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First published online January 10, 2008
doi: 10.1242/10.1242/jcs.021253
Hypothesis |
Immune Signalling Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria 2002, Australia and Center for MicroPhotonics, Faculty of Engineering and Industrial Sciences, Swinburne University of Technology, Victoria 3122, Australia
e-mail: sarah.russell{at}petermac.org
Accepted 6 November 2007
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Summary |
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 Top Summary IntroductionDifferent forms of polarity...Switching between different...Polarity in T-cell fate...Functional consequences of...Future directionsReferences |
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Key words: T cells, Polarity, Immunological synapse
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Introduction |
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TopSummaryIntroductionDifferent forms of polarity...Switching between different...Polarity in T-cell fate...Functional consequences of...Future directionsReferences |
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). Antigen presentation generally occurs in the lymph node and is preceded by migration of the T cells to the lymph node and scanning of multiple APCs within the node, which again involves polarisation. After activation, the T cell divides multiple times to produce effector progeny, which migrate to the site of infection or immune activation. The different progeny then perform a myriad of tasks, including direct killing of target cells (cytotoxicity) and coordination of the immune response through direct cell-cell contact and cytokine secretion. Finally, most of the T cells die, leaving a small proportion of cells termed memory T cells that remain for many years and retain the capacity to respond rapidly to the antigen (Williams and Bevan, 2007).
Understanding the mechanisms by which T-cell polarity is regulated, and by which polarity influences T cell signalling, should provide important insights into immune regulation. Cells as diverse as epithelial cells, neurons and migrating astrocytes all utilise a network of proteins, which are highly conserved in worms, flies and mammals, to dictate the axis of polarity in either apico-basal orientation, directional migration, or asymmetric cell division (Nelson, 2003). Recent observations indicate that T-cell polarity is regulated by the same mechanisms (Humbert et al., 2006; Krummel and Macara, 2006). Analogies with other cell types not only suggest mechanisms by which T-cell polarity is regulated but also suggest new concepts by which polarity can regulate T-cell function. Here I draw parallels between polarity in lymphocytes and other cell types and explore how concepts developed from other systems might help us further understand the role of polarity in T cells.
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Different forms of polarity in T cells |
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TopSummaryIntroductionDifferent forms of polarity...Switching between different...Polarity in T-cell fate...Functional consequences of...Future directionsReferences |
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; Krummel and Macara, 2006). Below I briefly describe the most common forms of T-cell polarity, but refer readers to the many excellent reviews found elsewhere (Cemerski and Shaw, 2006; Krummel and Macara, 2006).
Polarity during T-cell migration (Fig. 1Ai) has been well studied, and not only dictates the direction of movement but also allows the coordinated cytoskeletal modifications that mediate propulsion (Krummel and Macara, 2006). Migrating T cells have a single protrusion at the rear of the cell called a uropod, which has the microtubule organising centre (MTOC) at its base and is rich in adhesion molecules (McFarland, 1969). This uropod has also been identified in T cells undergoing homotypic adhesion and in leukaemic cells (which were termed `hand-mirror cells') (*Lancet, 1978; del Pozo et al., 1997; Lilleyman et al., 1992).
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; Huang and Burkhardt, 2007; Krummel and Macara, 2006). The MTOC and secretory granules are recruited to the immunological synapse; in T-cell cytotoxicity this allows the release of cytotoxic granules specifically in the cleft between the T cell and its target, maximising killing efficiency (Kupfer et al., 1986; Stinchcombe et al., 2006). Polarisation of activated CD4 helper T cells mediates directed secretion of certain cytokines, such as interleukin 2, whereas other cytokines are secreted in a non-polarised fashion (Huse et al., 2006). By contrast, and despite intensive efforts using sophisticated in vitro approaches, a convincing function for the immunological synapse in activation of naive T cells has been elusive (Cemerski and Shaw, 2006). It might allow a T cell to focus on antigen presentation in the presence of other conflicting signals (see below). Note that the `virological synapse' triggered by the retroviruses HIV and HTLV-1 that provides a bridge to facilitate transfer of virus from infected to uninfected T cells is a related structure. Similarly, this triggers the recruitment of the MTOC and proteins such as CD4 to the site of receptor ligation (Barnard et al., 2005; Sol-Foulon et al., 2007).
