Lymphocytes: Recirculation

Sirpa Jalkanen, University of Turku and National, Turku, Finland
Marko Salmi, University of Turku and National, Turku, Finland

Published online: February 2013

DOI: 10.1002/9780470015902.a0001200.pub3

Abstract

Successful immunosurveillance requires endless patrolling of lymphoid tissues by lymphocytes in search of foreign antigens. Lymphocytes enter the lymphoid tissues either through the blood vessel walls or via the afferent lymphatic vessels. To leave the circulation, bloodborne lymphocytes first tether to the endothelial lining of the vessels and start to roll. After an activation step they firmly adhere and transmigrate through the vessel wall. They then navigate through the tissue stroma following chemotactic and other guidance molecules, possibly encounter their cognate antigens and eventually return via the lymphatic vessels back into the blood to be dispersed to the other tissues of the body. In this tightly controlled process called lymphocyte recirculation, different adhesion molecules and activation signals on the two opposing cell types play a critical role. Dysregulated lymphocyte recirculation is involved in the pathogenesis of many inflammatory diseases and immunodeficiencies, and nowadays several drugs target this process.

Key Concepts:

  • Lymphocytes continuously recirculate between blood and lymphoid organs.

  • Majority of the lymphocytes enter the lymph nodes via specialised vessels called high endothelial venules (HEV).

  • The remaining lymphocytes (15–20%), together with dendritic cells and antigens, enter the lymph nodes via afferent lymphatics.

  • Lymphocytes leave the lymph nodes via efferent lymphatics.

  • Lymphocyte recirculation allows the lymphocytes to meet their cognate antigens and other leucocyte subsets to evoke an efficient immune response.

  • Lymphocytes interact with the vessel wall in a multistep fashion, using several leucocyte surface molecules, which recognise their counter receptors on endothelial cells.

  • The rolling and tethering of lymphocytes on the vessel wall is mediated by selectins.

  • Chemokines and their receptors are needed to activate leucocyte integrins.

  • Activated integrins mediate firm adhesion between lymphocytes and endothelium.

  • The transmigration of leucocytes into the tissues requires adhesion molecules, proteinases and repair mechanisms.

Keywords: adhesion molecules; endothelium; extravasation; homing; transmigration; lymphatics

Figure 1.

Multistep cascade of lymphocyte extravasation. The bloodborne cell makes initially transient contacts with endothelial cells, which then result in rolling along the vascular lining. If the cell becomes activated, it can subsequently firmly adhere to the endothelial cells, seek for interendothelial junctions (crawling) and migrate through the endothelial monolayer (via para‐ or transcellular routes) and basement membrane into the tissue. The contribution of major super families of adhesion and activation molecules at each step is depicted below. E, endothelial layer; Bm, basement membrane.
Figure 2.

Molecules mediating lymphocyte recirculation. The most relevant proteins involved in lymphocyte–endothelial cell interactions are shown as receptor–ligand pairs.
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References

von Andrian UH and Mempel TR (2003) Homing and cellular traffic in lymph nodes. Nature Reviews Immunology 3(11): 867–878.

Brinkmann V, Billich A, Baumruker T et al. (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nature Reviews Drug Discovery 9(11): 883–897.

Bromley SK, Mempel TR and Luster AD (2008) Orchestrating the orchestrators: chemokines in control of T cell traffic. Nature Immunology 9(9): 970–980.

Butcher EC and Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272(5258): 60–66.

Cyster JG and Schwab SR (2012) Sphingosine‐1‐phosphate and lymphocyte egress from lymphoid organs. Annual Review of Immunology 30: 69–94.

Etzioni A (2010) Defects in the leukocyte adhesion cascade. Clinical Reviews in Allergy and Immunology 38(1): 54–60.

Förster R, Braun A and Worbs T (2012) Lymph node homing of T cells and dendritic cells via afferent lymphatics. Trends in Immunology 33(6): 271–280.

Girard JP, Moussion C and Forster R (2012) HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nature Reviews Immunology. 12: 762–773.

