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Roles for Integrins and Associated Proteins in the Haematopoietic System

, , and *.

* Corresponding Author: Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands. E-mail: c.figdor@ncmls.kun.nl

Summary

The haematopoietic system is a highly dynamic system where cell adhesion and cell migration are tightly controlled. During both embryonic and adult haematopoiesis, the finely orchestrated action of several integrins contributes to the generation of all different mature blood cells. Within the immune system, integrins regulate cell-cell and cell-extracellular matrix interaction during homeostasis as well as inflammation. Accumulating evidence suggests that many of the integrin-mediated functions occur through physical interaction of integrins with other associated proteins. The goal of this chapter is to describe the role of integrins -particularly α4, β2, and β7- and integrin-interacting molecules in the haematopoietic and immune systems.

Introduction

The haematopoietic system consists of stem cells that self replicate and differentiate into specific progenitor cells to eventually generate all the different mature blood cells (fig. 1).

Figure 1. Haematopoietic lineage.

Figure 1

Haematopoietic lineage. Pluri haem = pluripotent haematopoietic stem cell; lymphoid = lymphoid progenitor; myeloid = myeloid progenitor; pDC = plasmacytoid dendritic cell; NK cell = natural killer cell; granu/MF = granulocyte/macrophage progenitor; megak/ery (more...)

In steady-state conditions, stem cells and progenitors reside in the bone marrow (BM) microenvironment, where various cytokines and extracellular matrix (ECM) components are secreted.1 Stem cells as well as progenitor cells express several adhesion receptors (selectins, integrins, and sialomucins) that mediate specific cell-cell and cell-ECM contacts.2,3 These contacts play an important role in the regulation of homing and retention of progenitors within the BM and their growth, survival and differentiation.4-6 However, so far no adhesion receptor has been identified that is exclusively expressed on stem cells. Likewise, no adhesive ligand, except haemonectin for the granulocyte lineage,7 has been identified to be specifically present in the BM microenvironment.

The adhesive processes of leukocytes have been the subject of numerous studies. These bone-marrow derived cells with diverse form and function circulate in the blood in a resting state of low adhesiveness. They display a particular pattern of adhesion receptors that can change in a signal- and time-dependent manner.

While some of these receptors, among which β1 integrins, are present also in other cell types, the β2 and β7 integrins are exclusively expressed on the cell surface of leukocytes.8

The β2 integrins family comprehends four members, αLβ2 (CD11a/CD18; LFA-1), αMβ2 (CD11b/CD18; MAC-1), αXβ2 (CD11c/CD18; p150,95), and αDβ2 (CD11d/CD18).9 Each of the β2 integrins recognizes one or more members of the intercellular adhesion molecule (ICAM) family.9 In addition, αLβ2 binds to JAM-1, expressed at the tight junction of resting endothelium,10 and αDβ2 binds to vascular cell adhesion molecule-1 (VCAM-1),11 while αMβ2 and αβ2 can also interact with polysaccharides.12,13 The RGD motif, a critical feature in many integrin ligands, is not required for ligands of the β2 integrins family. The most extensively studied member of this family is αLβ2. This integrin mediates leukocyte migration across the endothelium both during normal lymphocyte recirculation and in response to inflammatory signals.14-17 αLβ2 has also been shown to be involved in the formation of the “immunological synapse”, the contact site between T lymphocytes and antigen presenting cells.18

The β7 integrins are specifically expressed by distinct subsets of T lymphocytes and in the murine immune system they can be found also on subsets of skin-derived dendritic cells (DCs) in peripheral lymph nodes.19 This family consists of only two members: α4β7, expressed on a subset of memory CD4+ and CD8+ T lymphocytes, which binds to the mucosal addressin cell adhesion molecule (MAdCAM-1),20 and αEβ7, which interacts with epithelial-specific cadherin (E-cadherin).21,22

In this chapter, we shall focus on the above-mentioned families of integrins and their role in both the haematopoietic and the immune system. Finally, the importance of functional integrins will be discussed in the context of integrin-associated disorders.

