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(Journal of Leukocyte Biology. 2003;73:556-563.)
© 2003 by Society for Leukocyte Biology

Leukocyte uropod formation and membrane/cytoskeleton linkage in immune interactions

Stefano Fais* and Walter Malorni{dagger}

Laboratories of
* Immunology and
{dagger} Ultrastructures, Istituto Superiore di Sanità, Rome, Italy

Correspondence: Dr. Stefano Fais, M.D., Ph.D., Laboratory of Immunology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: Fais{at}iss.it


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ABSTRACT
 
The acquisition of a cell polarity is a crucial requirement for migration, activation, and apoptosis of leukocytes. The polarization of leukocytes involves the formation of two distinct poles: the leading edge—the attachment cell site to the substrate allowing directional movements of the cell—and on the opposite side, the uropod—mostly involved in cell-to-cell interaction and in a variety of leukocyte activities including activation and apoptosis. However, the uropod takes shape in neutrophils, monocytes, and natural killer cells, and the formation of this cell protrusion seems to exert an important role in immune interactions. In fact, the polarization sites of leukocytes are involved in a complex cross-talk between cells and extracellular matrix components, and a number of receptors and counter-receptors crowd in the contact sites to allow efficient cell-to-cell or cell–substrate interaction. The membrane/cytoskeleton interaction plays a crucial role in tuning these activities and in "predisposing" leukocytes to their function through the acquisition of a polarized phenotype. This review is focused on the mechanisms underlying the formation of the leukocyte uropod, the role of cytoskeleton in defining its structure and function, and the involvement of the uropod in the complex interplay between immune cells.

Key Words: polarization • immunologic synapse • activation • apoptosis


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INTRODUCTION
 
The functional state of leukocytes depends on the occurrence of complex interactions among membrane proteins, cytoskeleton, and signaling networks. Membrane/cytoskeleton association acts as a supervisor for the maintenance of a dynamic cell shape and the continuous re-modeling of immune cell "signaling architecture." The ultimate reflection of this dynamic interaction is cellular polarization with the formation of distinct morphological and functional poles with a unidirectional orientation of leukocyte movement (reviewed in refs. [1 2 3 4 ]).


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LEUKOCYTE POLARIZATION
 
Although differing in function and architecture, most cell types polarize during the acquisition of a final phenotype (e.g., epithelial cells, neurons; reviewed in refs. [5 6 7 8 ]) or in a transient manner during the development of a specific function (e.g., leukocytes; reviewed in ref. [9 ]). In fact, leukocytes develop their polarized morphology when they undergo migration, activation, and cell-to-cell interaction. Between leukocytes, T lymphocyte polarization is the best known and characterized. It was described as an anterior-posterior polarity with the formation of two functionally and morphologically distinct poles: the leading edge, rich in chemokine receptors (CCRs) and substrate-adhesion molecules, and the uropod, described as the trailing edge of the cell and rich in various intercellular adhesion molecules (ICAMs) [10 ] (reviewed in refs. [9 , 11 ]). Studies obtained with human T cells adhering to polylysine-coated chamber slides, thus moving on a substrate mimicking the extracellular maxtrix (ECM) without passively floating in a medium, as in the typical culture conditions, suggested that general features of uropods include the following: a rapid outgrowth and withdrawal with the recovery of normal cell shape; the capacity to reach a spectacular size (up to six times the cell body); the presence of transient ruffles in the apical portion of the uropod; and the capacity to exert continuous movements leading to a meticulous "scanning" of the surrounding environment with reciprocal "touching and tasting" of the encountering cells [12 13 14 ]. These features can be well visible by time-lapse videomicroscopy (TLVM) analyses, where the above-depicted features can be easily appreciated. Different time frames obtained by TLVM (one frame every 10 s) of T lymphoblastoid cells clearly show that uropod formation occurs as a fast and reversible phenomenon visible in the great majority of the cells (Fig. 1 ). Moreover, the typical uropod is clearly distinguishable from the other well-known protruding cell-surface structures of leukocytes (Fig. 2 ). In fact, the uropod is an enormous cell protrusion as compared with dendrites and lamellipodia. Further morphological observation of T cell uropods provided straightforward images of T cells with uropods attached to the ECM substrate (Fig. 3A and 3B ) or "scanning" the environment as a sensory end (Fig. 3C) or in a reciprocal touching between encountering T cells (Fig. 3D) , suggesting the involvement of this lymphocyte protrusion in complex interactions with the microenvironment. In fact, leukocytes, including lymphocytes (Fig. 3E) , monocytes (Fig. 3F) , NK cells (Fig. 3G) , DC (Fig. 3H) , and granulocytes, have been shown to polarize in response to a variety of stimuli [15 , 16 ] (reviewed in refs. [9 , 17 ]). As shown in the figures, the polarized structures may differ from cell to cell, as uropods are typical of lymphocytes and monocytes and dendrites of DC. A great deal of evidence also suggested that the state of polarization of a cell is determined by specific interaction between the plasma membrane and the actin cytoskeleton, through actin/membrane-binding proteins (reviewed in ref. [18 ]). Ezrin, radixin, and, moesin (ERM) are three closely related proteins (4.1 band/ERM) playing a major role in the linkage between the actin cytoskeleton and cell-surface molecules in a variety of cells [19 , 20 ] (reviewed in refs. [3 , 4 , 21 , 22 ]). This linkage allows ERM proteins to actively participate in the polarization of the cells and in particular, of motile cells such as leukocytes, although other proteins (e.g., vinculin, {alpha}-actinin, pallidin, and talin) may participate in the establishment of leukocyte polarization [23 24 25 ] (reviewed in ref. [21 ]).



