Leukocyte migration in the interstitial space of non-lymphoid organs

• Published in: Nature reviews. Immunology Vol. 14; no. 4; pp. 232 - 246
• Main Authors: Weninger, Wolfgang, Biro, Maté, Jain, Rohit
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2014; Nature Publishing Group
• Subjects: 631/250/1619/554; 631/250/2504/223/1699; 631/250/98; 631/250/98/571; 631/80/84; Actin; Animals; Biomedicine; Cell interactions; Cell migration; Cell Movement - immunology; Cell Movement - physiology; Cells; Cellular Microenvironment - immunology; Cellular Microenvironment - physiology; Chemotactic factors; Chemotaxis, Leukocyte - immunology; Chemotaxis, Leukocyte - physiology; Cytoskeleton; Decision making; Dermatology; Diapedesis; Endothelial cells; Environmental factors; Extracellular Fluid - cytology; Extravasation; Humans; Immune response; Immunology; Intracellular signalling; Leukocyte migration; Leukocytes; Leukocytes (neutrophilic); Leukocytes - immunology; Leukocytes - physiology; Lymphocytes; Lymphocytes T; Macrophages; Mast cells; Microenvironments; Microscopy; Models, Biological; Motility; Neutrophils; Neutrophils - immunology; Neutrophils - physiology; Organ Specificity; Pathogens; Pericytes; Phenotypes; Physiological aspects; Physiological research; review-article; Signal transduction; Small intestine; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - physiology; Tissues; Tumor Microenvironment - immunology; Tumor Microenvironment - physiology; Australia; New South Wales Australia
• ISSN: 1474-1733; 1474-1741; 1474-1741
• DOI: 10.1038/nri3641

Key Points Optimized interstitial migration of leukocytes is necessary for their timely arrival at sites of tissue injury and microbial assault. This process is regulated by a multitude of cell-intrinsic and environmental factors. Intravital imaging studies have shed new light on the dynamics and regulation of interstitial leukocyte migration in non-lymphoid organs. These studies are discussed in this Review, with a focus on neutrophils and T cells. The actin cytoskeleton regulates the formation of a polarized cellular shape, which defines the 'amoeboid' migration mode of leukocytes in the interstitial space. Transendothelial migration of leukocytes and their entry into the interstitial space is regulated by the perivascular extravasation unit (PVEU), which is composed of endothelial cells, pericytes, perivascular macrophages, mast cells and the basement membrane. The PVEU provides physical and biochemical guidance for leukocytes during and after diapedesis. Neutrophil migration towards a focus of tissue injury is regulated by a multistep process defined by scouting, amplification and stabilization phases. Scouting is the initial process whereby scarce neutrophils accumulate at the focus. In a feedforward loop, these cells then attract waves of additional neutrophils, which form a cluster around the focus in order to contain tissue injury and pathogens. Directional decision making by migrating neutrophils is mediated by temporally and spatially coordinated gradients of chemoattractants and chemorepellents within tissues, and by physical guidance structures provided, for example, by pericytes. Multiple competing signals are integrated by intracellular signalling molecules in crawling neutrophils. Migrating effector T cell populations scan tissues for the presence of antigen. Signals delivered by the T cell receptor regulate both migratory stops — which are necessary for target cell interactions — and also the highly active migratory phenotype of T cells. Investigation of T cell population dynamics suggests that Lévy walk behaviour underlies the search strategies of T cells, and optimizes target screening behaviour. Functional impairment of T cells, such as a tolerized or exhausted state, is paralleled by impaired migration. Co-stimulatory and co-inhibitory pathways have been implicated in regulating the migration of functionally impaired T cells. A variety of innate immune cell subsets display active screening behaviour in non-lymphoid organs, which underlies the rapid detection of tissue debris or pathogens. This Review follows neutrophils and T cells as they journey from the blood into tissues in search of sites of infection or injury. It highlights the mediators, which form temporally and spatially coordinated gradients within the tissues, and the mechanisms, including physical structures, that guide this directional migration. Leukocyte migration through interstitial tissues is essential for mounting a successful immune response. Interstitial motility is governed by a vast array of cell-intrinsic and cell-extrinsic factors that together ensure the proper positioning of immune cells in the context of specific microenvironments. Recent advances in imaging modalities, in particular intravital confocal and multi-photon microscopy, have helped to expand our understanding of the cellular and molecular mechanisms that underlie leukocyte navigation in the extravascular space. In this Review, we discuss the key factors that regulate leukocyte motility within three-dimensional environments, with a focus on neutrophils and T cells in non-lymphoid organs.