Immunological Adhesion and Homing Molecules

Abstract

The immunosurveillance function of leukocytes requires a strictly controlled trafficking between lymphoid and nonlymphoid tissues. Thus, white blood cells are continuously scanning the body for sign of infection or damage with lineage‐specific pathways. Triggered by chemokines and other danger signals, those movements require selective interactions mediated by adhesion and homing molecules expressed by immune and endothelial cells. Typically, the transendothelial migration is initiated by specific interactions between selectins and glycosylated proteins, which allow the initial tethering and rolling of leukocytes on endothelial cells. In the presence of chemokines, rolling is followed by firm arrest mediated by active integrins binding to immunoglobulin superfamily ligands and culminates with extravasation. The expression pattern and structural features of those adhesion molecules dictated the cell‐specific homing governing the immune response.

Key Concepts

  • Leukocytes exit from circulation to home at secondary lymphoid organs and peripheral tissues.
  • Essential steps of extravasation are tethering, rolling, firm adhesion and diapedesis.
  • The typical homing cascade sees selectins binding to glycoproteins during rolling, followed by chemokine mediated integrin activation promoting firm adhesion.
  • Endothelial cells have an active role in lymphocyte recruitment, presentation of chemokines and transendothelial transport of leukocytes.
  • Homing molecules are controlled by the engagement by ligands and by the shear force applied to them.

Keywords: integrins; selectins; vascular addressins; immunoglobulin superfamily; transendothelial migration

