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Review
Nature Immunology - 7, 1143 - 1149 (2006)
Published online: 19 October 2006; | doi:10.1038/ni1404

Maintenance and modulation of T cell polarity

Matthew F Krummel1 & Ian Macara2

1 Department of Pathology, University of California at San Francisco, San Francisco, California 94143-0511, USA.

2 Center for Cell Signaling, Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0577, USA.

Correspondence should be addressed to Matthew F Krummel matthew.krummel@ucsf.edu or Ian Macara igm9c@virginia.edu

As T cells move through the lymphatics and tissues, chemokine receptors, adhesion molecules, costimulatory molecules and antigen receptors engage their ligands in the microenvironment and contribute to establishing and maintaining cell polarity. Cytoskeletal assemblies, surface proteins and vesicle traffic are essential components of polarity and probably stabilize the activity of lymphocytes that must negotiate their 'noisy' environment. An additional component of polarity is a family of polarity proteins in T cells that includes Dlg, Scrib and Lgl, as well as a complex of partitioning-defective proteins. Ultimately, the strength of a T cell response may rely on correct T cell polarization. Therefore, loss of polarity regulators or guidance cues may interfere with T cell activation.
T cells traffic through a signal-rich environment. In the blood, they receive cues from chemokines, which permit attachment and extravasation into tissues. In secondary lymphoid environments, receptors on the T cell surface integrate signals from ligands bound to other cells or to the extracellular matrix and from gradients of soluble mediators. At the sites of effector function, T cells encounter secreted products of activated macrophages, neutrophils and natural killer cells, which may result in polarized or nonpolarized stimulation of cytokine receptors on T cells. Underlying a successful T cell response, then, is the ability to 'prioritize' these cues and subsequently orient effector mechanisms toward the optimal targets. This review discusses polarity 'themes' in T cells and their potential inter-relationships and will postulate how polarity is modulated when T cell receptor (TCR) stimuli are encountered.

Polarity 'themes' in motile lymphocytes
Like a musical partita, the five systems of T cell morphology are variations on a shared polarity 'theme'. The actin cytoskeleton, tubulin cytoskeleton, surface proteins, vesicle traffic and conserved polarity proteins are all polarized relative to the motility axis. Among the best studied of those systems are the actomyosin cytoskeleton and the GTPases associated with promoting actin nucleation (Fig. 1a). Actin fibers are inherently polar fibers with their barbed ('plus') end at the site of monomer addition and in the direction of actin-based protrusion. That constitutes the leading edge in lymphocytes and is probably very similar to the lammellipodial regions generated in other motile cell types, in that free actin filaments drive protrusion independently of myosin II crosslinking activities1. However, behind the leading edge and extending through the midbody is a zone of high myosin II accumulation2 in which it is likely that actin is organized by myosin in rods that are mostly parallel. In epithelial cells, this region corresponds to the lamella, and the myosin II in this zone causes retrograde flow of actin filaments and attached membranes toward the rear of the cell1. Rearward movement of surface-bound beads toward the uropod has demonstrated that retrograde cortical flow also occurs in T cells3. Myosin II 'motors' are probably responsible for retrograde flow, as shown by the accumulation of myosin II at sites of leading edge retraction and the subsequent retrograde flow of those motors into the uropod2.

Figure 1. Five polarity systems in motile T lymphocytes.
Figure 1 thumbnail

(a,b) Polarity can be described from the perspective of the actomyosin cytoskeleton (a) or tubulin cytoskeleton (b), which are polarized relative to the direction of migration (green arrow). (c) A front-to-back 'footprint' of integrins on substrates (red shading) and uropodal accumulation of receptors further delineates the polarity. (d) Both directional migration and the associated cycling of integrins require the movement of material through the cytoplasm by means of an endocytic-exocytic loop. (e) Evidence places evolutionarily conserved polarity proteins in distinct locales during migration.



Full FigureFull Figure and legend (39K)
The microtubule cytoskeleton and related kinesin and dynein motors comprise a second polarized cytoskeleton (Fig. 1b). Like actin filaments, microtubules are inherently polarized. Microtubules are organized around a microtubule-organizing center (MTOC). That arrangement creates another level of polarity, as the MTOC is invariably in the uropod and behind the nucleus.