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  		Figure 1. Uropod formation. (a–f) Single frames of a time-lapse cinematography movie showing a sequence of pictures obtained by phase contrast microscopy from a culture of human lymphoblastoid cells adherent to polylysin-covered glass chamber slides. The sequence shows the continuous uropod formation and retraction occurring in the living cells within 1–2 h. The arrows point to a cell undergoing mitosis (a–c) and the uropod formation of the two derived cells immediately after division (d–f). Frames were taken every 15 min. Original magnification: 1500x.



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  		Figure 2. Leukocyte cell protrusions. Some surface structures of human leukocytes as detected by scanning electron microscopy. (A) Unpolarized T cell showing several short microvillous structures randomly distributed on the cell surface. (B) A T cell forming a long, protruding, antenna-like cell projection floating apically with respect to the cell body (uropod, arrow). (C) A long filopodium of a dendritic cell (DC; arrow) that can be distinguished from the typical, ramified, dendritic-like protrusions (D, arrows). A monocyte showing the typical ruffling appearance of lamellipodia (E, arrows). (F) Several long and thin retraction fibers left on the substrate by a monocyte are shown. Original magnification: A, C–F, 8000x; B, 2000x.



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  		Figure 3. (A–D) A series of scanning electron microscopy pictures showing polarized human T cells adhering on polylysine-coated slides, with the uropod (K) floating in the microenvironment and the leading edge (LE) adhering to the substrate. The T cell uropod appears as an emerging cell protrusion disposed side-by-side with the substrate on the opposite pole of the leading edge (A), arising from the substrate (B), or apically with respect to the cell body and perpendicularly to the substrate as an antenna-like cell projection (C). With their more apical sites, T cell uropods may get in touch with the encountering T cells (D). Original magnifications: 4000x. (E) Immunocytochemistry of a cytospin preparation of a human T cell line showing a straightforward polarization of CD44 on a cell uropod. Immunophenotyping of fixed cells was performed using the peroxidase-antiperoxidase (PAP) method (Dako, Denmark). AEC was used as chromogen (Dako) and Mayer’s haematoxylin for the counterstaining. Final, original magnification: 2500x. (F) Immunocytochemistry in slide-chamber preparation of human monocytes showing two monocytes with unidirectionally oriented uropods, adhering properly to a giant macrophage at the site of ICAM-1 polarization. Immunophenotyping of adherent monocytes was performed using the alkaline phosphatase-antialkaline phosphatase method (Dako). Fast red was used as chromogen (Dako) and Mayer’s haematoxylin for the counterstaining. Final, original magnification: 2500x. (G) Polarization of the CD44 molecule in natural killer (NK) cells forming conjugates with K562 target cells (TC) as detected by immunofluorescence. Note that polarized NK cells in different stages of the conjugation process are visible (arrows). Original magnification: 1200x. (H) Immunocytochemistry of a homotypic culture of human DC seeded on polylysine-covered glass chamber slides. DC are shown forming a synapse far from the cell body. Note the intense staining for the CD44 antigen on the DC and the way the CD44 staining highlights the thin and long dendrites connecting in the center of the field. Immunophenotyping of fixed cells was performed using the PAP method (Dako). AEC was used as chromogen (Dako) and Mayer’s haematoxylin for the counterstaining. Original magnification: 1000x.

