Leukocyte migration in the interstitial space of non-lymphoid organs

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.

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Polarization of cytoskeletal dynamics governs leukocyte shape and migration.
Figure 2: The perivascular extravasation unit assists in neutrophil emigration.
Figure 3: Three-step cascade guides neutrophils to the site of sterile injury in the skin.
Figure 4: Context-dependent mechanisms of neutrophil attraction to injury sites.
Figure 5: CD8+ effector T cell behaviour in the tumour microenvironment.

References

  1. 1

    Nourshargh, S., Hordijk, P. L. & Sixt, M. Breaching multiple barriers: leukocyte motility through venular walls and the interstitium. Nature Rev. Mol. Cell Biol. 11, 366–378 (2010).

    CAS  Article  Google Scholar 

  2. 2

    Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Rev. Immunol. 7, 678–689 (2007).

    CAS  Article  Google Scholar 

  3. 3

    Jain, R. & Weninger, W. Shedding light on cutaneous innate immune responses: the intravital microscopy approach. Immunol. Cell Biol. 91, 263–270 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4

    Mueller, S. N. Effector T-cell responses in non-lymphoid tissues: insights from in vivo imaging. Immunol. Cell Biol. 91, 290–296 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5

    Coombes, J. L. & Robey, E. A. Dynamic imaging of host-pathogen interactions in vivo. Nature Rev. Immunol. 10, 353–364 (2010).

    CAS  Article  Google Scholar 

  6. 6

    Cahalan, M. D. & Parker, I. Choreography of cell motility and interaction dynamics imaged by two-photon microscopy in lymphoid organs. Annu. Rev. Immunol. 26, 585–626 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7

    Germain, R. N., Robey, E. A. & Cahalan, M. D. A decade of imaging cellular motility and interaction dynamics in the immune system. Science 336, 1676–1681 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Bousso, P. T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nature Rev. Immunol. 8, 675–684 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Vicente-Manzanares, M. & Sanchez-Madrid, F. Role of the cytoskeleton during leukocyte responses. Nature Rev. Immunol. 4, 110–122 (2004).

    CAS  Article  Google Scholar 

  10. 10

    Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Lämmermann, T. & Sixt, M. Mechanical modes of 'amoeboid' cell migration. Curr. Opin. Cell Biol. 21, 636–644 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12

    Charras, G. & Paluch, E. Blebs lead the way: how to migrate without lamellipodia. Nature Rev. Mol. Cell Biol. 9, 730–736 (2008).

    CAS  Article  Google Scholar 

  13. 13

    Bergert, M., Chandradoss, S. D., Desai, R. A. & Paluch, E. Cell mechanics control rapid transitions between blebs and lamellipodia during migration. Proc. Natl Acad. Sci. USA 109, 14434–14439 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14

    Plotnikov, S. V. & Waterman, C. M. Guiding cell migration by tugging. Curr. Opin. Cell Biol. 25, 619–626 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15

    Gardel, M. L., Schneider, I. C., Aratyn-Schaus, Y. & Waterman, C. M. Mechanical integration of actin and adhesion dynamics in cell migration. Annu. Rev. Cell Dev. Biol. 26, 315–333 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16

    Renkawitz, J. et al. Adaptive force transmission in amoeboid cell migration. Nature Cell Biol. 11, 1438–1443 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17

    Lämmermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453, 51–55 (2008). This paper demonstrates that leukocytes can migrate within the interstitial space in the absence of integrins.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18

    Jorrisch, M. H., Shih, W. & Yamada, S. Myosin IIA deficient cells migrate efficiently despite reduced traction forces at cell periphery. Biol. Open 2, 368–372 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19

    Malawista, S. E., de Boisfleury Chevance, A. & Boxer, L. A. Random locomotion and chemotaxis of human blood polymorphonuclear leukocytes from a patient with leukocyte adhesion deficiency-1: normal displacement in close quarters via chimneying. Cell. Motil. Cytoskel. 46, 183–189 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Overstreet, M. G. et al. Inflammation-induced interstitial migration of effector CD4+ T cells is dependent on integrin αV. Nature Immunol. 14, 949–958 (2013). This paper suggests that CD4+ effector T cells use integrins to migrate within inflamed skin.

    CAS  Article  Google Scholar 

  21. 21

    Wolf, K. et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J. Cell Biol. 201, 1069–1084 (2013).

    CAS  Article  Google Scholar 

  22. 22

    Nathan, C. Neutrophils and immunity: challenges and opportunities. Nature Rev. Immunol. 6, 173–182 (2006).