Lymphocyte capping is another facet of polarity. Cell signalling, commonly initiated by the ligation and subsequent clustering of cell surface receptors, is often conceived as an aggregation of the few receptors in the local area of membrane exposed to the extracellular ligand. However, we have known for decades that in both B and T cells, ligation often involves relocation of receptors from the entire cell surface to patches or a cap at one pole of the cell – so called lymphocyte capping (Schreiner and Unanue, 1977). In at least some instances, the cap aligns with the axis of polarity, and proteins often form a cap at the tip of the uropod (Fig. 1Aiii) (Stackpole et al., 1974), which suggests that polarity and capping are mechanistically connected.
These different forms of polarity are unified by the concept of an axis of polarity that connects two distinct poles of unique composition, and passes through the MTOC, Golgi complex and nucleus. Both the orientation of the axis and the composition of the poles are dictated by a network of polarity proteins in epithelial and neuronal polarity (Humbert et al., 2006; Margolis and Borg, 2005). These proteins, which include the Par3 and Scribble complex, are expressed and polarised in T cells, and T-cell polarity is abrogated when Scribble or its partner, Dlg, is depleted (Krummel and Macara, 2006; Ludford-Menting et al., 2005; Round et al., 2005; Russell and Oliaro, 2006; Xavier et al., 2004). Pharmacological inhibition of the atypical protein kinase C, PKC
, part of the Par3 polarity complex in other cell types, prevents capping of the integrin, LFA-1, in response to the chemokine CCL21 (Giagulli et al., 2004). A fundamental property of the polarity network in other systems is the orientation of the axis of polarity and the definition of two different poles, ensuring for instance that there is only a single axon in neurons and apicobasal polarity in epithelial cells (Humbert et al., 2006; Wiggin et al., 2005). Studies of the polarity network in T cells suggest that it exerts similar functions in this system (Ludford-Menting et al., 2005; Round et al., 2005; Xavier et al., 2004), defining an axis of polarity during migration and antigen presentation.
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Switching between different forms of polarity |
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TopSummaryIntroductionDifferent forms of polarity...Switching between different...Polarity in T-cell fate...Functional consequences of...Future directionsReferences |
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). Polarity during chemotaxis of Dictyostelium dictates the response to new signals, allowing the cell to respond better to signals that are aligned with the axis of polarity, compared with signals that are perpendicular to that axis (Kimmel and Firtel, 2004). The notion that the axis of polarity facilitates certain cell functions, and the observations that extracellular signals can alter the axis of polarity, suggest the possibility that switching between polarisation states can provide a positive feedback loop to influence the response of a cell to competing signals.
The first indication that signals compete to dictate T-cell polarity came from observations that TCR signals induced migrating cells to round up and lose their uropods (Jacobelli et al., 2004; Ludford-Menting et al., 2005; Negulescu et al., 1996). TCR signalling seems to trigger loss of the polarity associated with migration, and this is required for the adoption of a new polarity associated with immunological synapse formation and optimal T-cell activation (Krummel and Macara, 2006). Interestingly, the polarity associated with migration affects T-cell signalling, because the regions of the cell surface that are sensitive to TCR signalling are at the leading edge, aligned with the axis of migratory polarity (Wei et al., 1999). Thus, not only does antigen presentation disrupt the polarity associated with migration, but this migratory polarisation can perhaps also influence the response of the T cell to antigen presentation.