Many monocyte functions directly depend on the ability of the monocyte to polarize following cytoskeleton activation. In fact, cytoskeleton activation and monocyte polarization are involved in adhesion, spreading, fusion, transendothelial migration, and antigen-presenting cell (APC) function [26 27 28 29 30 ] (reviewed in refs. [3 , 17 ]). Actin and ERM have a major role in monocyte polarization, which mostly involves the recruitment of intercellular adhesion molecules on the monocyte uropod, as efficient as monocyte-to-lymphocyte, monocyte-to-monocyte, or monocyte-to-EC adhesion (reviewed in refs. [3 , 17 ]). However, recent findings suggest the involvement of cell polarization and cytoskeleton in functions not directly related to immune interactions, such as the unidirectional secretion of cationic molecules in the tissue microenvironment. In fact, evidence has been provided that ezrin molecule colocalizes with the multidrug-resistance protein-1 (p170), related to the function of a cationic pump, in uropods of monocytes and lymphoid cells [27 , 31 ]. This is further supported by the fact that cytoskeleton remodeling is an important requirement for the polarized secretion of T cells toward the cells with which they are interacting [32 ] and that the majority of calcium release is first located in the uropod of T cells [32 , 33 ]. Further studies suggest that the p170 cationic pump is involved in the regulation of apoptotic mechanisms [34 , 35 ], and the colocalization of p170 with the ERM in the uropod [31 ] supports a key role of membrane/cytoskeleton interactions in the regulation of the apoptotic mechanisms.

Neutrophils circulate in the blood as spherical resting cells. In response to inflammatory stimuli, they leave the blood vessels by diapedesis and locomote across the ECM to the inflamed area. In fact, in response to various chemoattractants, P-selectin glycoprotein ligand 1 (PSGL-1), ICAM-3, CD43, and CD44 are redistributed to a newly formed uropod in human neutrophils, and PSGL-1 and ICAM-3 colocalize with ERM in the uropod of stimulated neutrophils [36 ]. By analogy with NK cells and lymphocytes [37 ], it appears highly conceivable that the polarization of activated neutrophils may be implicated in their killer activity.