    CAS  Article  Google Scholar 

  23. 23

    Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nature Rev. Immunol. 13, 159–175 (2013).

    CAS  Article  Google Scholar 

  24. 24

    Muller, W. A. Mechanisms of leukocyte transendothelial migration. Ann. Rev. Pathol. 6, 323–344 (2011).

    CAS  Article  Google Scholar 

  25. 25

    Abbott, N. J., Ronnback, L. & Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nature Rev. Neurosci. 7, 41–53 (2006).

    CAS  Article  Google Scholar 

  26. 26

    Obermeier, B., Daneman, R. & Ransohoff, R. M. Development, maintenance and disruption of the blood-brain barrier. Nature Med. 19, 1584–1596 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27

    Sorokin, L. The impact of the extracellular matrix on inflammation. Nature Rev. Immunol. 10, 712–723 (2010).

    CAS  Article  Google Scholar 

  28. 28

    Rowe, R. G. & Weiss, S. J. Breaching the basement membrane: who, when and how? Trends Cell Biol. 18, 560–574 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Winkler, E. A., Bell, R. D. & Zlokovic, B. V. Central nervous system pericytes in health and disease. Nature Neurosci. 14, 1398–1405 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30

    Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    CAS  Article  Google Scholar 

  31. 31

    Wang, S. et al. Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. J. Exp. Med. 203, 1519–1532 (2006). This paper defines the preferential exit points of neutrophils through the basement membrane of venules in vivo.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Voisin, M. B., Probstl, D. & Nourshargh, S. Venular basement membranes ubiquitously express matrix protein low-expression regions: characterization in multiple tissues and remodeling during inflammation. Am. J. Pathol. 176, 482–495 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Proebstl, D. et al. Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J. Exp. Med. 209, 1219–1234 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Hyun, Y. M. et al. Uropod elongation is a common final step in leukocyte extravasation through inflamed vessels. J. Exp. Med. 209, 1349–1362 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Sontheimer, R. D. Perivascular dendritic macrophages as immunobiological constituents of the human dermal microvascular unit. J. Invest. Dermatol. 93, 96S–101S (1989).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36

    Bruns, R. R. & Palade, G. E. Studies on blood capillaries. I. General organization of blood capillaries in muscle. J. Cell Biol. 37, 244–276 (1968).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Nayak, D., Zinselmeyer, B. H., Corps, K. N. & McGavern, D. B. In vivo dynamics of innate immune sentinels in the CNS. Intravital 1, 95–106 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Mrass, P. & Weninger, W. Immune cell migration as a means to control immune privilege: lessons from the CNS and tumors. Immunol. Rev. 213, 195–212 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  39. 39

    Abtin, A. et al. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nature Immunol. 15, 45–53 (2014). This paper defines a new role of perivascular macrophages in neutrophil extravasation during skin inflammation.

    CAS  Article  Google Scholar 

  40. 40

    Middleton, J. et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 385–395 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41

    Woodfin, A. et al. The junctional adhesion molecule JAM-C regulates polarized transendothelial migration of neutrophils in vivo. Nature Immunol. 12, 761–769 (2011).

    CAS  Article  Google Scholar 

  42. 42

    Abraham, S. N. & St John, A. L. Mast cell-orchestrated immunity to pathogens. Nature Rev. Immunol. 10, 440–452 (2010).

    CAS  Article  Google Scholar 

  43. 43

    Nourshargh, S. & Marelli-Berg, F. M. Transmigration through venular walls: a key regulator of leukocyte phenotype and function. Trends Immunol. 26, 157–165 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44

    Dangerfield, J., Larbi, K. Y., Huang, M. T., Dewar, A. & Nourshargh, S. PECAM-1 (CD31) homophilic interaction up-regulates α6β1 on transmigrated neutrophils in vivo and plays a functional role in the ability of α6 integrins to mediate leukocyte migration through the perivascular basement membrane. J. Exp. Med. 196, 1201–1211 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Hartl, D. et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nature Med. 13, 1423–1430 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46

    Stillie, R., Farooq, S. M., Gordon, J. R. & Stadnyk, A. W. The functional significance behind expressing two IL-8 receptor types on PMN. J. Leuk. Biol. 86, 529–543 (2009).

    CAS  Article  Google Scholar 

  47. 47

    Friedl, P. & Weigelin, B. Interstitial leukocyte migration and immune function. Nature Immunol. 9, 960–969 (2008).