Conversely, a preformed immunological synapse can be dismantled by alternative polarising events. This has been well established in T cells interacting with more than one APC or target cell. In these cases, the T cell retains contact with both interacting cells, but the MTOC and secretory organelles physically relocate to a stronger TCR signal (Depoil et al., 2005; Kuhn and Poenie, 2002). Recent studies using a photoactivatable agonist to control antigen density and timing of TCR signalling confirm that stronger TCR signals can redirect polarisation within minutes (Huse et al., 2007). A periodic disruption of the `bulls eye' pattern of the immunological synapse has recently been observed in T cells interacting with lipid bilayers (Sims et al., 2007), and it is possible that this might facilitate subsequent responses of the T cell to repolarising signals.
Chemokine signals can alter the T-cell response to antigen presentation (Bromley et al., 2000) and might regulate the duration of interaction between T cells and APCs by either reinforcing or changing the axis of polarity depending on how they are presented (Molon et al., 2005). Indeed, the effect of chemokines during antigen presentation is conditional on their placement in space and time (Friedman et al., 2006). TCR signalling might also be affected by a competing signal during thymic selection. In this instance, thymocytes (which require TCR signalling to develop into mature T cells) maintain prolonged interaction with the thymic stromal cells via an immunological synapse (Bhakta and Lewis, 2005). A reduction in TCR signalling corresponds with rapid migration of the thymocyte away from the stromal cell, suggesting that the thymocyte is subject to a competing chemokine signal that can override TCR signals to change the axis of polarity (Bhakta and Lewis, 2005).
Two further examples indicate that competition for the axis of polarity impacts upon much more than the decision to migrate or form an immunological synapse. Given the shared components described above, a virological synapse probably cannot exist in parallel with an immunological synapse. Indeed, HTLV-1 infection reduces MTOC recruitment to sites of ligation of the TCR component CD3 (Barnard et al., 2005), although the role of the virological synapse in this has not been explored. Ligation of other lymphocyte surface receptors, such as the complement and pathogen receptor CD46, can also recruit the MTOC and perforin-containing granules (Oliaro et al., 2006). The fact that polarisation in response to CD46 ligation prevents immunological synapse formation and subsequent T-cell activation and natural killer cell cytotoxicity (Oliaro et al., 2006) is evidence that this recruitment can affect polarisation towards, and the response to, secondary signals. Conversely, CD46 signals presented at the same site as TCR ligation can enhance the TCR signal, perhaps by reinforcing the axis of polarity (Astier et al., 2000; Oliaro et al., 2006; Russell, 2004). Thus, the polarity associated with lymphocyte capping might provide a general mechanism to regulate responses to TCR signalling by preventing polarisation towards the TCR signal.
T cells thus seem to preferentially focus on particular signals by polarising towards them, and then become less sensitive to alternative signals (Fig. 1B, Table 1). Polarity therefore might provide a positive feedback mechanism by which polarisation towards one signal raises the threshold above which an alternative signal will be recognised. Conversely, two signals presented from the same site might enhance each other by reinforcing the axis of polarity. The notion of competition for the axis of polarity raises the possibility that the immunological synapse, rather than facilitating T-cell receptor signalling per se, might be more important for protecting the T cell from other distractions in a complex environment. Determining the mechanisms by which polarity switches from one signal to another will be key to elucidating how responses to signals are triaged by the T cell.
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Polarity in T-cell fate decisions – a new role for asymmetric cell division |
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TopSummaryIntroductionDifferent forms of polarity...Switching between different...Polarity in T-cell fate...Functional consequences of...Future directionsReferences |
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; Sugimoto and Yasuda, 1983), and periodic discussions of this idea in reviews (Dustin and Chan, 2000; Mullbacher and Flynn, 1996), most have assumed that any differences between the daughters must depend on chance differences in the distribution of cell fate determinants in each daughter or differential exposure to extracellular cues following cell division (Grossman et al., 2004; Sallusto et al., 2004). These assumptions were reinforced by the observed short duration of contact between T cells and APCs in most in vitro experiments, which would suggest that the parent T cell is not provided with a polarising cue. However, this notion must be revised given new in vivo evidence indicating that such interactions can last for hours and might even be maintained through cytokinesis (Henrickson and von Andrian, 2007; Stoll et al., 2002). In cells other than T cells, the polarity network maintains an asymmetry long after the initial polarising event, perhaps the most striking example being the asymmetric division of the Caenorhabditis elegans zygote, in which entry of the sperm initiates polarisation, and sustained asymmetry is orchestrated by the Par proteins until cytokinesis (Cowan and Hyman, 2004). These observations suggest the possibility that asymmetric cell division could be orchestrated by the APC even if it detaches from the T cell before cell division.