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THE ROLE OF POLARIZATION IN THE IMMUNE RESPONSE
 
Initiation of an immune response requires an interaction between APCs, such as DC and T cells. After this interaction, i.e., after the binding of a T cell to an APC, cell-surface molecules redistribute into distinct patterns, forming an organized interface termed the immunological synapse (IS). Similar, reorganized interfaces have recently been observed with CD8 T cells, DC, and NK cells, suggesting that the formation of a cell-to-cell, synaptic complex is a key phenomenon in immune-cell interaction (reviewed in ref. [32 ]). Cell polarization in the IS appears to be associated with cytoskeleton rearrangement and is characterized by redistribution of adhesion molecules, the T cell receptor (TCR) plus the peptide–human leukocyte antigen pair and the CD28-B7 pair (reviewed in refs. [38 39 40 ]). Scanning electron microscopy analysis of this interaction has also shown that the formation of the IS between DC and lymphocytes involves other dramatic events, such as docking T cells through their uropods onto large and veiled protrusions of DC, which rearrange their membranes following the early contact and "embrace" the T cells [41 ]. These images show that T cells contact the APCs as hand mirror-shaped cells [42 ], through their uropod, maintaining this morphology all along the intimate contact [41 ]. However, the specific role of the lymphocyte poles (uropod and leading edge) in the early steps of IS formation still appears controversial [33 ]. In fact, data obtained with antibody-coated beads showed that initial contact between a T cell and an APC may occur through the leading edge [33 , 43 ], and the morphological observations seem to indicate the involvement of the lymphocyte uropod in the early steps of IS formation [41 ]. Thus, although the importance of lymphocyte polarization in IS formation seems unquestionable, the specific roles of uropod and leading edge in lymphocyte/DC interaction deserve further investigation. Conversely, it has recently been suggested that DC actively polarize their actin cytoskeleton during interaction with T cells and that DC cytoskeletal rearrangement is critical for the clustering and the activation of resting T cells [44 ]. Accordingly, various membrane proteins involved in lymphocyte adhesion and migration polarize and colocalize with the actin-based cytoskeleton in the uropod region of T cells (Table 1 ). For some of these proteins, a specific linkage to actin through the ERM proteins has been shown (reviewed in refs. [4 , 18 , 22 ]); for some others, including the TCR, data are often incomplete or inconsistent. In fact, although an association between the actin cytoskeleton and some of the TCR {zeta} chain molecules has been suggested, a specific role of ERM in this linkage has not been clearly demonstrated (reviewed in refs. [4 , 21 , 48 ]). However, beads coated with antibodies specific for the TCR–CD3 complex induce T cell polarization toward the bead-attachment site, reorientation of the microtubule-organizing center (MTOC), and actin polymerization [49 ]. This implies a complex cross-talk between actin filaments, TCR, and microtubule-associated proteins (reviewed in refs. [21 , 48 ]). Moreover, the dendrites of mature DC contain CD44 [16 ], stably linked to actin through ERM proteins (reviewed in refs. [3 , 4 , 18 , 22 ]). It seems highly reasonable that ERM proteins may be involved initially in promoting T cell polarization, allowing the T cell membrane to come into close contact with the APC. However, once signaling has begun, removal of ERM proteins might allow membranes to flatten out, as supported by electron microscopy studies [50 , 51 ] (reviewed in ref. [4 ]). This is further supported by the fact that following the formation of IS, the TCR on the T cell and the major histocompatibility complex molecules on the APC undergo a central distribution in the IS, and the lymphocyte function-associated antigen-1–ICAM-1 pair occupies the periphery of this scaffold [33 ]. The possible participation of IS in triggering apoptosis is currently under investigation in different cell model systems [52 ] (reviewed in ref. [53 ]), supporting a key role of cellular polarization and of uropod in many events regulating cell-to-cell interaction and determining the fate of the immune cells.


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  		Table 1. General Features of T Cell Polarization