Integrins in the Haematopoiesis

Development of haematopoietic stem cells and their differentiated progeny occurs during fetal as well as adult life and relies on interactions with the BM microenvironment that provides support and stimuli for proliferation and differentiation.

During embryo development, gradual colonization of all haematopoietic organs occurs,23 and in mouse after embryonic day 10 definitive pluripotent progenitors are found in the fetal liver, thymus, bone marrow, and spleen. However, active haematopoiesis begins at different time points, depending on the development of each haematopoietic environment. In humans, after birth, erythropoiesis, myelopoiesis, B lymphopoiesis, and generation of T lymphocyte progenitors, occurs in the BM, while in mouse erythropoiesis and myelopoiesis can take place both in the BM and in the spleen.

Especially the use of knock-out or chimera mice has been instrumental in dissecting the role of specific receptors in embryonic and adult haematopoiesis.

Several in vivo studies have demonstrated the involvement of integrins in multiple steps of haematopoiesis. In particular, the expression of α4 integrins is regulated during haematopoiesis; these receptors are expressed on early multipotent progenitors but are downregulated during erythrocyte and neutrophil differentiation.24 In addition, α4 integrins present on the progenitor cells mediate their interaction with BM stromal cells, which express VCAM-1.25

The analysis of α4-null mice has shown that while erythropoiesis in the yolk sac can occur in the absence of α4 integrins, definitive haematopoiesis in spleen and BM is severely compromised. 26 More specifically, α4-null erythroid progenitors can colonize fetal liver, BM, and spleen, where they can differentiate, although they produce only low numbers of mature erythrocytes. This suggests a defect in proper expansion of the erythroid populations in absence of α4 integrins and is in agreement with in vitro data showing an inhibition of erythroid development when anti- α4 integrin antibodies were used.27

Studies in α4-null mice have also shown that myeloid and lymphoid development depends on α4 integrins. Although terminal differentiation of T and B lymphocytes, monocytes, and granulocytes occurs during fetal development in the absence of α4 integrins, only a small percentage of α4-null progenitors can complete differentiation. This defect becomes more evident after birth, when the bone marrow starts playing a major role in haematopoietic development.28

A widely accepted model for the function of α4 integrins in the regulation of hematopoiesis is based on the assumption that within the stroma, three different compartments for progenitor cells exist: self-renewal, expansion, and maturation.29 The balance among different signals (cytokines, chemokines, and cell-cell contacts) in each niche would determine the fate of the committed progenitors. α4 integrins could provide a retention signal for progenitors to remain in the expansion compartment. As a consequence, α4-deficient progenitors prematurely detach, lacking the expansion phase, and rapidly shift towards differentiation. This might explain the low numbers of progenitors found in α4-deficient hematopoietic organs and the low yield of mature cells. In this way, α4 integrins act as major regulators of the balance between proliferation and differentiation during hematopoiesis.26 This hypothesis is further substantiated by studies regarding adult hematopoiesis in α4 conditional-knockout mice.30 Here, a dramatic increase of circulating progenitors was observed, suggesting their early release from the BM. Moreover, these circulating α4-null progenitor cells were partially unable to home to the BM, in agreement with the observation that α4 integrin-function-blocking antibodies were able to selectively reduce BM homing. Since the α4 subunit can associate with either the β1 or the β7 subunit, α4-null hematopoietic cells lack both α4β1 and α4β7 integrins. Nevertheless, no defects in hematopoietic cell development were observed in β7-null mice,31 suggesting a primary role for the α4β1 combination.

Although β7 integrins seem to play a minor role in haematopoiesis, it should be mentioned that up-regulation of their expression levels together with a parallel down-regulation of β1 and α5 integrins accompanies eosinophilic-basophilic lineage commitment (fig. 1).32

Further supporting evidence of the dominant role of β1 integrins in haematopoiesis comes from numerous studies on the involvement of β1 integrins in fetal and adult haematopoiesis. The use of antibodies against β1 integrins has been shown to severely reduce the reentry of hematopoietic progenitors into the spleen and the BM, after human stem cell transplantation.25 The absence of β1 integrins also causes an impaired migration of haematopoietic stem cells towards the fetal liver.33

