Adequate immune response ensured by binary IL-2 and graded CD25 expression in a murine transfer model

The IL-2/IL-2Ralpha (CD25) axis is of central importance for the interplay of effector and regulatory T cells. Nevertheless, the question how different antigen loads are translated into appropriate IL-2 production to ensure adequate responses against pathogens remains largely unexplored. Here we find that at single cell level, IL-2 is binary (digital) and CD25 is graded expressed whereas at population level both parameters show graded expression correlating with the antigen amount. Combining in vivo data with a mathematical model we demonstrate that only this binary IL-2 expression ensures a wide linear antigen response range for Teff and Treg cells under real spatiotemporal conditions. Furthermore, at low antigen concentrations binary IL-2 expression safeguards by its spatial distribution selective STAT5 activation only of closely adjacent Treg cells regardless of their antigen specificity. These data show that the mode of IL-2 secretion is critical to tailor the adaptive immune response to the antigen amount

T cell immunoengineering with advanced biomaterials

Recent advances in biomaterials design offer the potential to actively control immune cell activation and behaviour. Many human diseases, such as infections, cancer, and autoimmune disorders, are partly mediated by inappropriate or insufficient activation of the immune system. T cells play a central role in the host immune response to these diseases, and so constitute a promising cell type for manipulation. In vivo, T cells are stimulated by antigen presenting cells (APC), therefore to design immunoengineering biomaterials that control T cell behaviour, artificial interfaces that mimic the natural APC-T cell interaction are required. This review draws together research in the design and fabrication of such biomaterial interfaces, and highlights efforts to elucidate key parameters in T cell activation, such as substrate mechanical properties and spatial organization of receptors, illustrating how they can be manipulated by bioengineering approaches to alter T cell function

Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF)

AbstractMultiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination.Impact statementNanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS

Holocene ocean circulation and climate variability in Davis Strait and the North Labrador Sea, West Greenland : interpreted from diatoms

Diatom analyses were carried out on two sediment cores, one from the North Labrador Sea and one from Davis Strait, West Greenland, in order to investigate Holocene climatic variability in relation to ocean circulation. While the Davis Strait record showed very low diatom abundance, the diatom record from the North Labrador Sea showed diatom abundance high enough for making an approximate quantitative analysis, revealing clear trends in environmental changes. The record from the North Labrador Sea locality is found to reflect West Greenland Current (WGC) variability, which can be linked to North Atlantic Circulation variability. The record further indicates a Holocene warming between 9800-9600 14C yr BP. From around 8800-8600 14C yr BP the influence of warm Atlantic water masses weakened, and hence a cooler climate occurred. There have been found some indications of the 8200 cal. years BP cold event . At around 4800-4600 14C yr BP the diatom record indicates Neoglaciation. From around 3800 14C yr BP to present diatom abundance was very low, pointing towards unfavourable growth conditions

Idiopathic Intracranial Hypertension (IIH) in the Aftermath of COVID-19

We describe three cases of fulminant IIH seen at our walk-in clinic in New York City, the epicenter of the pandemic in the United States, and highlight challenges that influenced their clinical course