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POLARIZATION, CYTOSKELETON, AND APOPTOSIS
 
When T cells acquire a polarized phenotype, the CCRs (e.g., CCR2 and CCR5) at the leading edge direct the migration, and various adhesion molecules (e.g., ICAMs and CD44), integrins, the TCR, coreceptors, and larger transmembrane molecules (e.g., CD43, CD45; reviewed in refs. [9 10 11 , 33 ]) in the uropod support its role in the establishment of cell–cell interactions and lymphocyte recruitment. However, recent data have also shown that polarization and the cytoskeleton are involved in conferring susceptibility to apoptotic stimuli in lymphocytes [14 , 54 ] (reviewed in ref. [55 ]). Polarization of Fas on lymphocytes seems to be associated with marked susceptibility to Fas-mediated apoptosis [14 ]. On uropod, Fas colocalizes with ezrin in CD4+ T lymphoid cells and activated lymphocytes (but not in resting lymphocytes). Moreover, Fas coimmunoprecipitates with ezrin, and treatments with ezrin antisense oligonucleotides (AO) significantly inhibited susceptibility to Fas-mediated apoptosis and Fas polarization in T cells. It is interesting that the same effects were not obtained with the moesin AO, suggesting a specific role of ezrin in the Fas linkage to actin in T cells. This was consistent with the inhibition of uropod formation, Fas polarization, and proneness to Fas-mediated apoptosis following treatments with microfilament-targeted drugs such as cytochalasins. Further studies also hypothesize a mechanism in which the Rho guanosine triphosphate (GTP)ases affect apoptosis by modulating the actin cytoskeleton [54 ] (reviewed in ref. [55 ]). Proteins belonging to the Rho family (Rho, Rac1, and cdc42) are in fact known to act as supervisors of actin-dependent phenomena, such as stress fibers formation (Rho), ruffling activity (Rac1), and filopodia extension (cdc42). The activity of the Rho family proteins may be nicely modulated by some bacterial toxins able to induce (e.g., by Escherichia coli CNF1 toxin) or inhibit (e.g., by Clostridium difficile B toxin) cell polarization phenomena and susceptibility to apoptosis [54 , 56 ] (reviewed in ref. [55 ]). In fact, Rho family proteins appear to exert a key role in the process of activation and inhibition of ERM [57 ], in turn suggesting an important role of small GTPases in regulating the polarization process.

Sphingolipid and cholesterol-based structures, membrane rafts, have received much attention in the last few years. Evidence is accumulating that lymphocyte polar segregation parallels the specific redistribution of membrane proteins associated with each raft subfraction, suggesting that raft partitioning is a major determinant for protein redistribution in polarized T cells [10 , 45 ] (reviewed in ref. [46 ]). Moreover, the acquisition of a motile phenotype in T cells results in the asymmetric redistribution of ganglioside GM3- and GM1-enriched raft domains to the leading edge and to the uropod, respectively [10 ]. Notably, recent data have shown a translocation of Fas into membrane rafts following Fas-triggering [58 ] and an essential role of membrane rafts in the initiation of Fas-mediated cell death signaling [59 ]. Moreover, GD3 associates with ezrin in the uropods after Fas-triggered apoptosis [60 ], and the F-actin filaments have been shown to play a key role in the initiation of Fas signaling [61 ]. Thus, ezrin seems to have a major role in connecting actin to Fas and downstream molecules of the Fas multiple cascades. This, in turn, suggests that uropods contain a multimolecular, death-inducing signaling complex whose assembly might be dependent on actin multiple connections, and activated ezrin may have a key role in allowing the actin connections to the various molecules contained in the complex (Fig. 4 ).



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  		Figure 4. The possible role of uropod cytoskeleton in Fas-induced apoptosis. Recent literature data are suggestive for a specific role of the microfilament system in the uropod formation as well as in the regulation of Fas-induced cell death. In particular, a rearrangement and redistribution of cytoskeleton components, e.g., MTOC, rho GTPases, and ezrin molecules, lead to uropod formation. An association between lipid rafts as well as ezrin cytoskeleton with a Fas molecule has recently been hypothesized (see text).


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POLARIZATION AND NK CELL ACTIVITY
 