However, α4 and β1 integrins are not the only adhesion receptors that regulate haematopoiesis. A synergistic contribution of β2 integrins was also reported. Although deficiencies in β2 integrins alone do not have a major impact on homing and repopulation kinetics, the addition of an a4 functional blockade to β2 deficiency results in over 90% reduction of the homing in contrast to the 40% inhibition observed with α4 blockade alone.34

Similar synergy between β1 and β2 integrins is observed in the mobilization of hematopoietic stem and progenitor cells from the BM to the blood. Function-blocking antibodies against β1 and β2 integrins, used separately or in combination, together with β2-null mice have shown that abrogation of β2 integrin function contributes significantly to cell mobilization when α4β1 integrin function is inhibited simultaneously.35 However, it remains unclear at what stage this synergy occurs: at the stage of reversible adhesion or by enhancement of migration. A direct role for β2 integrins, particularly αLβ2 and αMβ2, in cytokine-induced mobilization was also established. Specifically, anti-αLβ2 blocking antibodies, but not anti-α4β1 antibodies, prevent mobilization of hematopoietic progenitor cells induced by IL-8.36 In contrast, administration of antibodies against αLβ2 and αMβ2 synergistically enhances stem cell-mobilization induced by granulocyte colony-stimulating factor (G-CSF).37 The exact mechanisms regulating retention in- and mobilization from the BM are largely unknown; however, recent studies indicate that a fine-tuned interplay between cytokines/chemokines, proteases, and adhesion molecules is fundamental. A clear example is the regulation of integrin-dependent adhesion by the chemokine CXCL12 during B lymphopoiesis.38 In human BM, CXCL12, also known as stromal cell-derived factor 1, triggers a sustained α4β1-dependent adhesion response in progenitor B cells. This response decreases during B cell development in the BM and is completely absent in circulating fully mature B cells, which only exhibit transient CXCL12-enhanced adhesion.38 These observations provide a developmental cell-stage specific mechanism where chemokines regulate hematopoiesis through sustained rather than short-lived activation of integrin adhesion.

In conclusion, during all different stages of haematopoiesis, cell-cell and cell-extracellular matrix interactions via adhesion receptors are tightly regulated both in time and space to guarantee the correct balance between retention and mobilization as well as proliferation and differentiation of stem cells and their progenitors.

Integrins in the Immune System

The human body is protected against pathogens such as viruses, bacteria, and parasites by the constantly alert immune system. This sophisticated defense system is guaranteed by a multitude of well-orchestrated interactions between different cell types, which derive from a specific progenitor cell generated from haematopoietic stem cells. Immune cells belong to either the innate or the adaptive immune system. Innate immunity is mediated by macrophages, natural killer (NK) cells, granulocytes, and monocytes that interact with pathogens in a nonspecific manner. The adaptive immunity is based on T and B lymphocytes that specifically recognize a certain pathogenic antigen (Ag) and build up an immunological memory, which will provide a faster and enhanced reaction upon repeated encounter with the same Ag. At the interface between innate and adaptive immunity are the dendritic cells (DCs). These highly specialized cells take up and process Ag at the periphery and then migrate to the lymph nodes, where they present Ag-derived peptides to resting lymphocytes, thereby initiating the adaptive immune response.

Integrins play important roles in various phases of the immune response by mediating cell-pathogen, cell-cell, and cell-extracellular matrix interactions. They are not merely ‘sticky’ receptors, but deliver ‘outside-in’ signals across the cell membrane by establishing cis associations with other receptors on the same cell, thus forming multi-molecular assemblies (fig. 2).

Figure 2. β2 integrins and interacting proteins in the immune system.

Figure 2

β2 integrins and interacting proteins in the immune system. Integrins are involved in cell-cell interactions (A), cell-endothelium interactions (B) and cell-pathogen interactions (C). Interacting proteins are involved in activating integrins, (more...)

Several integrin-associated proteins have been identified that can modulate integrin function in different ways: by altering the affinity of the integrin for the ligand by directly altering integrin conformation; by multimerization and recruitment of additional integrin receptors to form integrin clusters; or by the association of integrins with other molecules to form an active signaling complex that also acquires increased ligand binding potential.