Gowans JL and Knight EJ (1964) The route of re‐circulation of lymphocytes in rat. Proceedings of the Royal Society of London Series B 159: 257–282.

Hogg N, Patzak I and Willenbrock F (2011) The insider's guide to leukocyte integrin signalling and function. Nature Reviews Immunology 11(6): 416–426.

Kinashi T (2012) Overview of integrin signaling in the immune system. Methods in Molecular Biology 757: 261–278.

Kupper TS (2003) Immunologic targets in psoriasis. New England Journal of Medicine 349(21): 1987–1990.

Ley K, Laudanna C, Cybulsky MI and Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Reviews Immunology 7(9): 678–689.

Luo BH, Carman CV and Springer TA (2007) Structural basis of integrin regulation and signaling. Annual Review of Immunology 25: 619–647.

Luster AD, Alon R and von Andrian UH (2005) Immune cell migration in inflammation: present and future therapeutic targets. Nature Immunology 6(12): 1182–1190.

Mackay CR (2008) Moving targets: cell migration inhibitors as new anti‐inflammatory therapies. Nature Immunology 9(9): 988–998.

Muller WA (2011) Mechanisms of leukocyte transendothelial migration. Annual Review of Pathology 6: 323–344.

Nourshargh S, Hordijk PL and Sixt M (2010) Breaching multiple barriers: leukocyte motility through venular walls and the interstitium. Nature Reviews Molecular and Cellular Biology 11(5): 366–378.

Ropper AH (2006) Selective treatment of multiple sclerosis. New England Journal of Medicine 354(9): 965–967.

Sallusto F and Baggiolini M (2008) Chemokines and leukocyte traffic. Nature Immunology 9(9): 949–952.

Salmi M and Jalkanen S (2005) Cell‐surface enzymes in control of leukocyte trafficking. Nature Reviews Immunology 5(10): 760–771.

Vestweber D (2012) Novel insights into leukocyte extravasation. Current Opinion in Hematology 19(3): 212–217.

Zarbock A, Ley K, McEver RP and Hidalgo A (2011) Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 118(26): 6743–6751.

Further Reading

Allen SJ, Crown SE and Handel TM (2007) Chemokine:receptor structure, interactions, and antagonism. Annual Review of Immunology 25: 787–820.

Alon R and Shulman Z (2011) Chemokine triggered integrin activation and actin remodeling events guiding lymphocyte migration across vascular barriers. Experimental Cell Research 317(5): 632–641.

Cahalan MD and Parker I (2006) Imaging the choreography of lymphocyte trafficking and the immune response. Current Opinion in Immunology 18(4): 476–482.

Engelhardt B and Ransohoff RM (2005) The ins and outs of T‐lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends in Immunology 26(9): 485–495.

Islam SA and Luster AD (2012) T cell homing to epithelial barriers in allergic disease. Nature Medicine 18(5): 705–715.

Mebius RE and Kraal G (2005) Structure and function of the spleen. Nature Reviews Immunology 5(8): 606–616.

Scholten DJ, Canals M, Maussang D et al. (2012) Pharmacological modulation of chemokine receptor function. British Journal of Pharmacology 165(6): 1617–1643.

Schulz C, von Andrian UH and Massberg S (2009) Hematopoietic stem and progenitor cells: their mobilization and homing to bone marrow and peripheral tissue. Immunology Research 44(1–3): 160–168.

Thomas S and Baumgart DC (2012) Targeting leukocyte migration and adhesion in Crohn's disease and ulcerative colitis. Inflammopharmacology 20(1): 1–18.

Wang H, Lim D and Rudd CE (2010) Immunopathologies linked to integrin signalling. Seminars in Immunopathology 32(2): 173–182.

Related Sub-Topics:

Cell Motility and Transport | Cells of the Immune System | Structure of Cell–Cell Interactions | Cell Motility
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Article Title: Lymphocytes: Recirculation
 
How to Cite close
Jalkanen, Sirpa, and Salmi, Marko(Feb 2013) Lymphocytes: Recirculation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001200.pub3]