Cell polarization and cytoskeleton have an important role in NK and cytotoxic lymphocyte (CTL) function. Particularly, NK cells require cytoskeleton integrity and function to migrate, bind, and kill their targets [62 , 63 ]. Polarization occurs in NK cells and TC (Fig. 5 ) and is considered of crucial importance during NK cell migration, the development of the so-called "NK–TC conjugate," and TC killing [64 , 65 ]. A role for microfilament system elements has been suggested in conjugate formation and junction avidity (binding process), and microtubular apparatus seems to play a key role in cytotoxicity (killing process) [66 ]. In fact, perturbance of the microtubular apparatus hindered TC killing, without affecting NK cell polarization and NK/TC binding [67 , 68 ]. Interleukin (IL)-15 and Rantes induce a redistribution of actin filament and adhesion molecules, amplifying conjugate formation and suggesting that ILs and chemokines may exert a key role in NK cell polarization [15 ]. Conversely, cytoskeleton also appears to be involved in the suicide behavior exerted by TC after binding with NK cells. In fact, a remodeling of the actin cytoskeleton and TC polarization was detected during induction of apoptosis, and disruption of F-actin cytoskeleton by cytochalasins results in the disappearance of uropods and ICAM-2 polarization and consequently, in the TC survival [63 , 69 ]. Accordingly, in some human pathologies (e.g., AIDS), lack of TC polarization and cytoskeleton rearrangement is associated with a decreased proneness to NK cell-mediated cytotoxicity [68 ]. Notably, ezrin cDNA transfection in TC leads to uropod formation, ICAM redistribution, and TC sensitization toward NK cell-killing activity, suggesting by analogy with lymphocytes, a key role of ERM proteins in triggering TC death [69 ]. Additionally, a relevant mechanism of FasL trafficking, occurring in NK cells and CTL, has recently been reported as involving specific intracellular transport of FasL on lysosomal-like vesicles that are unidirectionally polarized on the membrane of NK and T cells [37 ], suggesting a cytoskeleton-mediated, vectorial transport of these vesicles toward the contact sites between the killer and TC. Moreover, recent findings have shown that an active and polarized secretion of FasL-bearing exosomes, able to kill Fas-positive lymphocytes, may occur in melanoma cells and lymphoid cells [70 ], and the lytic granule of NK cells and melanosomes belongs to the same family of lysosomal-like vesicles (reviewed in ref. [71 ]). This, in turn, suggests that the unidirectional secretion of FasL-bearing microvesicles may represent a major mechanism used by various cell types to kill their targets. Notably, it has recently been shown that ezrin and radixin have a key role in the polarization of perforin granules in the NK/TC contact sites [72 ] and that the actin-regulatory protein Wiskott-Aldrich syndrome protein (WASp; see below) is expressed in human NK cells and localizes to the activating immunologic synapse with F-actin [73 ]. These data further support the hypothesis that connection with the actin cytoskeleton is a crucial requirement for lytic granule directional trafficking in NK cells and for the activation of NK cell function.



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  		Figure 5. Polarization in NK/TC pairs. Scanning electron microscopy. The micrograph shows two NK cells bound to a TC (K562 cells) seeded on a polylysine-coated slide. Uropod of the TC appears as a short protrusion to which NK cells adhere to exert their killing activity.


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CYTOSKELETON AND POLARIZATION ABNORMALITIES IN IMMUNE-RELATED DISORDERS
 
Two examples of human immune deficiencies associated with defects or activation of cytoskeletal function illustrate its importance in cell–cell interactions: WAS and human immunodeficiency virus (HIV)-1 infection. WAS is a rare, X-linked, primary immunodeficiency arising from mutation(s) in the WASp gene, which in normal cells, is involved in the control of cytoskeleton organization (reviewed in ref. [74 ]). In WAS lymphocytes, neutrophils, monocytes, and DC show a marked derangement in cytoskeletal organization, together with important impairment of leukocyte in response to various stimuli (reviewed in ref. [74 ]), suggesting that cytoskeleton abnormalities underlie this immunodeficiency. This abnormality is also associated with an increased proneness to apoptotic stimuli [75 ] and a decreased phagocytosis of apoptotic cells [76 ]. It is interesting that in this disease, a defect in the formation of uropod-bearing lymphocytes [42 ] and in monocyte polarization [77 ] has been shown, supporting the importance of the cytoskeleton-driven cell polarization for the occurrence of a proper immune response in vivo. An "opposite" example of a human disorder involving an altered immune-cell cytoskeleton is HIV-1 infection. HIV-1 replication is a dynamic process influenced by a combination of viral and host factors, whose interactions may influence the natural history of HIV-1 infection in AIDS patients. Among the host factors, the state of activation/differentiation of the immune system at the moment of primary infection is a crucial factor in determining the extent of HIV-1 infection and CD4+ T cell depletion [77 ] (reviewed in ref. [17 ]). Moreover, the chronic state of activation of lymphocytes (reviewed in ref. [78 ]) and the cell polarization induced by HIV-1 virions during cell-to-cell infection [79 ] may predispose lymphocytes to a Fas-mediated apoptosis [14 ]. In fact, lipid rafts have been shown to exert an important role in the preferential budding of HIV-1 in the uropods [80 ] and the lateral assemblies required for HIV-1 infection [81 ]. Moreover, indirect consequences of the aberrant polarization of virion-producing cells, primarily involved in cell-to-cell infection during the cytoskeletal-driven, unidirectional budding are the ICAMs and HIV-1 colocalization in lymphocyte uropods [79 ] and lymphocyte fusion in the region of uropod formation with the generation of syncytia, leading to the well-known cytopathic and proapoptotic effect of HIV-1 (reviewed in ref. [17 ]). As far as monocytes are concerned, a state of monocyte polarization may favor HIV-1 cell-to-cell infection [82 ] and multinucleated giant cell formation with persistent HIV-1 infection [83 ]. These data support the hypothesis that the state of polarization of lymphocytes and monocytes may have an important role in HIV-1 pathogenesis.