Most integrin-associated proteins identified so far do not share any common structural relationship (see Table 1). Both GPI-anchored, trans-membrane or cytoplasmic proteins have been reported to associate with integrins.39-41

Table 1. Beta 1, 2 and 7 interacting proteins in the haematopoietic system.

Table 1

Beta 1, 2 and 7 interacting proteins in the haematopoietic system.

The association of integrins with GPI-linked proteins has raised the question whether integrin function could be modulated by the lipid microenvironment on the cell membrane. Indeed, there is increasing evidence that lipid microdomains enriched in glycosphingolipids and cholesterol, also known as lipid rafts (see Box 1) provide scaffolding platforms where different types of receptors—including integrins—having similar affinity for a certain lipid microenvironment, can meet and subsequently mediate specific signaling events.

Box Icon

Box

Box 1. What are lipid rafts? The plasma membrane has a nonrandom and asymmetrical distribution of lipid molecules within the bilayer. These lipids are mainly phospholipids, (glyco)-spingolipids, and cholesterol. Phospholipids tend to be loosely packed (more...)

In general, the involvement of integrins in membrane supramolecular complexes constituted by proteins as well as specific lipids is an emerging area of research particularly important in the immune system.

Antigen Recognition

A central element in immunity is the recognition of invading pathogens by leukocytes. The latter can be broadly divided into lymphocytes and phagocytes. Phagocytes (monocytes, macrophages, and granulocytes) form the ‘first line’ of defense and are equipped with a variety of pathogen uptake receptors including Fc receptors (FcR), complement receptors, among which CR3 (the αMβ2 integrin also known as Mac-1) and CR4 (the αXβ2 integrin also known as p150/95), and more recently discovered carbohydrate-binding proteins (such as C-type lectins and scavenger receptors). As discussed above, cross-talk between associating FcR and αMβ2 or αXβ2 enhances their functional activity.42

Using Fluorescence Resonance Energy Transfer (FRET), which allows detection of interacting molecules within 10 nm distance, FcRIIIB was shown to interact with αMβ2 on neutrophils membrane.43 In fact, since FcRIIIB is a GPI-anchored molecule without intracellular portion, it completely depends on lateral association with αMβ2 for signal transduction. This association is invaluable to effectively promote antibody-dependent phagocytosis of opsonized microorganisms.43 Similarly, it has recently been shown that an interaction between FcγRIII and αMβ2 enhances binding to iC3b, a critical complement-3 fragment that opsonizes pathogens and apoptotic cells after complement activation, on monocytes.44 This interaction is lost during monocyte differentiation into dendritic cells (DCs),45 potent antigen-presenting cells, where binding of iC3b via αMβ2 is impaired.44

Another GPI-linked molecule that associates with αMβ2 is CD14. This protein binds to bacterial lipopolysaccharide and subsequently associates with αMβ2 contributing to the generation of proinflammatory cytokines. Interestingly, this association occurs only in cell that circulate in the blood and is lost upon adhesion on a substrate, emphasizing the dynamic nature of these lateral interactions.43

The integrin αMβ2 is involved in pathogen recognition by mediating adhesion of lymphocytes to the fungus Candida albicans.46 This interaction occurs via cooperation between the I domain of the α subunit and the lectin-like domain of the β2 chain. The αMβ2-mediated adhesion of lymphocytes to C.albicans is a fundamental prerequisite to trigger the antifungal effect of lymphocytes and to inhibit hyphal growth of this pathogenic fungus.46

Several other microorganisms have also been shown to exploit this β2 integrin to gain access into the host cells. For example, interaction between αMβ2 and Histoplasma capsulatum, Blastomyces dermatitidis,47 Mycobacterium tuberculosis,48 and Leishmania sp.49 have been documented.