Figure 1. Schematic representation of lymphocyte homing pathways. In principle, lymphocytes can home from the blood to any tissue in the body (red arrows), but different lymphocyte subsets prefer distinct target organs. Naive lymphocytes and central memory cells home preferentially to secondary lymphoid organs, that is lymph nodes (LNs), tonsils, spleen and the organised lymphoid aggregates in the wall of the small intestine called Peyer's patches. B cells are the predominant subset in most mucosa‐associated lymphoid tissues, whereas T cells are more frequent in peripheral LNs. Effector memory cells migrate preferentially to nonlymphoid tissues. Extravascular lymphocytes return to the blood via the lymphatic system (blue arrows) or when they reside in the spleen, enter the bloodstream directly. Ag, antigen. Reproduced with permission from Lucila . © John Wiley & Sons.
Figure 2. Leucocyte behaviour in the microcirculation. Leucocytes enter the microvasculature via arterioles with diameters ranging from 15 to 100 μm (1). Many capillaries (5–10 μm diameter) are narrower than the average diameter of a leucocyte (6–10 μm). Thus, the relatively stiff leucocytes must deform before they can enter the capillary ostium (2). During their passage through the narrow capillary, red blood cells (RBCs) pile up behind the slow‐moving leucocytes (3). Upon entry into postcapillary venules (diameter 10–100 μm), the RBCs pass the slow‐moving cells. Collisions with RBCs force leucocytes towards the margin of the bloodstream, allowing the cells' microvilli to touch the vessel wall (4). If the venular endothelial cells express appropriate ligands for microvillus‐associated adhesion receptors, leucocytes become tethered and roll slowly downstream (5). The rolling cells are pushed further against the vascular wall by the flowing blood. This allows contact of additional adhesion molecules on the planar cell body with the endothelial surface. In the presence of an appropriate activating stimulus, these molecules bind more strongly and arrest the cell (6). Subsequently, the stuck cell begins to spread and extends a pseudopodium through the endothelial barrier (7). Eventually, adherent leucocytes emigrate and enter the extravascular compartment. In most organs, adhesion is supported only by endothelial cells in venules (broken lines indicate the capillary–venular border) but not in arterioles or capillaries. This spatial distinction may have evolved from the need to preserve tissue perfusion. The temporary reduction in vessel diameter associated with leucocyte adhesion causes a concomitant increase in vascular resistance. As arterioles are the main resistance vessels of the body, leucocyte adhesion in arterioles could affect organ perfusion significantly. Similarly, leucocyte adhesion in a capillary would result in complete luminal occlusion until the cell has diapedesed through the endothelial lining. The contribution of venules to the overall resistance of a microvascular bed is very small. Thus, the haemodynamic effects of leucocyte recruitment in venules are negligible (Note: Most RBCs were omitted from this drawing for clarity; the physiological ratio of RBCs leucocytes is about 1000:1.). Reproduced with permission from Lucila . © John Wiley & Sons.
Figure 3. The multistep adhesion cascade. Frequent collisions occur between blood cells that move at different relative positions within a vessel because cells move faster in the centreline of microvessels and slower at the vessel wall (arrows on left indicate a typical laminar flow profile). Collisions with RBCs facilitate leucocyte contact with endothelial cells. When leucocyte microvilli touch the endothelium, several different adhesion pathways can function either alone or in concert to mediate tethering. As soon as adhesive contact has been initiated, the tethered cells begin to roll slowly downstream. The adhesion molecules that mediate tethering and rolling are largely the same, but tethering is greatly facilitated by leucocyte receptors, which occur at high density on the tips of microvilli, whereas subsequent rolling is not influenced by the topography of adhesion receptors. When a rolling cell encounters a chemoattractant stimulus such as a chemokine, the activating signal induces rapid activation of β2 or α4 integrins, which bind to endothelial IgSF members. The engagement of L‐selectin with its endothelial ligand, peripheral lymph node addressin (PNAd), can also trigger intracellular signalling events that may contribute to integrin activation. The subsequent step, transmigration, is the least understood event in the cascade. Some IgSF members, as well as α4 and β2 integrins, have been suggested to play a role in this process. CD, cluster of differentiation; ESL, E‐selectin ligand; ICAM, intercellular adhesion molecule; JAM, junctional adhesion molecule; LFA, leucocyte functional antigen; LT, leukotriene; MAdCAM, mucosal addressin cell adhesion molecule; Mac, macrophage antigen; PAF, platelet‐activating factor; PECAM, platelet endothelial cell adhesion molecule; PSGL, P‐selectin glycoprotein ligand; VAP, vascular adhesion protein; VCAM, vascular cell adhesion molecule. Reproduced with permission from Lucila . © John Wiley & Sons.
Figure 4. The major primary adhesion pathways. All the leucocyte‐expressed primary adhesion molecules shown here are clustered on the tips of microvilli. They are thus strategically positioned to mediate rapid tethering. Primary adhesion molecules are constitutively active, that is they bind to their counterreceptors without the need for previous stimulation. Most primary interactions occur directly between leucocytes and endothelial cells. In addition, L‐selectin can also bind to P‐selectin glycoprotein ligand 1 (PSGL‐1) on the surface of other leucocytes (broken arrow). This interaction may be relevant when large numbers of adherent cells have accumulated in a vessel. These cells are effectively part of the vessel wall and may contribute to the recruitment of additional leucocytes via the L‐selectin–PSGL‐1 pathway (PSGL‐1 requires sulfation of at least one of three tyrosine residues (sulfation sites are identified by ‘S’) to interact efficiently with P‐ and L‐selectin, whereas E‐selectin binding is sulfation independent). MAdCAM, mucosal addressin cell adhesion molecule. PNAd, peripheral lymph node addressin. PSGL, P‐selectin glycoprotein ligand. S, sulfate. SGP200, sialylated glycoprotein. sLeX, sialyl‐LewisX. VCAM, vascular cell adhesion molecule. Reproduced with permission from Lucila . © John Wiley & Sons.
Figure 5. The major secondary adhesion pathways. Leucocyte activation is necessary for binding of the β2 integrins to their immunoglobulin ligands, intercellular adhesion molecule 1 (ICAM‐1) and ICAM‐2. Enhanced binding activity is also required for the α4 integrins, α4β1 and α4β7, to mediate firm arrest on vascular cell adhesion molecule 1 (VCAM‐1) and mucosal addressin cell adhesion molecule 1 (MAdCAM‐1), respectively. LFA, leucocyte functional antigen; Mac, macrophage antigen. Reproduced with permission from Lucila . © John Wiley & Sons.
Figure 6. The selectins. Each selectin has a C‐type (Ca2+ dependent) lectin domain at the N‐terminus. This domain contains the recognition site for selectin ligands. The epithelial growth factor (EGF)‐like domain is required for optimal lectin function in P‐selectin. The short consensus repeats (SCRs) are thought to function as modular spacers to elevate the lectin domain above the cell surface. The membrane‐proximal region of L‐selectin contains a cleavage site for a metalloprotease, which rapidly removes L‐selectin from the cell surface when leucocytes become activated. Reproduced with permission from Lucila . © John Wiley & Sons.
Figure 7. Biosynthesis of LewisX (LeX) and sialyl‐LewisX (sLeX). Both carbohydrates are expressed abundantly on myeloid cells. Expression of sLeX is upregulated on many activated and memory lymphocytes, particularly on T‐helper 1 cells, due to transcriptional induction of the α1,3‐fucosyltransferase (FucT)‐VII. The enzymatic steps that lead to Core 1 or 2 O‐glycan synthesis (by core 1 or 2 β1,6‐N‐acetylglucosaminyltransferase) and α1,3‐fucosylation of core 1 or 2 branches, which consist of one or more lactosamines, are necessary for selectin ligands expressed on leucocytes. FucT‐VII is also required for the expression of peripheral lymph node addressin (PNAd) in high endothelial venules. The major product of FucT‐IV is LeX, which is not a selectin ligand. When the supply of Core 2 O‐glycan (or perhaps α2,3‐sialyl transferase or sialic acid) is limited, FucT‐IV competes with FucT‐VII for the shared substrate and, thus, can reduce the biosynthesis of selectin ligands. FucT‐IV can also fucosylate sialylated core 2 glycans and produce a small amount of sLeX. Sialylated glycans may be further modified, for example by sulfotransferase(s), which add a sulfate (SO4) moiety to the 6' or 6 position of galactose or N‐acetylglucosamine (GlcNAc), respectively. These modifications have been identified in GlyCAM, a sialomucin that is decorated with the MECA 79 epitope. Sulfation of PNAd is critical for L‐selectin binding. Reproduced with permission from Lucila . © John Wiley & Sons.
Figure 8. Selected leucocyte‐expressed integrins and their ligands. Each of the integrins shown has been implicated in leukocyte homing, but so far only the adhesion pathways indicated by thick lines have been proved to be important in this context. Ligands expressed on the luminal surface of endothelial cells are highlighted by black frames ICAM, intercellular adhesion molecule; LFA, leucocyte functional antigen; Mac, macrophage antigen; MAdCAM, mucosal addressin cell adhesion molecule; VCAM, vascular cell adhesion molecule; VLA, very late antigen. Reproduced with permission from Lucila . © John Wiley & Sons.
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Further Reading