Surface receptors and perhaps membrane lipid rafts are also polarized such that some are localized toward the uropod, whereas others, activated integrins in particular, are likely to cycle toward and accumulate at the leading edge4 (Fig. 1c). Actomyosin and membrane movement from the front of the cell to the rear of the cell probably accounts for the general accumulation of many surface receptors at the uropod: TCRs, CD2, CD43 and CD44 accumulate at the uropod before activation5, 6, 7, 8; ICAM, CD43 and CD44 in particular are probably localized as a result of their association with the C terminus–phosphorylated form of ezrin-radixin-moesin (cpERM), which associates with actin5, 6. In comparison, adhesive receptors such as LFA-1 are selectively retained along the 'midbody' of the cell by adhesion4. Cholesterol-rich rafts may also be polarized along with those receptors9.

Integrins may also be specifically recycled to the leading edge by as-yet-unidentified selective vesicular traffic from the uropod to the leading edge (Fig. 1d). Cycling is important, as forward motility requires the internalization of highly adhesive integrins at the front and midbody at the uropod and that they be recycled 'forward' to contribute to new projections. It is highly probable that endocytosis and exocytosis are generally polarized along the axis of movement and also reinforce other systems of polarity by asymmetrically depositing material at one end of the cell or the other. Much vesicle movement probably involves the Rab family of proteins that direct the fusion of vesicles with the plasma membrane and also associate with specific myosins or kinesins for directional transport. The targeting and docking of vesicles with membranes involves the recognition of vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptors (v-SNAREs) by target SNAREs (t-SNAREs) that are enriched at specific sites along the membrane. SNAREs typically consist of syntaxin and SNAP proteins, some of which have been identified in T lymphocytes10, 11. Polarized distribution of t-SNAREs at the leading edge of motile T cells remains to be assessed, but would be predicted to 'encourage' delivery of vesicles in the direction of motility.

The proteins scribbled (Scrib), lethal giant larvae (Lgl) and discs large (Dlg), together with partitioning-defective (PAR) polarity proteins (Fig. 1e), have emerged as a fifth set of participants regulating many aspects of lymphocyte biology. Scrib, Lgl and Dlg proteins were first identified by genetic screens in flies or worms and are key conserved elements required for polarization of cells in many contexts. For example, Scrib was identified in a screen for genes involved in apical versus basal polarity in drosophila embryonic epithelium, but it also functions in synaptic vesicle dynamics12 and acts as a tumor suppressor13. Scrib interacts genetically with the two other tumor suppressors Lgl and Dlg, which are also essential for maintaining apical versus basal polarity. Somewhat unexpectedly, no existing evidence indicates the involvement of mammalian Scrib protein in the maintenance of apical versus basal polarity, but Scrib has been linked to the regulation of planar polarity of the inner ear epithelium14, in epithelial cell-cell adhesion15, in endocytosis and recycling of G protein–coupled receptors (GPCRs)16 and, most unexpectedly, in T cell polarization17.

PAR proteins were first identified in a screen for genes affecting the first asymmetric division of the Caenorhabditis elegans zygote. Of the six PAR genes that have been cloned, those encoding PAR-3, PAR-6 and atypical protein kinase C (aPKC) interact both genetically and physically. PAR-6 seems to function at least in part as a targeting subunit for aPKC, to which it binds constitutively. The PAR proteins also interact with Scrib, Lgl and Dlg proteins. For example, PAR-6 can recruit Lgl, which is then phosphorylated by aPKC18, 19, 20.

Polarized assemblies in motile lymphocytes
T cells have a directional axis of motility, and a fundamental driving force for the polarization and migration of T cells is the dynamic remodeling of actin cytoskeletal elements. In most cell types that have been studied, remodeling is controlled by the Rho family of GTPases through a plethora of effector proteins. Rac and Cdc42 GTPases, in particular, have been associated with the protrusion of the leading edge and in the orientation of migration (Fig. 2a). Overexpression of mutant forms of either GTPase results in loss of polarity and defective chemotaxis toward the chemokine SDF-1 (refs. 21,22). 'Downstream' effectors of Rac and/or Cdc42 include the Wiskott-Aldrich syndrome protein (WASP), neural WASP and the related WAVE (also called Scar) family of proteins, which induce actin nucleation through the complex of Arp2 and Arp3. WASP is required for optimal chemotaxis23, 24, but evidence has indicated WAVE2 is a predominant participant in hematopoietic cell migration25, 26, 27. WAVE2 is required for actin cap formation at the immunological synapse (IS) and forms a complex with the Hem-1 linker protein26. Hem-1 is required for actin protrusions in neutrophils and augments leading-edge identity by inhibiting activation of the myosin light chain at that site25.