Another member of the β2 integrin family, αLβ2, has been shown to mediate the attachment of bacteria to the host cell. More specifically, the periodontopathogenic organism, Porphyromonas gingivalis, possess fimbriae on its cell surface that mediate adherence to human monocytes. The bacterium uses these fimbriae to bind CD14, Toll-like receptor-2 and the αL subunit, thereby inducing production of proinflammatory cytokines, such as IL-6. The interaction does not seem to depend on the intact αLβ2 dimer, since antibodies against αL, but not β2, inhibited IL-6 production on monocytes after challenge with P. gingivalis.50 The same integrin also contributes to cell-to-cell transmission of HIV-1 by interacting with virus-anchored host ICAM-1.51,52 In this way, virus dissemination exploits interactions between host molecules that are incorporated within HIV-1 and their natural counter-receptors.

A further example of viruses exploiting integrins to gain entry to host cell is the human parvovirus B19 that requires activation of α5β1 for internalization.53 The major cell surface receptor for this virus is the blood group P antigen, which only allows binding but not internalization. Replication of the pathogenic parvovirus B19 is restricted to erythroid progenitor cells. Mature red blood cells, which express high levels of P antigen but not the α5β1 integrin, bind parvovirus but do not allow viral entry. By contrast, primary human erythroid progenitor cells express high levels of both P antigen and α5β1, which facilitate β1 integrin-mediated entry of parvovirus B19.53

Antigen Presentation

A stable interaction between a T lymphocyte and an antigen-presenting cell (APC) is a prerequisite to effectively trigger the signaling cascade for T cell activation and effector function.54

The sole interaction between TCR and peptide/MHC complex is not strong enough to mediate this stable interaction. The αLβ2 integrin, highly expressed on T cells, and its counter receptor ICAM-1, present on the surface of APCs, are key mediators of this interaction.14,55 More specifically, αLβ2, together with the integrin-associated cytoskeletal protein talin, forms an external ring surrounding a central area rich in TCR, thus participating to the establishment of the immunological synapse (IS) during antigen-dependent interactions with APCs.56 After 1 hour of conjugation, the TCR disappears from the IS, while clustered aLβ2 is present up to 4 hours.57 This suggests that prolonged localization of αLβ2 at the T cell-APC facilitates molecular engagements at the contact site necessary for complete T cell activation, which results in T cell proliferation and enhancement of IL-2 production. Besides stabilizing the T cell-APC contact, αLβ2 can provide costimulatory signals, other than CD28, that support and promote TCR-induced T cell activation.58,59 As such, αLβ2 modulates IL-2 transcription level by interacting with Jun-activating binding protein 1 (JAB-1).60 JAB-1 colocalizes with αLβ2 at the cell surface by associating to the integrin cytoplasmic tails. The activation of αLβ2 induces phosphorylation of the β2 integrin chain and subsequent release of JAB-1. The nuclear pool of JAB-1 increases and binding of c-Jun-containing activator protein-1 (AP-1)-complexes to their DNA consensus site is enhanced, resulting in activation of AP-1-driven transcription.56 Along the same line, a second cytoplasmic protein, cytohesin-1 (Cyh-1), contributes to αLβ2-mediated costimulation in a JAB-1 independent manner.61 Cyh-1, a guanine-nucleotide exchange factor originally identified as dynamic regulator of αLβ2 function in leukocyte arrest on endothelium,62 is able to mediate Erk1/2 activation that is required for IL-2 production. The underlaying mechanism is based on physical interactions between the C-terminal PH domain of Cyh-1 and the β2 cytoplasmic tail of αLβ2, which results in enhanced clustering of the integrin at the cell surface and strengthening of ICAM-1 binding both in monocytic and lymphocytic cell lines.62

An additional partner of αLβ2 that contributes to costimulatory signals is the leukocyte adhesion molecule DNAM-1 (CD226).63 Upon stimulation of peripheral blood T lymphocytes by anti-CD3, physical association between αLβ2 and DNAM-1 has been reported. Once associated, cross-linking of LFA-1 induces Fyn-mediated tyrosine phosphorylation of DNAM-1. This complex of αLβ2, DNAM-1 and Fyn is found at the IS both in CD4+ and CD8+ T cells. However, while in CD4+ T cells this complex colocalizes with lipid rafts, on CD8+ T cells the αLβ2-mediated costimulatory signal seems lipid raft independent.63 The relevance of this different involvement of lipid rafts in the different T cell subsets however remains unclear.

