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.
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.
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The authors thank members of the Immune Imaging Program at the Centenary Institute, Australia, for critical reading of the manuscript and helpful discussion. This work was supported by the National Health and Medical Research Council, Australia (grant numbers: 1010680, 1030145, 1030147, 1032670 and 1047041), and the Australian Research Council (grant numbers: DP110104429 and DP120103359). W.W. and M.B. were supported by fellowships from the Cancer Institute New South Wales, Australia. M.B. was supported by Cure Cancer Australia Foundation/Cancer Australia grant number1070498 and an ECR grant from the Sydney Medical School, Australia.
The authors declare no competing financial interests.
Dynamic extensions of the cytosol and cortex that cyclically protrude from the cell body. The term is now mostly restricted to extensions, such as filopodia, that are driven by protrusive rather than contractile forces.
- Molecular clutch
As actin filaments undergo retrograde flow, proteins that link actin to integrins transmit cytoskeleton-mediated forces to the extracellular matrix (ECM), thereby enabling forward traction of cells in adhesion-dependent migration. These linker proteins form part of a molecular clutch mechanism, as they allow for the engagement and disengagement of the actin cortex from the ECM, and thus govern the transience of the adhesiveness of cells to their substrate.
Distance (measured in μm) between cell location at the start and end of the observation.
- Pearl-chain nuclei
The transient 'pearls on a string' rearrangement of the segmented nuclei of neutrophils that are migrating through a confined space.
- Perivascular macrophages
A subset of macrophages that localizes in close proximity to post-capillary venules in peripheral organs, including the skin, muscles and central nervous system. These cells are involved in leukocyte recruitment to inflamed tissues.
A stable, thin, elongated and contractile posterior protrusion that gives rise to the characteristic 'hand mirror' shape of polarized migrating cells.
- Neutrophil extracellular traps
(NETs). Webs of chromatin fibres that trap and kill microorganisms. Chromatin from the nuclei of neutrophils is extruded to form these extracellular nets, which also contain proteases from the azurophil granules of neutrophils.
The process of directional cell migration towards soluble, freely-diffusing gradients of chemoattractants.
A phenomenon used to describe cells responding to soluble pro-migratory cues with non-directional migration. Soluble, short-lived chemoattractive or chemorepulsive gradients can be rapidly adjusted to enhance or suppress leukocyte migration, respectively. However, the extent to which soluble chemotactic gradients are established within tissues is currently unclear.
The process of directed cell migration along immobilized chemoattractant gradients, which may be adhesion- dependent or adhesion- independent. Many chemoattractants can be immobilized by binding to heparan sulphates presented on cell surfaces or extracellular matrix fibres. These gradients are generally long lived and are crucial for guiding leukocytes in the interstitial space.
Random cell motility along two-dimensional surfaces or within three-dimensional spaces guided by immobilized chemoattractants. In two-dimensional haptokinesis, migration relies on firm substrate adherence of the migrating leukocyte, which is mostly mediated by integrins. During three-dimensional haptokinesis, leukocyte motility in the extracellular matrix network is mostly independent of adhesion. The spatial confinement of the migrating leukocyte is sufficient to provide mechanical or weakly-adhesive anchorage to assist in migration.
The migration of leukocytes away from certain mediators.
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Weninger, W., Biro, M. & Jain, R. Leukocyte migration in the interstitial space of non-lymphoid organs. Nat Rev Immunol 14, 232–246 (2014). https://doi.org/10.1038/nri3641
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