Figure 2. Distinct zones in motile lymphocytes.
Figure 2 thumbnail

Various functional compartments serve to stabilize crawling activity. All these molecules have been found in the locations here except those in gray italics, which have not yet been assessed in T cells. (a) A protrusive complex that uses a WASP family member to activate actin elongation is probably associated with the Hem-1 molecule in a cassette, which inhibits myosin light-chain activation. N-WASP, neural WASP. (b) A contractile cassette 'downstream' of chemokine receptors and integrins may use Rho to activate ROCK and thereby induce myosin II contractility. Additional signaling (such as via phosphatidylinositol-3-OH kinase) is not presented here. MLC, myosin light chain. (c) The uropod is proposed to be the site of a cpERM-based internalization 'engine'. The cpERM-mediated recruitment of Dlg may also recruit Scrib via a GUK-holder (not yet identified in T cells). Scrib localization in the uropod in turn may recruit and activate Arf proteins via the assembly of betaPIX-GIT complexes. (d) PAR-6–aPKC–based cassettes throughout the cytoplasm may prevent actin elongation through PAR-3-mediated binding of LIMK or Tiam1. Alternatively, PAR-6–aPKC complexes can interact with Lgl, which interacts with syntaxins and myosin.



Full FigureFull Figure and legend (41K)
In contrast to Rac and Cdc42, which promote actin nucleation, the GTPase RhoA activates a protein kinase, ROCK, that phosphorylates myosin light chains and thus increases the contraction of actin filaments relative to each other (Fig. 2b). Rho is 'downstream' of chemokine GPCRs and is required for increases in integrin affinity28, 29. Thus, it is likely that in contrast to Rac and Cdc42, Rho proteins located at the site of GPCR signaling activate myosin, which triggers sliding of this membrane patch toward the cell uropod, thereby generating forward thrust in the rest of the cell. Although that model is likely, the system is more complex locally, as a Rac complex with its effector PAK have also been linked to the chemotaxis of both macrophages and T cells30, 31. As Rac often antagonizes Rho function32, the details of how these GTPases function in concert remains a mystery.

In T cells, Rho is also required for uropod formation, possibly because of its involvement in augmenting phosphorylation of ERM33. That function is important, because cpERM in the uropod may tether a complex that aids in recycling components back to the leading edge through vesicle trafficking mediated by ADP-ribosylation factor (Arf; Fig. 2c). Arf family GTPases control vesicle movement during motility in autologous systems34, although the function of these proteins in T cells has not been established. The PDZ domains of mammalian Scrib associate with the C terminus of the Rac guanine-exchange factor betaPIX35, which in turn binds to GIT1, a scaffold protein with an Arf GTPase-activating protein domain. This Scrib-betaPIX-GIT1 complex has been linked to the recycling of GPCRs16 in autologous systems, suggesting a similar function in T cells. Scrib is localized in the uropod17, but how does that localization occur? In drosophila neurons, Dlg determines the localization of Scrib, and these two proteins form a complex that is mediated via the scaffold protein 'GUK-holder'36. A mammalian homolog of GUK-holder has been identified, but it has not yet been shown to be functionally equivalent to the fly protein, and its expression in T cells is untested. However, human Dlg is targeted to membranes by its association with ERM37, and Dlg proteins are found in the T cell uropod alongside cpERM proteins17. Notably, Scrib-deficient T cells fail to maintain polarity and cease movement, consistent with requisite involvement of these proteins in a motility cycle17.

