The dendritic cell (DC) coordinates innate and adaptive immunity to fight infections and cancer. Our observations reveal that DCs exposed to the microbial danger signal lipopolysaccharide (LPS) in the presence of interferon-γ (IFN-γ) acquire a continuously changing activation/maturation phenotype. The DCs’ initial mode of action is pro-inflammatory via up-regulation among others of the signaling molecule interleukin (IL) 12, which polarizes IFN-γ secreting type 1 helper T-cells (Th1). Within 24 hours the same DC switches from the pro- into an anti-inflammatory phenotype. This is mediated by autocrine IL-10 release and secretion of soluble IL-2 receptor alpha (sIL-2RA) molecules. T-cells, when contacted with DCs during their anti-inflammatory phase loose their proliferative capacity and develop regulatory T-cell (Treg) -like anti-inflammatory functions indicated by IL-10 secretion and elevated FoxP3 levels. Studying the kinetics of IL-12 and IL-10 expression from LPS/IFN-γ activated myeloid DCs on a single cell level confirmed these observations. When T-cells are separated from DCs within 24 hours, they are spared from the anti-inflammatory DC activity. We conclude that, in addition to differentiation of DCs into distinct subsets, the observed sequential functional phases of DC differentiation permit the fine-tuning of an immune response. A better understanding of time-kinetic DC features is required for optimally exploiting the therapeutic capacity of DCs in cancer immune therapy.

2021 was clearly not a year for geopolitical optimism. Almost every month, a new crisis dominated the news, contributing to a sense that this mounting tide of crises threatens to overwhelm us.Against this backdrop, it is not surprising that in Europe and beyond, concern about a growing loss of control is prevalent (Chapter 1). In fact, findings from the Munich Security Index 2022 not only reflect the high level of risk perceived by respondents in the G7 and BRICS countries; they also suggest the emergence of "collective helplessness" in the face of a plethora of crises that reinforce each other. Just like people can suffer from "learned helplessness" -a psychological term describing the feeling that nothing one does can effect positive change -societies, too, may come to believe that they are unable to get a grip on the challenges they are facing. Whether it is the seemingly endless pandemic, the increasingly tangible threat of climate change, the vexing vulnerabilities of an interconnected world, or increasing geopolitical tensions, all these challenges contribute to a feeling of a loss of control. Liberal democracies appear to feel particularly overwhelmed. This perception is highly dangerous because it can turn into a self-fulfilling prophecy. Societies that have concluded that they cannot solve humankind's most challenging problems might no longer even try to turn the tide. Will our stressed and overburdened societies end up accepting what they see as their fate, although they have the tools and resources to change it? Unfortunately, 2021 overall did not alleviate these concerns. With the chaotic withdrawal from Afghanistan, for instance, the past year has also reinvigorated a debate about what international interventions are able to realistically accomplish. In light of the limited achievements of the United States and its partners in Afghanistan (Chapter 2), hard questions arise about the West's ability to build capable, legitimate state structures and promote stability elsewhere in the world. As Afghanistan now finds itself on the brink of the world's worst humanitarian crisis, with civil liberties being severely restricted under Taliban rule, the investments of two decades of external intervention are at risk. While the West has ended an "endless war," people in Afghanistan are looking toward an uncertain future.Is the world at the edge of an abyss? Is humanity losing control over its own fate? What can be done to overcome a widespread feeling of helplessness in the face of crises that reinforce each other? Are liberal democracies -and the transatlantic partners in particular -able to unlearn helplessness and turn the tide of mounting crises?

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