    CAS  Article  Google Scholar 

  48. 48

    Deng, Q. & Huttenlocher, A. Leukocyte migration from a fish eye's view. J. Cell Sci. 125, 3949–3956 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Mathias, J. R. et al. Resolution of inflammation by retrograde chemotaxis of neutrophils in transgenic zebrafish. J. Leukoc. Biol. 80, 1281–1288 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50

    Chtanova, T. et al. Dynamics of neutrophil migration in lymph nodes during infection. Immunity 29, 487–496 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Ng, L. G. et al. Visualizing the neutrophil response to sterile tissue injury in mouse dermis reveals a three-phase cascade of events. J. Invest. Dermatol. 131, 2058–2068 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52

    Peters, N. C. et al. In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies. Science 321, 970–974 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Lämmermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013). References 50–53 demonstrate that scouting neutrophils induce the recruitment of large numbers of additional neutrophils to sites of tissue damage.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. 54

    Stark, K. et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs. Nature Immunol. 14, 41–51 (2013). This paper identifies stromal cells as guidance structures for migrating leukocytes in the interstitium.

    CAS  Article  Google Scholar 

  55. 55

    Kreisel, D. et al. In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. Proc. Natl Acad. Sci. USA 107, 18073–18078 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56

    Liese, J., Rooijakkers, S. H., van Strijp, J. A., Novick, R. P. & Dustin, M. L. Intravital two-photon microscopy of host-pathogen interactions in a mouse model of Staphylococcus aureus skin abscess formation. Cell. Microbiol. 15, 891–909 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57

    McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362–366 (2010). This paper identifies a multistep attraction cascade for neutrophils towards sites of sterile tissue injury in the liver.

    CAS  Article  Google Scholar 

  58. 58

    Kim, J. V., Kang, S. S., Dustin, M. L. & McGavern, D. B. Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457, 191–195 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59

    Yipp, B. G. et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nature Med. 18, 1386–1393 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60

    Afonso, P. V. et al. LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev. Cell 22, 1079–1091 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Malavasi, F. et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol. Rev. 88, 841–886 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62

    Partida-Sanchez, S. et al. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nature Med. 7, 1209–1216 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63

    Niethammer, P., Grabher, C., Look, A. T. & Mitchison, T. J. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459, 996–999 (2009). This paper demonstrates the generation of a chemoattractant gradient for neutrophils during wound-healing responses.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

    Yoo, S. K., Starnes, T. W., Deng, Q. & Huttenlocher, A. Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. Nature 480, 109–112 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65

    Deng, Q., Harvie, E. A. & Huttenlocher, A. Distinct signalling mechanisms mediate neutrophil attraction to bacterial infection and tissue injury. Cell. Microbiol. 14, 517–528 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66

    Sarris, M. et al. Inflammatory chemokines direct and restrict leukocyte migration within live tissues as glycan-bound gradients. Curr. Biol. 22, 2375–2382 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67

    Weber, M. et al. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339, 328–332 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68

    Chou, R. C. et al. Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis. Immunity 33, 266–278 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Bajenoff, M. et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25, 989–1001 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70

    Bromley, S. K., Mempel, T. R. & Luster, A. D. Orchestrating the orchestrators: chemokines in control of T cell traffic. Nature Immunol. 9, 970–980 (2008).

    CAS  Article  Google Scholar 

  71. 71

    Foxman, E. F., Campbell, J. J. & Butcher, E. C. Multistep navigation and the combinatorial control of leukocyte chemotaxis. J. Cell Biol. 139, 1349–1360 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Campbell, J. J., Foxman, E. F. & Butcher, E. C. Chemoattractant receptor cross talk as a regulatory mechanism in leukocyte adhesion and migration. Eur. J. Immunol. 27, 2571–2578 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73

    Heit, B., Tavener, S., Raharjo, E. & Kubes, P. An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients. J. Cell Biol. 159, 91–102 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Heit, B. et al. PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils. Nature Immunol. 9, 743–752 (2008).

    CAS  Article  Google Scholar 

  75. 75

    Huttenlocher, A. & Poznansky, M. C. Reverse leukocyte migration can be attractive or repulsive. Trends Cell Biol. 18, 298–306 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Mirakaj, V. et al. Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation. Proc. Natl Acad. Sci. USA 108, 6555–6560 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77

    Sumaria, N. et al. Cutaneous immunosurveillance by self-renewing dermal γδ T cells. J. Exp. Med. 208, 505–518 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Starnes, T. W. & Huttenlocher, A. Neutrophil reverse migration becomes transparent with zebrafish. Adv. Hematol. 2012, 398640 (2012).