A final functional cassette is probably in the motile cell and consists of PAR-3, Lgl, PAR-6 and aPKC-zeta which are all localized in the midbody17. In epithelial cells, Lgl can associate not only with myosin II and PAR-6 but also with syntaxins, which control vesicle delivery to specific target membranes. As mentioned above, PAR-6 seems to function at least in part as a targeting subunit for aPKC, to which it binds constitutively. Thus, in drosophila embryonic epithelial cells, PAR-6 can recruit Lgl, which is then phosphorylated by aPKC18, 19, 20, which in turn triggers disassociation of the complex from the cell cortex. The PAR-6–aPKC complex can also bind to and phosphorylate the ubiquitin E3 ligase Smurf1, one target of which is RhoA38. A key function of the PAR-6 polarity cassette might therefore be to trigger local degradation of RhoA, which would reduce actin contractility and block Rho-induced phosphorylation of cpERM proteins. In addition, PAR-6–aPKC binds to and phosphorylates PAR-3 (refs. 39, 40, 41). As PAR-3 is capable of binding to and spatially restricting the activity of the Rac guanine-exchange factor Tiam1, the PAR-6–aPKC–PAR-3 interaction probably also regulates actin dynamics42, 43. Tiam1 was first identified as a T cell lymphoma invasion and metastasis gene44. The association of PAR-3 with LIM kinase (LIMK) may further regulate actin in the area through LIMK regulation of cofilin43. Variations in the composition of PAR-6–aPKC complexes may create unique actin dynamics in the midbody that facilitate both forward motility through actomyosin regulation and vesicle trafficking through syntaxin regulation (Fig. 2d). The nature of those complexes remain to be elucidated.

Cytoskeletal polarity in the IS
In a signal-rich environment, interrelated feedback systems like those described above are important for stabilizing cellular activity. In contrast, TCR signaling initiates a transformation from high motility to the stable IS45, 46. How might that signal create the conditions in which proteins are repolarized, and how is a stable IS maintained?

The reorientation of the T cell during engagement with an antigen-presenting cell (APC) and formation of the IS are reminiscent of the switch in polarization that occurs during the epithelialization of mesenchymal cells. In both cases, cells undergo substantial morphological changes, which are driven by remodeling of the actin and microtubule cytoskeletons and by relocalization of polarity proteins. During the mesenchymal-epithelial transition, anterior-posterior polarity is converted into apical-basal polarity. Microtubules and actin reorganize to form bands around the cell periphery, the Rac GTPase redistributes from the leading edge to the lateral membrane, and polarity protein such as PAR-3, Scrib, and Dlg translocate to the cell-cell junctions. A functionally similar switch occurs in T cells: the uropod at the posterior of the T cell disappears46 and polarity proteins such as Scrib and Dlg transiently redistribute from the uropod to the front of the cell where the IS forms17, 47, 48.

A first step in this transformation may be the disassembly of existing cytoskeletal structures (Fig. 3a). TCR signaling transiently leads to the dephosphorylation of cpERM, and that modification results in cytoskeletal relaxation, probably because of release of the membrane-actin linkage anchored by ERM49. That occurs through Rac activation49, which may antagonize Rho-induced ERM phosphorylation33. Such relaxation may release cell surface receptors and proteins such as Dlg and Scrib, which can then traffic to the leading edge. TCR signaling also induces the calcium-dependent phosphorylation of myosin II (ref. 2). Myosin heavy-chain phosphorylation results in loss of myosin filamentation50, probably releasing the aligned actin filaments in the midbody and uropod and permitting reorganization of the components formerly located in those regions.

Figure 3. Early events in polarity modulation.
Figure 3 thumbnail

Specific multiprotein complexes are suggested to mediate changes in polarity and morphology. (a) Cytoskeletal relaxation is thought to occur as a result of cpERM dephosphorylation as well as debundling of myosin II (MyoII) filaments. (b) Specific multiprotein complexes then assemble at the T cell–APC membrane contact site. These include TCR-actin complexes, Scrib complexes (perhaps containing betaPIX and PAK), TCR-Dlg complexes (perhaps nucleating actin) and crumbs complexes (perhaps recruiting Pals and PAR-6 complexes). Molecules in gray italics have not yet been assessed in T cells, but all others have been localized as presented here. All interactions are not always presented here (for example, Zap70 has been linked to WASP through multiple pathways). (c) Active transport is suggested to complete repolarization. Myosin motors may be instrumental in recruiting uropodal components along the membrane or through the cell. Similarly, microtubule-based motors may recruit molecules toward or within the IS. PI(3)K, phosphatidylinositol-3-OH kinase.