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CONCLUSIONS AND PERSPECTIVES
 
T cell movement implies not only rolling, tethering, and transmigration but also the unremitting search for other cells. The latter task is performed by the uropod, a specialized surface subdomain where a complex interplay between receptors and counter-receptors occurs. We propose the following sequence of events that emphasizes the role of leukocyte uropod in immune interactions (Fig. 6 ): Following various stimuli (cytokines, chemokines, viral proteins), various membrane receptors redistribute to the T cell uropod, determined by the cytoskeleton/membrane linkage through phosphorylated ERM proteins; the uropod-bearing cell interacts with other cells including EC, monocytes, DC, and killer cells (CTL, NK), which in turn, may become polarized; and the uropod-bearing cell undergoes migration, activation, or apoptosis depending on the cell type (counter-receptors) it encounters during transendothelial or tissue migration. A more fanciful way to imagine this phenomenon is that uropods may represent a set of enormous and puckered cell "lips," through which lymphocytes are highly predisposed to receive or give a "kiss of life" or a "kiss of death" by soluble factors or following intimate contact with other circulating or tissue cells.



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  		Figure 6. The possible role of the cytoskeleton-driven uropod formation in determining the fate of lymphocytes. The initial event is the activation of ERM proteins that underly the uropod formation following cytokine, chemokine, and/or viral protein stimulation of resting T cells. This implies the polarization of various membrane proteins (e.g., ICAMs, CD44, CD43, TCR, CD2, CD95) on the lymphocyte uropod. The polarized lymphocytes may undergo intimate contact with different immune cells expressing the specific counter-receptor(s) of the membrane proteins on the lymphocyte uropod. The reciprocal interaction of the polarized receptors and counter-receptors may in turn determine the fate of lymphocytes such as immune activation, following interaction with DC, or monocytes/macrophages (M{phi}); transendothelial migration, following interaction with endothelial cells (EC); or a rapid apoptosis, following interaction with killer cells (CTL, NK cells). Lymphocytes that have undergone immune activation and polarization may in turn undergo migration or apoptosis depending on the cell/counter-receptors they encounter in the tissue microenvironment.


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ACKNOWLEDGEMENTS
 
This work was supported in part by grants from the Italian Ministry of Health (40/D.5 and 30/D.9, National Research Program on AIDS), the Coordinated Grant Identification of the New Human Tumor Antigens and Strategies to Enhance their Immunogenicity and Override Tumor Escape, Associazione Italiana per la Ricerca sul Cancro (Milan), and CNR Project 99.01366.ST. We are grateful to Dr. Luis Montaner for helpful suggestions in preparing this review. We thank Dr. Mario Falchi for his invaluable technical assistance.

Received November 19, 2002; revised January 24, 2003; accepted January 28, 2003.


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