    PubMed  PubMed Central  Google Scholar 

  79. 79

    Mrass, P., Petravic, J., Davenport, M. P. & Weninger, W. Cell-autonomous and environmental contributions to the interstitial migration of T cells. Semin. Immunopathol. 32, 257–274 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  80. 80

    Dustin, M. L., Bromley, S. K., Kan, Z., Peterson, D. A. & Unanue, E. R. Antigen receptor engagement delivers a stop signal to migrating T lymphocytes. Proc. Natl Acad. Sci. USA 94, 3909–3913 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81

    Mrass, P. et al. Random migration precedes stable target cell interactions of tumor-infiltrating T cells. J. Exp. Med. 203, 2749–2761 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82

    Boissonnas, A., Fetler, L., Zeelenberg, I. S., Hugues, S. & Amigorena, S. In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J. Exp. Med. 204, 345–356 (2007). References 81 and 82 visualized the behaviour of effector CTLs within the tumour microenvironment for the first time.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83

    Egawa, G. et al. In vivo imaging of T-cell motility in the elicitation phase of contact hypersensitivity using two-photon microscopy. J. Invest. Dermatol. 131, 977–979 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84

    Breart, B., Lemaitre, F., Celli, S. & Bousso, P. Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J. Clin. Invest. 118, 1390–1397 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85

    Wilson, E. H. et al. Behavior of parasite-specific effector CD8+ T cells in the brain and visualization of a kinesis-associated system of reticular fibers. Immunity 30, 300–311 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86

    Schaeffer, M. et al. Dynamic imaging of T cell-parasite interactions in the brains of mice chronically infected with Toxoplasma gondii. J. Immunol. 182, 6379–6393 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87

    Kawakami, N. et al. Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J. Exp. Med. 201, 1805–1814 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88

    Siffrin, V. et al. In vivo imaging of partially reversible Th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity 33, 424–436 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89

    Filipe-Santos, O. et al. A dynamic map of antigen recognition by CD4 T cells at the site of Leishmania major infection. Cell Host Microbe 6, 23–33 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90

    Muller, A. J. et al. CD4+ T cells rely on a cytokine gradient to control intracellular pathogens beyond sites of antigen presentation. Immunity 37, 147–157 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91

    Egen, J. G. et al. Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. Immunity 28, 271–284 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92

    Egen, J. G. et al. Intravital imaging reveals limited antigen presentation and T cell effector function in mycobacterial granulomas. Immunity 34, 807–819 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93

    Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94

    Ariotti, S. et al. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc. Natl Acad. Sci. USA 109, 19739–19744 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95

    Jiang, X. et al. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483, 227–231 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96

    Schneider, H. et al. Reversal of the TCR stop signal by CTLA-4. Science 313, 1972–1975 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97

    Fife, B. T. et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nature Immunol. 10, 1185–1192 (2009).

    CAS  Article  Google Scholar 

  98. 98

    Zinselmeyer, B. H. et al. PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis. J. Exp. Med. 210, 757–774 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

    Matheu, M. P. et al. Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block. Immunity 29, 602–614 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100

    Mrass, P. et al. CD44 mediates successful interstitial navigation by killer T cells and enables efficient antitumor immunity. Immunity 29, 971–985 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101

    Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102

    Harris, T. H. et al. Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells. Nature 486, 545–548 (2012). This paper identifies Lévy walk behaviour as an improved target searching strategy of CTLs in situ.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103

    Gunzer, M. et al. Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity 13, 323–332 (2000).

    CAS  Article  Google Scholar 

  104. 104

    Marangoni, F. et al. The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells. Immunity 38, 237–249 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105

    Lodygin, D. et al. A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity. Nature Med. 19, 784–790 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. 106

    Pesic, M. et al. 2-photon imaging of phagocyte-mediated T cell activation in the CNS. J. Clin. Invest. 123, 1192–1201 (2013). References 104–106 used fluorescent markers to follow T cell activation in situ.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107

    Griffith, J. W. & Luster, A. D. Targeting cells in motion: migrating toward improved therapies. Eur. J. Immunol. 43, 1430–1435 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108

    Mackay, C. R. Moving targets: cell migration inhibitors as new anti-inflammatory therapies. Nature Immunol. 9, 988–998 (2008).