The new observations raised the possibility that T-cell fate is controlled by asymmetric cell division, a process used by many other cell types to dictate differential fates of daughter cells (Fig. 1C). The process has been best studied in model organisms such as Drosophila, where the fate of neuroblasts and sensory organ precursors is dictated by precisely controlled asymmetric distribution of cell fate determinants (both protein and mRNA) during cytokinesis (Betschinger and Knoblich, 2004; Wodarz, 2005). To achieve this, the parent cell utilises an external cue to dictate the axis of polarity, recruits cell fate determinants to one pole of the axis and aligns the mitotic spindle along the same axis of polarity. Not surprisingly, the proteins that control this process include the polarity network, which also regulates T-cell polarity (Betschinger and Knoblich, 2004; Krummel and Macara, 2006; Wodarz, 2005).
Evidence for asymmetric division of T cells has now been obtained in an in vivo murine model system (Chang et al., 2007). Analysis of antigen-stimulated T cells extracted from mice revealed that cells engaged in mitosis or cytokinesis asymmetrically distribute several proteins. Furthermore, the progeny of the first division asymmetrically express many of these proteins, which strongly suggests that the asymmetric distribution observed during mitosis is maintained during cytokinesis, such that the two daughters inherit different quantities of the proteins. Importantly, many of the asymmetrically localised molecules have previously been implicated in asymmetric cell division in other systems or in T-cell fate decisions.
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Functional consequences of asymmetric cell division |
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TopSummaryIntroductionDifferent forms of polarity...Switching between different...Polarity in T-cell fate...Functional consequences of...Future directionsReferences |
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; Wodarz and Huttner, 2003). This allows rapid expansion of a cell population without compromising the integrity of the precursor cell, which could clearly apply to many phases of lymphocyte expansion. Asymmetric cell division can also dictate that the two daughters follow alternative differentiation pathways, or that one daughter is more predisposed to die than the other. These concepts are particularly pertinent to the observations of Chang et al. (Chang et al., 2007), which suggest that asymmetric division of T cells gives rise to one daughter destined to become a memory T cell and one that produces effector T cells. It has long been known that a single T cell can give rise to both rapidly proliferating, short-lived effector cells and long-lived memory cells (Williams and Bevan, 2007), and the precedents in other cells suggests that asymmetric cell division has the capacity to dictate not just the differentiation potential of the two daughters into effector versus memory cells, but also their proliferative capacity, sensitivity to apoptosis and self-renewal capacity.
The influence of asymmetric cell division is perhaps most elegantly demonstrated in Drosophila sensory organ precursors, where asymmetric cell division precisely programs the death, proliferation and differentiation not only of each daughter but also of each descendent in subsequent generations (Lai and Orgogozo, 2004). To decipher the role of asymmetric cell division in the control of immune cells, we need to answer the following questions: (1) how widely is asymmetric cell division utilised by T cells and other lymphocytes; (2) how is it influenced by extracellular events; (3) what molecules can be segregated by this process; and (4) how does their asymmetry influence subsequent cell functions?
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) (Fig. 2). Early studies suggested that it might also occur during thymocyte development (Metcalf and Wiadrowski, 1966; Sugimoto and Yasuda, 1983). One could also envisage asymmetric cell division occurring, for instance, in activation of resting memory cells or following the contact-dependent influence of suppressor T cells. Other triggers of polarity could also cause asymmetric cell division, including chemokines and pathogens (Table 1). It is likely that each trigger of polarity might differently segregate molecules into the two daughter cells, thereby effecting different cell fate decisions. Indeed, antigen presentation is likely to dictate a different polarisation of molecules depending upon, for instance, the type of cell that presents antigen and the costimulatory molecules it expresses on its surface. This would mean that changing the mode of antigen presentation (for instance, the subclass of dendritic cell) could induce subtle changes in the distribution of molecules between the daughter cells that influence subsequent cell fate. In each case, verification of a role for asymmetric cell division will involve visualising the differential allocation of molecules to each daughter, identifying a difference in cell fate for the proximal and distal daughters, and/or identifying a change in cell fate if asymmetric cell division is altered or disrupted.
Perhaps the most informative initial clues to how asymmetric cell division might influence cell fate will come from identifying asymmetrically distributed molecules already known to influence cell fate. The interferon 
receptor is asymmetrically distributed during T-cell division (Chang et al., 2007), which suggests that proximal and distal daughters might, at least initially, respond differently to interferon . Note that even a transient difference in interferon signalling should cause profound differences in cell fate, even if the level of protein in each daughter is rapidly normalised.
In other systems, a diverse range of molecules, including regulators of transcription and translation, surface receptors and signalling molecules, is asymmetrically distributed (Betschinger and Knoblich, 2004; Wodarz and Huttner, 2003). Of particular interest is the regulator of Notch signalling Numb, which was one of the first cell fate determinants shown to be asymmetrically distributed in neuroblasts. Its asymmetric distribution leads to subsequent differences in Notch activity of the daughters and has profound effects on cell fate (Betschinger and Knoblich, 2004; Wodarz, 2005). Significantly, Notch signalling is influential in T-cell development and function, and Numb is distributed asymmetrically into daughter T cells (Chang et al., 2007). Even a transient difference in the levels of cell fate determinants such as Numb, or in surface receptors or transcriptional/translational regulators, could have far-reaching consequences. Indeed, recent data suggest that the two daughters inherit opposing differentiation and proliferation characteristics (Chang et al., 2007). The possibility that asymmetric cell division might bestow rapid proliferation potential to one daughter cell, and self renewal potential (stem-cell-like fate) to the other, has important implications for immune memory. Disruption of asymmetric cell division in developing murine neuronal cells leads to lesions similar to human primitive neuroectodermal tumours (Klezovitch et al., 2004); perhaps compromised asymmetric cell division is involved in lymphoproliferative diseases such as leukaemia.
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Future directions |
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TopSummaryIntroductionDifferent forms of polarity...Switching between different...Polarity in T-cell fate...Functional consequences of...Future directionsReferences |
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The notion that T cells can undergo asymmetric cell division opens up a number of new avenues of investigation. Asymmetric cell division must first be conclusively demonstrated by live imaging, and the molecules whose distribution is asymmetric during cytokinesis catalogued in different stages of T-cell development and activation. A powerful approach to elucidating the role of asymmetric cell division in other cell systems has been to disrupt polarity during division. Given the role of the Scribble complex in asymmetric cell division (Albertson and Doe, 2003; Bellaiche et al., 2001) and in T-cell polarity (Krummel and Macara, 2006; Ludford-Menting et al., 2005), as well as the asymmetric distribution of Scribble during T-cell mitosis (Chang et al., 2007), it seems likely that the mechanisms are conserved across cell types. Similarly the polarisation of PKC during asymmetric cell division (Chang et al., 2007) suggests that, as in neuroblasts, the Par3 complex regulates asymmetric divison of T cells. Consequently, previous approaches to disrupting asymmetric cell division could be exploited in T cells. By learning how asymmetric cell division is regulated, in terms of the internal molecular mechanisms and the influence from external signals, new mechanisms to influence the function of T cells, and perhaps other immune cells, might be developed.
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Acknowledgments |
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TopSummaryIntroductionDifferent forms of polarity...Switching between different...Polarity in T-cell fate...Functional consequences of...Future directionsReferences |
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