Interestingly, when DNAM-1 is recruited into lipid rafts, it can associate with another αLβ2 interacting protein: the small GTPase Rap-1.64 The constitutively active form of Rap-1 (Rap1V12) increases both affinity and avidity of LFA-1 for ICAM-1, thereby regulating adhesion strength between T cell and APC.65 This occurs by association of Rap-1 with its effector RAPL.62 Identified by yeast two-hybrid screening, RAPL was found to associate with the constitutively active Rap1V12, but not with inactive Rap-1, and to coimmunoprecipitate with αLβ2 in cells expressing Rap1V12.66 Moreover, in vivo RAPL has been reported to colocalize with αLβ2 at membrane protrusions and at the IS, thereby perhaps controlling spatial regulation of αLβ2.66

The interaction of αLβ2 with several partners at the IS triggers multiple lymphocyte signaling pathways that eventually will lead to proper T cell activation and expansion.

Leukocyte Migration

Resting T lymphocytes continuously circulate between blood and lymph nodes, waiting for the right APC to provide the proper stimulus. This constant movement of naïve T cells ensures that the immune system continuously surveys for as many different intruders as possible. The ability of naïve T cells to enter lymph nodes or tissues relays on sets of adhesion molecules that are used in a specific time- and space-dependent manner.67 Although the majority of integrins on unstimulated T cells exist in an inactive state, a small subset of integrins are in a high-affinity state and are particularly important for spontaneous adhesion to endothelium.68 Under shear flow, the initial interaction of T cells with endothelium consists in rolling of the T cells on the endothelial surface. Besides selectins, also the integrin α4β1 contributes by establishing quick low-affinity interactions with its counter receptor VCAM-1.69 While affinity modulation does not seem to play any role in regulating tethering and rolling, sub-second induction of α4β1 clustering at the leukocyte-substrate contact zone, upon chemokine stimulation, enhances leukocyte avidity to VCAM-1.70 This α4β1-mediated transient rolling is a prerequisite for firm adhesion to and migration through the endothelial barrier for lymphocytes as well as monocytes. Recently, it has been shown that the lateral association of α4β1 with the tetraspanin CD81 is critical for rapid adhesion strengthening in monocytes and primary murine B cells interacting with VCAM-1 under shear flow.71

Most recent studies show that α4β1 can also mediate firm adhesion of human lymphoid cells onto endothelium by forming a bimolecular complex with CD44.72 This receptor mediates rolling of activated T cells on hyaluronan on endothelial cells. By both coimmunoprecipitation and transfection studies, it was shown that CD44 specifically associates with α4β1 and not with αLβ2, and that its cytoplasmic tail is essential for this interaction. Lack of the cytoplasmic tail of CD44 abrogates the α4β1 function, inhibiting in vivo lymphocyte trafficking to sites of inflammation.72

Engagement of α4β1 with VCAM-1 increases binding between αLβ2 and ICAM-1.73 More specifically, this α4β1-mediated enhancement of αLβ2 adhesiveness requires the presence of the urokinase receptor (uPAR; CD87) as an activation transducer on the leukocyte cell membrane.74 This GPI-linked receptor can, besides its role in the fibrinolytic system, upregulate cell adhesion by forming a multimeric receptor complex where tyrosine kinases as well as β2 integrins localize.75 In this way, the a4 integrin which mediates rolling also stimulates the β2 integrins to initiate firm adhesion and transmigration.

The αLβ2-ICAM-1 pair mediates migration of T cells across the endothelium by stabilizing the formation of a docking structure between T and endothelial cells.76 Recently, the junctional adhesion molecule-1 (JAM-1) was shown to be a ligand of the integrin αLβ2 during T cell transmigration.77

T cells must not only cross the endothelium but must also migrate through the perivascular basement membrane into the tissue or lymph node.