    CAS  Article  Google Scholar 

  109. 109

    Allegretti, M., Cesta, M. C., Garin, A. & Proudfoot, A. E. Current status of chemokine receptor inhibitors in development. Immunol. Lett. 145, 68–78 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110

    Di Gennaro, A. & Haeggstrom, J. Z. Targeting leukotriene B4 in inflammation. Exp. Opin. Ther. Targets 18, 79–93 (2014).

    CAS  Article  Google Scholar 

  111. 111

    Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nature Rev. Immunol. 12, 269–281 (2012).

    CAS  Article  Google Scholar 

  112. 112

    Lam, P.-Y. & Huttenlocher, A. Interstitial leukocyte migration in vivo. Curr. Opin. Cell. Biol. 25, 650–658 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113

    Petrie, R. J. & Yamada, K. M. At the leading edge of three-dimensional cell migration. J. Cell Sci. 125, 5917–5926 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114

    Lorentzen, A., Bamber, J., Sadok, A., Elson-Schwab, I. & Marshall, C. J. An ezrin-rich, rigid uropod-like structure directs movement of amoeboid blebbing cells. J. Cell Sci. 124, 1256–1267 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  115. 115

    Diz-Munoz, A. et al. Control of directed cell migration in vivo by membrane-to-cortex attachment. PLoS Biol. 8, e1000544 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  116. 116

    Lee, J. H. et al. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J. Cell Biol. 167, 327–337 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117

    Biro, M. et al. Cell cortex composition and homeostasis resolved by integrating proteomics and quantitative imaging. Cytoskeleton (Hoboken) http://dx.doi.org/10.1002/cm.21142 (2013).

  118. 118

    Charras, G. T., Hu, C. K., Coughlin, M. & Mitchison, T. J. Reassembly of contractile actin cortex in cell blebs. J. Cell Biol. 175, 477–490 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119

    Paluch, E. K. & Raz, E. The role and regulation of blebs in cell migration. Curr. Opin. Cell Biol. 25, 582–590 (2013).

    CAS  Article  Google Scholar 

  120. 120

    Renkawitz, J. & Sixt, M. Mechanisms of force generation and force transmission during interstitial leukocyte migration. EMBO Rep. 11, 744–750 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121

    Nishibu, A. et al. Behavioral responses of epidermal Langerhans cells in situ to local pathological stimuli. J. Invest. Dermatol. 126, 787–796 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122

    Ng, L. G. et al. Migratory dermal dendritic cells act as rapid sensors of protozoan parasites. PLoS Pathog. 4, e1000222 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. 123

    Kubo, A., Nagao, K., Yokouchi, M., Sasaki, H. & Amagai, M. External antigen uptake by Langerhans cells with reorganization of epidermal tight junction barriers. J. Exp. Med. 206, 2937–2946 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124

    Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125

    Chieppa, M., Rescigno, M., Huang, A. Y. & Germain, R. N. Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement. J. Exp. Med. 203, 2841–2852 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126

    McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345–349 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127

    Gray, E. E., Suzuki, K. & Cyster, J. G. Cutting edge: Identification of a motile IL-17-producing γδT cell population in the dermis. J. Immunol. 186, 6091–6095 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128

    Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nature Immunol. 14, 564–573 (2013).

    CAS  Article  Google Scholar 

  129. 129

    Cheng, L. E., Hartmann, K., Roers, A., Krummel, M. F. & Locksley, R. M. Perivascular mast cells dynamically probe cutaneous blood vessels to capture immunoglobulin E. Immunity 38, 166–175 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130

    Geissmann, F. et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol. 3, e113 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  131. 131

    Lee, W. Y. et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nature Immunol. 11, 295–302 (2010).

    CAS  Article  Google Scholar 

  132. 132

    Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007). This paper describes the presence of crawling monocytes in non-inflamed blood vessels.

    CAS  Article  Google Scholar 

  133. 133

    Carlin, L. M. et al. Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell 153, 362–375 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134

    Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neurosci. 8, 752–758 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  135. 135

    Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    CAS  Article  Google Scholar 

  136. 136

    Beattie, L. et al. Dynamic imaging of experimental Leishmania donovani-induced hepatic granulomas detects Kupffer cell-restricted antigen presentation to antigen-specific CD8 T cells. PLoS Pathog. 6, e1000805 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Wolfgang Weninger.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Pseudopodia

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.

Displacement

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.

Uropod

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.

Chemotaxis

The process of directional cell migration towards soluble, freely-diffusing gradients of chemoattractants.

Chemokinesis

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.

Haptotaxis

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.

Haptokinesis

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.

Chemorepulsion

The migration of leukocytes away from certain mediators.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing