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BackgroundVγ9Vδ2 T-cells are antitumor immune effector cells that can detect metabolic dysregulation in cancer cells through phosphoantigen-induced conformational changes in the butyrophilin (BTN) 2A1/3A1 complex. In order to clinically exploit the anticancer properties of Vγ9Vδ2 T-cells, various approaches have been studied including phosphoantigen stimulation, agonistic BTN3A-specific antibodies, adoptive transfer of expanded Vγ9Vδ2 T-cells, and more recently bispecific antibodies. While Vγ9Vδ2 T-cells constitute a sizeable population, typically making up ~1-10% of the total T cell population, lower numbers have been observed with increasing age and in the context of disease. MethodsWe evaluated whether bivalent single domain antibodies (VHHs) that link Vδ2-TCR specific VHHs with different affinities could support Vγ9Vδ2 T-cell expansion and could be incorporated in a bispecific engager format when additionally linked to a tumor antigen specific VHH. ResultsBivalent VHHs that link a high and low affinity Vδ2-TCR specific VHH can support Vγ9Vδ2 T-cell expansion. The majority of Vγ9Vδ2 T-cells that expanded following exposure to these bivalent VHHs had an effector or central memory phenotype and expressed relatively low levels of PD-1. Bispecific engagers that incorporated the bivalent Vδ2-TCR specific VHH as well as a tumor antigen specific VHH triggered antitumor effector functions and supported expansion of Vγ9Vδ2 T-cells in vitro and in an in vivo model in NOG-hIL-15 mice.ConclusionBy enhancing the number of Vγ9Vδ2 T-cells available to exert antitumor effector functions, these novel Vδ2-bivalent bispecific T cell engagers may promote the overall efficacy of bispecific Vγ9Vδ2 T-cell engagement, particularly in patients with relatively low levels of Vγ9Vδ2 T-cells.

While immunoglobulin A (IgA) is well known for its neutralizing and anti-inflammatory function, it is becoming increasingly clear that IgA can also induce human inflammatory responses by various different immune cells. Yet, little is known about the relative role of induction of inflammation by the two IgA subclasses i.e. IgA1, most prominent subclass in circulation, and IgA2, most prominent subclass in the lower intestine. Here, we set out to study the inflammatory function of IgA subclasses on different human myeloid immune cell subsets, including monocytes, and in vitro differentiated macrophages and intestinal CD103+ dendritic cells (DCs). While individual stimulation with IgA immune complexes only induced limited inflammatory responses by human immune cells, both IgA subclasses strongly amplified pro-inflammatory cytokine production upon co-stimulation with Toll-like receptor (TLR) ligands such as Pam3CSK4, PGN, and LPS. Strikingly, while IgA1 induced slightly higher or similar levels of pro-inflammatory cytokines by monocytes and macrophages, respectively, IgA2 induced substantially more inflammation than IgA1 by CD103+ DCs. In addition to pro-inflammatory cytokine proteins, IgA2 also induced higher mRNA expression levels, indicating that amplification of pro-inflammatory cytokine production is at least partially regulated at the level of gene transcription. Interestingly, cytokine amplification by IgA1 was almost completely dependent on Fc alpha receptor I (FcαRI), whilst blocking this receptor only partially reduced cytokine induction by IgA2. In addition, IgA2-induced amplification of pro-inflammatory cytokines was less dependent on signaling through the kinases Syk, PI3K, and TBK1/IKKϵ. Combined, these findings indicate that IgA2 immune complexes, which are most abundantly expressed in the lower intestine, particularly promote inflammation by human CD103+ intestinal DCs. This may serve an important physiological function upon infection, by enabling inflammatory responses by this otherwise tolerogenic DC subset. Since various inflammatory disorders are characterized by disturbances in IgA subclass balance, this may also play a role in the induction or exacerbation of chronic intestinal inflammation.

