Interrelationships between Natural Killer cells and neutrophils in the pulmonary vasculature

The lung comprises a vast surface area where the blood and intravascular immune cells are in direct contact with the outside environment and the air that we breathe. Immune cells in the lungs defend against invading pathogens and help to maintain physiological conditions. Innate immune cells can respond quickly to inflammatory stimuli, however, excessive pulmonary inflammation must be limited to preserve the thin barrier between the air and blood, required for oxygen diffusion. Neutrophils are the most abundant leukocyte within the pulmonary vasculature, and they react rapidly to infectious or inflammatory agents. This response can lead to tissue damage and must therefore be finely regulated. The early control of neutrophil influx may be pivotal for patient outcome during acute lung inflammation. Natural Killer (NK) cells are innate, granular lymphocytes, best described for their capacity to directly kill virus-infected or malignant cells. NK cells are enriched in the lungs compared to other tissues and they could play a role in fine tuning neutrophil responses. The aim of this thesis is to investigate the role of immune cell crosstalk between NK cells and neutrophils within the pulmonary vasculature. To study innate immune cell behaviour in the lungs, I used intravital microscopy to directly examine cells in their natural environment. Direct visualization of unperturbed, intravascular immune cells revealed unexpected functions and behaviours that would not have been recapitulated in more reductionist approaches. This work addresses a variety of cellular functions in the complex setting of the pulmonary capillary network. The introduction of this thesis provides a broad overview of the current understanding of innate immune cell communication in the context of the lungs. A special a focus is put on the influence modern lifestyles, particularly pollution and obesity, can impose on the physiologic function of innate immune cells in human and animal health. My results show that neutrophils and NK cells form close interactions within the pulmonary capillaries. In-depth tracking analysis revealed that neutrophil dynamic behaviour was altered when they interacted with an NK cell and cell surface material could be transferred from neutrophils to NK cells after interactions. Importantly, I show that NK cells limit the neutrophil accumulation in the lungs during acute lung inflammation. Better understanding of the regulatory role of NK cells could open new avenues for the treatment of acute lung inflammation.Open Acces

Intravital microscopy in historic and contemporary immunology

In this review, we discuss intravital microscopy of immune cells, starting from its historic origins to current applications in diverse organs. It is clear from a quantitative review of the literature that intravital microscopy is a key tool in both historic and contemporary immunological research, providing unique advances in our understanding of immune responses. We have chosen to focus this review on how intravital microscopy methodologies are used to image specific organs or systems and we present recent descriptions of fundamental immunological processes that could not have been achieved by other methods. The following target organs/systems are discussed in more detail: cremaster muscle, skin (ear and dorsal skin fold chamber), lymph node, liver, lung, mesenteric vessels, carotid artery, bone marrow, brain, spleen, foetus and lastly vessels of the knee joint

Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels

Some p53 mutants promote invasive migration of cancer cells and metastasis of tumours in vivo. However the key mechanistic details behind these phenomena remain unclear. Here the authors propose a non-cell autonomous mechanism involving fibroblasts, whereby mutant p53-expressing cancer cells activate an exosome-mediated mechanism that influences integrin recycling in fibroblasts, thus influencing extracellular matrix remodelling to favour cancer cell invasion and migration