Ali AJ, Abuelela AF and Merzaban JS (2017) An analysis of trafficking receptors shows that CD44 and P‐Selectin glycoprotein ligand‐1 collectively control the migration of activated human T‐cells. Frontiers in Immunology 8 (492). ISSN: 1664‐3224. https://www.ncbi.nlm.nih.gov/pubmed/28515724.

Bertoni A, Alabiso O, Galetto AS and Baldanzi G (2018) Integrins in T cell physiology. International Journal of Molecular Sciences 19 (2). ISSN: 1422‐0067. https://www.ncbi.nlm.nih.gov/pubmed/29415483.

Chigaev A and Sklar LA (2012) Aspects of VLA‐4 and LFA‐1 regulation that may contribute to rolling and firm adhesion. Frontiers in Immunology 3 (242). ISSN: 1664‐3224. https://www.ncbi.nlm.nih.gov/pubmed/22876249.

Ebnet K (2017) Junctional adhesion molecules (JAMs): cell adhesion receptors with pleiotropic functions in cell physiology and development. Physiological Reviews 97 (4): 1529–1554. ISSN: 1522‐1210. https://www.ncbi.nlm.nih.gov/pubmed/28931565.

Fu H, Ward EJ and Marelli‐Berg FM (2016) Mechanisms of T cell organotropism. Cellular and Molecular Life Sciences 73 (16): 3009–3033. ISSN: 1420‐9071. https://www.ncbi.nlm.nih.gov/pubmed/27038487.

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. ISSN: 1474‐1741. https://www.ncbi.nlm.nih.gov/pubmed/21597477.

Ivetic A (2018) A head‐to‐tail view of L‐selectin and its impact on neutrophil behaviour. Cell and Tissue Research 371 (3): 437–453. ISSN: 1432‐0878. https://www.ncbi.nlm.nih.gov/pubmed/29353325.

Liu Z, Yago T, Zhang N, et al. (2017) L‐selectin mechanochemistry restricts neutrophil priming in vivo. Nature Communications 8: 15196. ISSN: 2041‐1723. https://www.ncbi.nlm.nih.gov/pubmed/28497779.

Schnaar RL (2016) Glycobiology simplified: diverse roles of glycan recognition in inflammation. Journal of Leukocyte Biology 99 (6): 825–838. ISSN: 1938‐3673. https://www.ncbi.nlm.nih.gov/pubmed/27004978.

Zabel BA, Rott A and Butcher EC (2015) Leukocyte chemoattractant receptors in human disease pathogenesis. Annual Review of Pathology 10: 51–81. ISSN: 1553‐4014. https://www.ncbi.nlm.nih.gov/pubmed/25387059.

Zlotnik A and Yoshie O (2012) The chemokine superfamily revisited. Immunity 36 (5): 705–716. ISSN: 1097‐4180. https://www.ncbi.nlm.nih.gov/pubmed/22633458.

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Baldanzi, Gianluca(Aug 2019) Immunological Adhesion and Homing Molecules. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000925.pub3]