamin B metabolites presented by the MHC‐Ib molecule MR1. They are mainly detectable in the CD8⁺ and CD8^?CD4^? “double negative” T‐cell compartments of mammals and exhibit both Th1‐ and Th17‐associated features. As MAIT cells show a tissue‐homing phenotype and operate at mucosal surfaces with myriads of pathogenic encounters, we wondered how IL‐15, a multifaceted cytokine being part of the intestinal mucosal barrier, impacts on their functions. We demonstrate that in the absence of TCR cross‐linking, human MAIT cells secrete IFN‐γ, increase perforin expression and switch on granzyme B production in response to IL‐15. As this mechanism was dependent on the presence of CD14⁺ cells and sensitive to IL‐18 blockade, we identified IL‐15 induced IL‐18 production by monocytes as an inflammatory, STAT5‐dependent feedback mechanism predominantly activating the MAIT‐cell population. IL‐15 equally affects TCR‐mediated MAIT‐cell functions since it dramatically amplifies bacteria‐induced IFN‐γ secretion, granzyme production, and cytolytic activity at early time points, an effect being most pronounced under suboptimal TCR stimulation conditions. Our data reveal a new quality of IL‐15 as player in an inflammatory cytokine network impacting on multiple MAIT‐cell functions.     

Cross‐sectional survey of the disaster preparedness of nurses across the Asia–Pacific region

Healthcare workers who have received disaster preparedness education are more likely to report a greater understanding of disaster preparedness. However, research indicates that current nursing curricula do not adequately prepare nurses to respond to disasters. This is the first study to assess Asia–Pacific nurses' perceptions about their level of disaster knowledge, skills, and preparedness. A cross‐sectional survey was conducted with 757 hospital and community nurses in seven Asia–Pacific countries. Data were collected using the modified Disaster Preparedness Evaluation Tool. Participants were found to have overall low‐to‐moderate levels of disaster knowledge, skills and preparedness, wherein important gaps were identified. A majority of the variance in disaster preparedness scores was located at the level of the individual respondent, not linked to countries or institutions. Multilevel random effects modelling identified disaster experience and education as significant factors of positive perceptions of disaster knowledge, skills, and management. The first step toward disaster preparedness is to ensure frontline health workers are able to respond effectively to disaster events. The outcomes of this study have important policy and education implications.     

Antagonistic control of oxidative stress-induced cell death in Arabidopsis by two related,plant-specific zinc finger proteins

The most familiar form of plant programmed cell death is the hypersensitive response (HR) associated with successful plant immune responses. HR is preceded by an oxidative burst and the generation of both reactive oxygen intermediates (ROI) and NO. The Arabidopsis LSD1 gene encodes a negative regulator of plant programmed cell death that meets several criteria for a regulator of processes relevant to ROI management during pathogen responses. Here we demonstrate that a highly conserved LSD1 paralogue, LOL1, acts as a positive regulator of cell death. Manipulation of LOL1 expression alters both the superoxide-dependent, runaway cell death phenotype of lsd1 plants and the normal HR. We also show that LSD1 and LOL1 have antagonistic effects on copper-zinc superoxide dismutase accumulation, consistent with functions in cell death control via maintenance of ROI homeostasis.     

Effect of weight loss,with or without exercise,on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial

Introduction

Physical inactivity and overweight are risk factors for postmenopausal breast cancer. The effect of physical activity may be partially mediated by concordant weight loss. We studied the effect on serum sex hormones, which are known to be associated with postmenopausal breast cancer risk, that is attributable to exercise by comparing randomly obtained equivalent weight loss by following a hypocaloric diet only or mainly by exercise.

Methods

Overweight, insufficiently active women were randomised to a diet (N = 97), mainly exercise (N = 98) or control group (N = 48). The goal of both interventions was to achieve 5–6 kg of weight loss by following a calorie-restricted diet or an intensive exercise programme combined with only a small caloric restriction. Primary outcomes after 16 weeks were serum sex hormones and sex hormone-binding globulin (SHBG). Body fat and lean mass were measured by dual-energy X-ray absorptiometry.

Results

Both the diet (−4.9 kg) and mainly exercise (−5.5 kg) groups achieved the target weight loss. Loss of body fat was significantly greater with exercise versus diet (difference −1.4 kg, P < 0.001). In the mainly exercise arm, the reduction in free testosterone was statistically significantly greater than that of the diet arm (treatment effect ratio [TER] 0.92, P = 0.043), and the results were suggestive of a difference for androstenedione (TER 0.90, P = 0.064) and SHBG (TER 1.05, P = 0.070). Compared with the control arm, beneficial effects were seen with both interventions, diet and mainly exercise, respectively, on oestradiol (TER 0.86, P = 0.025; TER 0.83, P = 0.007), free oestradiol (TER 0.80, P = 0.002; TER 0.77, P < 0.001), SHBG (TER 1.14; TER 1.21, both P < 0.001) and free testosterone (TER 0.91, P = 0.069; TER = 0.84, P = 0.001). After adjustment for changes in body fat, intervention effects attenuated or disappeared.

Conclusions

Weight loss with both interventions resulted in favourable effects on serum sex hormones, which have been shown to be associated with a decrease in postmenopausal breast cancer risk. Weight loss induced mainly by exercise additionally resulted in maintenance of lean mass, greater fitness, greater fat loss and a larger effect on (some) sex hormones. The greater fat loss likely explains the observed larger effects on sex hormones.

Trial registration

ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01511276","term_id":"NCT01511276"}}NCT01511276. Registered on 12 January 2012.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-015-0633-9) contains supplementary material, which is available to authorized users.