The integrin α4β1 promotes cell migration and antagonizes cell spreading. In particular, the association of the cytoplasmic protein paxillin to the cytoplasmic tail of α4 is essential for α4β1-mediated inhibition of cell spreading.78 In fact, α4-paxillin interaction promotes focal adhesion kinase (FAK) phosphorylation, which in turn is essential for integrin-dependent cell migration and disassembly of focal adhesions.78,79

It has been already mentioned that α4β1-CD81 complexes strengthen the adhesion to VCAM-1 under shear flow. Recently, another cell-surface partner of α4β1, the 4 immunoglobulin domains trans-membrane protein EWI-2, has been documented to regulate α4β1-mediated inhibition of cell spreading rather than interaction with VCAM-1 under shear flow.80 EWI-2 sequesters α4β1-CD81 complexes into larger α4β1-CD81-EWI-2 complexes, thereby limiting the availability of α4β1 to spread and ruffle on VCAM-1.80

Cells move by coordinating the generation of protrusions (lamellipodia) at the front of the cell, which lead to new attachments, and the detachment of previous adhesions at the rear of the cell. The integrin αLβ2 has been also shown to mediate T cell migration on ICAM-1 by influencing the acto-myosin cytoskeleton dynamic organization. This occurs by a compartmentalized regulation of myosin light chain kinase (MLCK) and Rho kinase (ROCK), at the leading edge and at the trailing edge, respectively.81 The coordination between these two kinases mediates the forward movement of the migrating T cells.

Interestingly, not only do integrins influence the cytoskeletal organization, but the cytoskeleton also modulates integrin activity. The specific binding of the cytoskeletal protein talin to integrin β subunit cytoplasmic tail leads to conformational rearrangements of integrin extracellular domains, thereby increasing the affinity for the ligand.82 FRET measurements between cyan fluorescent protein- and yellow fluorescent protein-fused αL and β2 provided in vivo evidence for α—β tail associations in the inactive form that are disrupted or rearranged after talin binding and subsequent integrin activation.83 The unconventional myosin-X (Myo10) is an actin-based motor protein that was recently shown by yeast two-hybrid to interact with integrin β subunit cytoplasmic tail.84 Knock-down of Myo10 by short interfering RNA impaired integrin function in cell adhesion, whereas overexpression of Myo10 stimulated filopodia formation and elongation in an integrin-dependent fashion. Moreover, Myo10 is also able to relocalize β1 integrins at the tips of the filopodia.84 Both talin and Myo10 bind to the β chain cytoplasmic tail NPXY motif, which is conserved in six of eight human β integrin cytoplasmic domains (including β1, β2, and β7), and the interaction is mediated by the FERM domain present on both talin and Myo10.82,84 A tight control of these interactions is fundamental to the regulation of integrin-mediated adhesion and migration.

Although the mechanism regulating integrin-mediated migration can be common for almost all integrins, the integrin repertoire, responsible for different ligand specificity, expressed on the cell surface by each immune cell specifically determines the migration routes towards tissues and/or lymph nodes. In this way, integrins collaborate with other families of receptors involved in homing, such as selectins and chemokine receptors. Recent in vivo studies showed an impaired Th2, but not Th1, effector homing to lungs in allergen-challenged β2-null mice.85 Moreover, in the spleen, αLβ2 and α4β1 integrins function together to promote both T and B cell transit from the marginal zone into white pulp cords.86

β7 integrins are differentially expressed on two subsets of memory T lymphocytes, αEβ7HIα4β7LO and αEβ7LOα4β7HI, and regulate their trafficking to mucosal sites.87,a In particular, α4β7 is expressed on a distinct subset of memory CD4 and CD8 T cells and directs their trafficking to intestinal sites of inflammation, while αEβ7 is present on intraepithelial lymphocytes, where it mediates their retention between intestinal epithelial cells, and on CD4+CD25+ and CD4+CD25- regulatory T cells (Treg).87,88 The importance of β7 integrins in lymphocyte migration into gut-associated lymphoid organs is shown by the phenotype of L-selectin/β7 integrin double knock-out mice. In these animals, more than 95% lymphocytes were unable to attach to high endothelial venules of Peyer's patches and other lymphoid tissues.89 Using a yeast interaction trap screen, a human WD repeat protein, termed WAIT-1, was isolated that interacts with the integrin β7 cytoplasmic tail.90 WAIT-1 also binds to the cytoplasmic domains of α4 and αE but not to those of integrin β1, β2, and αL subunits. This association of WAIT-1 and β7 integrin was confirmed by coprecipitation, and the binding site for WAIT-1 was mapped to a short membrane-proximal region of the β7 cytoplasmic tail. How this interaction modulates the binding capacity of β7 integrins is at present unknown.