BackgroundPeriodontitis is a chronic multifactorial inflammatory disease of the supportive tissues of the teeth. In more recent years, remarkable epidemiological and pathophysiological associations between periodontitis and cardiovascular disease (CVD) have been presented. Whether or not treatment of periodontitis is valuable for primary or secondary prevention of cardiovascular disease, has not yet been fully established. In this practice-based pilot study we focused on primary prevention of cardiovascular disease, by investigating the effect of periodontal treatment on the earliest detectable stage of CVD; endothelial dysfunction.MethodsOtherwise healthy periodontitis and non-periodontitis participants 45–70 years of age were included in the study. One year after completing periodontal (non-surgical and surgical) treatment of the periodontitis patients and 1 year after inclusion of the controls, all baseline measurements were repeated. Full-mouth examinations were performed by a periodontist to determine their Periodontal Inflamed Surface Area (PISA) score and other dental parameters. To assess the cardiovascular conditions, endothelial function through the reactive hyperemia index (RHI) assessed by the EndoPAT™, and several physical and biochemical parameters were measured.Results21 patients with diagnosed, untreated periodontitis and 21 participants without periodontitis were included in this follow-up study. After periodontal therapy in the periodontitis patients, the PISA reduced significantly. The RHI did not show a significant improvement after treatment of the periodontitis patients (−0.1 ± 0.8, p = 0.524). Similarly, other secondary cardiovascular outcome measurements, hsCRP, total cholesterol, HDL cholesterol, triglycerides, HbA1c, and systolic blood pressure did not improve significantly after periodontal treatment. Controls did not show any significant changes in the RHI, in other CVD parameters and in the PISA after 1-year follow-up.ConclusionIn this practice-based pilot study, periodontal treatment did not improve the endothelial function in otherwise healthy adults with periodontitis. Future studies are needed to be of larger size and could focus on periodontitis patients with co-morbidities to investigate whether periodontal treatment has secondary preventive effect on endothelial function and other CVD parameters.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [ISRCTN55656827].

Interleukin (IL)-4 is a cytokine that affects both adaptive and innate immune responses. In the central nervous system, microglia express IL-4 receptors and it has been described that IL-4-exposed microglia acquire anti-inflammatory properties. We here demonstrate that IL-4 exposure induces changes in the cell surface protein expression profile of primary rhesus macaque microglia and enhances their potential to induce proliferation of T cells with a regulatory signature. Moreover, we show that Toll like receptor (TLR)-induced cytokine production is broadly impaired in IL-4-exposed microglia at the transcriptional level. IL-4 type 2 receptor-mediated signaling is shown to be crucial for the inhibition of microglial innate immune responses. TLR-induced nuclear translocalization of NF-κB appeared intact, and we found no evidence for epigenetic modulation of target genes. By contrast, nuclear extracts from IL-4-exposed microglia contained significantly less NF-κB capable of binding to its DNA consensus site. Further identification of the molecular mechanisms that underlie the inhibition of TLR-induced responses in IL-4-exposed microglia may aid the design of strategies that aim to modulate innate immune responses in the brain, for example in gliomas.

Using the Job Demands-Resources model literature and the life-span theory as scholarly frameworks, we examined the effects of job demands and job resources as mediators in the relationship between bundles of used HRM practices and employee outcomes. In addition, we tested for age differences in our research model. Findings confirmed the hypothesized original 2-factor structure representing maintenance and development HRM practices. Structural Equation Modeling analyses showed that the maintenance HRM bundle related directly and negatively to employee outcomes, without moderating effects of age. However, job resources appeared to mediate this relationship in a positive way as it also did for the development HRM bundle. Whereas this study showed the ‘driving power’ of the actual use of HRM bundles through job resources, regardless of the employee’s age, this study also suggests a ‘dark side’ of HRM. In particular, we found that development HRM bundles may also increase job demands, which, in turn, may result in lower levels of beneficial employee outcomes. These empirical outcomes demonstrate the strength of the driving power eliciting from job resources preceded by any HRM bundle. Moreover, this effect appears to apply to employees of all ages. Our moderated-mediation model appeared robust for several control variables. Overall, this study provides an extension of the well-known Job Demands-Resources model by including maintenance and development bundles of HRM practices used by employees that have a differential effect on job demands and job resources which in turn have an impact on employee outcomes.

This two-wave complete panel study aims to examine human resource management (HRM) bundles of practices in relation to social support [i.e., leader–member exchange (LMX), coworker exchange (CWX)] and employee outcomes (i.e., work engagement, employability, and health), within a context of workers aged 65+. Based upon the social exchange theory and the Job Demands-Resources (JD-R) framework, it was hypothesized that HRM bundles at Time 1 would increase bridge workers' outcomes at Time 2, and that this relationship would be mediated by perceptions of LMX and CWX at Time 2. Using a longitudinal design, hypotheses were tested in a unique sample of Dutch bridge employees (N = 228). Results of several structural equation modeling analyses revealed no significant associations between HRM bundles, and social support, moreover, no significant associations were found in relation to employee outcomes. However, the results of the best-fitting final model revealed the importance of the impact of social support on employee (65+) outcomes over time.