NK cells eliminate virus-infected and tumor cells by releasing cytotoxic granules containing granzyme B (GrzB) or by engaging death receptors that initiate caspase cascades. The orchestrated interplay between both cell death pathways remains poorly defined. Here we simultaneously measure the activities of GrzB and caspase-8 in tumor cells upon contact with human NK cells. We observed that NK cells switch from inducing a fast GrzB-mediated cell death in their first killing events to a slow death receptor–mediated killing during subsequent tumor cell encounters. Target cell contact reduced intracellular GrzB and perforin and increased surface-CD95L in NK cells over time, showing how the switch in cytotoxicity pathways is controlled. Without perforin, NK cells were unable to perform GrzB-mediated serial killing and only killed once via death receptors. In contrast, the absence of CD95 on tumor targets did not impair GrzB-mediated serial killing. This demonstrates that GrzB and death receptor–mediated cytotoxicity are differentially regulated during NK cell serial killing.

Key Points: CD107a protects cytotoxic lymphocytes from damage during degranulation. Interference with CD107a expression can cause the death of cytotoxic lymphocytes during degranulation.

The immune system and the nervous system are highly complex organs composed of various different cells that must interact with each other for proper function of the system. This communication can be mediated by soluble factors. The factors released by the nervous system (neurotransmitters) differ from those released by the immune system (cytokines). Nevertheless, the nervous and immune systems can influence each other’s activity because immune cells express neurotransmitter receptors, and neurons express cytokine receptors. Moreover, immune cells can synthesize and release neurotransmitters themselves, thus using neurotransmitter-mediated pathways via autocrine and paracrine mechanisms. Natural killer (NK) cells are innate lymphocytes that are important for early and effective immune reactions against infections and cancer. Many studies have shown the strong influence of stress and the nervous system on NK cell activity. This phenomenon may be one reason why chronic stress leads to a higher incidence of infections and cancer. Here, we review the effects of neuroendocrine factors on the different activities of NK cells. Understanding the effects of neuroendocrine factors on NK cell activities during physiological and pathophysiological conditions may result in novel therapeutic strategies to enhance NK cell functions against tumors.

Introduction: After the acute treatment phase, breast cancer patients often experience low quality of life and impaired mental health, which could potentially be improved by offering cognitive behavioural therapy (CBT) and addressing exercise and dietary habits. However, CBT and other behavioural interventions are rarely available beyond the acute treatment phase. Internet-based interventions could bridge such treatment gaps, given their flexibility and scalability. In this randomized controlled trial (RCT), we investigated the effects of such an intervention (“Optimune”) over three months.Methods: This RCT included 363 female breast cancer survivors (age range = 30–70), recruited from the community, who had completed the active treatment phase. Inclusion criteria were: breast cancer diagnosis less than 5 years ago and acute treatment completion at least 1 month ago. Participants were randomly assigned to (1) an intervention group (n= 181), in which they received care as usual (CAU) plus 12-month access toOptimuneimmediately after randomization, or (2) a control group (n= 182), in which they received CAU andOptimuneafter a delay of 3 months. Primary endpoints were quality of life (QoL), physical activity, and dietary habits at three months. We hypothesized that intervention group participants would report better QoL, more physical activity, and improved dietary habits after 3 months.Results: Intention-to-treat (ITT) analyses revealed significant effects on QoL (d= 0.27, 95% CI: 0.07–0.48) and dietary habits (d= 0.36, 95% CI: 0.15–0.56), but the effect on physical exercise was not significant (d= 0.30; 95% CI: 0.10–0.51).Discussion: These findings suggest the effectiveness ofOptimune, a new CBT-based Internet intervention for breast cancer survivors, in facilitating improvements in quality of life and dietary habits. Efforts to disseminate this intervention more broadly may be warranted.Trial registration: ClinicalTrials.gov,NCT03643640. Registered August 23rd 2018,https://clinicaltrials.gov/ct2/show/NCT03643640.

Significance: Human adenoviruses encode Early region 3 (E3) proteins that manipulate the host immune response to establish an infection or to persist longer. To date, only a few E3 functions from a single adenovirus species (C) have been characterized, all of which act directly on infected cells. Here we describe a secreted E3 protein that is uniquely expressed by species D adenoviruses. This protein targets noninfected leukocytes using a cell surface phosphatase as a receptor. We provide evidence that this interaction suppresses leukocyte activation and effector functions, implying that species D adenoviruses can affect the host distant from the site of infection.

This study investigated the effects of a temporally confined naturalistic stressor (academic stress) on immune functions. Furthermore, moderating influences of a number of psychological variables were assessed. Five blood samples were obtained from 20 students during an observation period of 8 weeks, starting 4.5 weeks before an exam period up to 1 week following the last exam. The analysis of 45 immune parameters revealed several time-dependent changes attributable to examination stress. We observed a reduction in the absolute numbers of natural killer (NK) cells and monocytes in peripheral blood and a shift towards more immature and naïve cells within NK and T cell populations. In addition, IL-6 and TNF-α production by LPS-stimulated monocytes was increased. Psychological variables were grouped by means of factor analyses into two factors. One factor, which was interpreted as an indication of chronic stress, moderated the relationships between academic stress and percentages of mature CD57⁺ NK cells. This chronic stress factor was also associated with an increase in memory and a decrease in naïve CD8 T cells and increased serum levels of IL-17. The present study identifies important potential psychological mediators of stress-induced changes in specific immunological parameters.