In conclusion, the multitude of integrin-mediated interactions illustrates the importance of these receptors for the immune system, not only to facilitate migration but also to assist in mediating antigen specific signals by stabilizing cell-cell interactions.

Integrin-Associated Disorders

One of the best characterized integrin-associated diseases is leukocyte adhesion deficiency (LAD), a rare autosomal-recessive immunodeficiency.91 This syndrome results from a variety of mutations in the β2 chain that prevent normal formation of the integrin heterodimer and almost completely abolish cell surface expression.91 This disease is associated with an inability of leukocytes to firmly adhere to blood vessels, with subsequent persistent leukocytosis, dramatically reduced accumulation of neutrophils and monocytes at extravascular sites, impaired tissue remodeling, and recurring life-threatening bacterial infection.92

Very recently, a variant of this syndrome, LAD-III, has been documented.93 Although LAD-III shares some clinical features with LAD-I, these patients have only moderately reduced levels of β2 integrins on the surface of circulating leukocytes. This syndrome is characterized by the defective ability of integrins, like α4β1 and all β2, to undergo G-protein coupled receptor-mediated stimulation at endothelial contacts.93 This results in normal leukocyte rolling but impaired firm adhesion in response to chemoattractants displayed on the endothelial surface. Therefore, in LAD-III patients, integrins are present at the cell surface but are unable to sense activating inside-out stimuli (an abnormal Rap-1 machinery seems to be the cause of this syndrome94), while they can normally respond to stimulatory antibodies or cations.93 Accumulating evidence indicates the contribution of abnormal expression and function of integrins to hematological malignancies.

Defective adhesion through α4β1 and α5β1 integrins on chronic myelogenous leukemia (CML) is in part responsible for the abnormal premature CML CD34+ cells in the blood.95 Impairment of integrin-mediated regulation of CML progenitor growth and subsequent increased ability of CML CD34+ cells to survive without interacting with the BM would contribute to the massive expansion of CML progenitors.95

Adhesion defects regarding α4β1 and αLβ2 have been documented for malignant cells within B-lineage acute lymphoblastic leukemia.96 In these patients, although the expression levels of the integrins were normal, no integrin-mediated adhesion could be detected, and on the majority of cases no activation with stimuli like phorbol 12-myristate 13-acetate (PMA) could be obtained for either αLβ2 or α4β1.96 Whether this integrin unresponsiveness is due to mutations in the integrin molecule or in integrin-associated molecules is not known. The integrin αLβ2 and its counter receptor ICAM-1 have been also reported to be involved in enhanced survival of T-lineage acute lymphoblastic leukemia cell on BM stroma.97

The study of LAD disorders and tumor-associated integrin impairments can provide useful genetic and biochemical models to identify integrin binding partners that regulate both inside-out and outside-in activation mechanisms.

Conclusion

In this chapter we discussed the role of integrins in cells of the hematopoietic system. During the past 20 years a wealth of information has become available illustrating the importance of this family of proteins, not only for the proper development of the many cell types that arise from stem cells, but also for the proper functioning of the immune system. By now we know that integrin functions can be regulated at multiple levels and are indispensable for a properly functioning immune system. However, the precise signaling mechanisms are still unresolved, illustrating the complexity of integrin signaling. Novel techniques such as multiphoton laser microscopy and high resolution fluorescence microscopy will certainly reveal the dynamics of fluorescent protein tagged integrins unraveling the remaining secrets of this intriguing family of receptors.

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Footnotes

a

HI and LO indicate high and low expression level, respectively.

Copyright © 2000-2013, Landes Bioscience.
Bookshelf ID: NBK6618

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