Full FigureFull Figure and legend (68K)
At the leading edge, TCR signaling induces actin complexes and the early assembly of microclusters of TCRs7, 51. Microclusters probably arise as a result of TCR-induced activation of the Lat and SLP-76 adaptor proteins, which trigger WASP and PAK activation, which promotes actin assembly52, 53, 54 (Fig. 3b). However, Dlg, which is found at the center of the contact, in the central-supramolecular activation cluster (c-SMAC), during the first minutes of contact17, 47, 48, 55, is probably another participant in this dynamic process. Dlg associates directly with the Src homology 3 domains of both the Zap70 and Lck tyrosine kinases48, 55. In that way, Dlg probably senses the proximity between Lck and Zap70 that occurs during clustering of TCR and CD4 proteins and might even promote further aggregation of those proteins (Fig. 3b). Dlg also interacts with microtubule kinesins56 and thus may act to initiate repolarization of the microtubule-based cytoskeleton. Finally, the Lck-Zap70-Dlg complex also seems to include WASP48, and formation of that complex may help to move WASP into proximity of active Cdc42. Transient phosphorylation of Zap70 and Lck when the TCR is activated may trigger conformational changes in that complex and promote its alteration from a motile to an IS form. Loss of Dlg from the IS at later times17 is consistent with loss of active Lck in the late IS57. It is perhaps notable that elimination of Dlg by means of short hairpin RNA in cell lines can alternatively augment47 or attenuate48 T cell activation. Those observations are perhaps indicative of the importance of polarity in making T cells receptive to signals in the first place or, alternatively, in stabilizing the newly emerging signal, and those disparate results may reflect the polarized nature of the stimulation provided in the various experiments.

Like Dlg, Scrib moves from the uropod, is transiently localized in the nascent IS and subsequently moves to a position mainly outside the IS17. In the IS, Scrib may function to recruit the Rac and Cdc42 guanine-exchange factor betaPIX (Fig. 3b). That protein has been shown to recruit PAK to the IS in T cells58. Therefore, defects in Scrib-deficient T cells17 and in T cells expressing dominant negative PAK59 may reflect a requirement for a Scrib-betaPIX-PAK complex during T cell activation.

Finally, the regulation of PAR-6-based cassettes may represent a more complex mechanism of influencing local polarity in response to signaling. The Par-6–aPKC heterodimer can bind several alternative partners through its PDZ domain, including Lgl, Par-3 and Pals1 (protein associated with Lin7)60. In eukaryotes, Pals1 is recruited to the cell surface by crumbs, the mammalian homolog of Lin7, and functions to recruit the PAR-6–aPKC complex to the cell cortex. In the case of T cell IS, crumbs1 is constitutively localized in the IS17 and thus may lend 'apical identity' to this surface (Fig. 3b). The mechanism by which crumbs is localized to the IS, however, is yet to be determined.

Release of cytoskeletal tension (Fig. 3a) and assembly of polarity complexes (Fig. 3b) are probably supplemented by an active transport mechanism that moves proteins from the former uropod into the IS (Fig. 3c). Surface movements exceeding the rate of diffusion have been noted for TCRs and for beads moving along the cell surface61 and have been shown to depend on phosphatidylinositol-3-OH kinase and myosin3. Conversely, movement of SLP-76 into the central IS seems to rely on microtubules62, suggesting that a microtubule-based movement, perhaps mediated by a kinesin, also functions to reorient critical signaling proteins.

Stabilization of polarity in the IS
In a stable IS, actin and actomyosin contraction is diverted away from rapid motility and functions in maintaining the contact. In that configuration, the bulk of TCRs and many other receptors are polarized toward the IS3, 10, 61, 63, 64. However, a second pool of those receptors often accumulates at the opposite end of the cell, in what is referred to as the 'distal pole complex'65. Once established, that asymmetric distribution is apparently stable for many hours.

Despite being relatively nonmotile, engaged lymphocytes continuously expand and contract away from the c-SMAC in the peripheral SMAC (p-SMAC) and distal SMAC (d-SMAC) regions, where new peptide–major histocompatibility complex ligands might be encountered and where microclusters of TCRs continue to form51, 66. One likely model proposes that actin fibers initiating at or beyond microclusters in the p-SMAC elongate into the c-SMAC, perhaps as a result of WASP activation 'downstream' of TCR signals67 (Fig. 4a). Engaged integrins in the p-SMAC might also promote activation of Cdc42 and WASP, as well as of aPKC, as they do in migrating astrocytes68. The elongating actin fibers might encounter resistance both from elements in the p-SMAC (generating a retrograde direction of movement that ultimately returns to the c-SMAC) and from pSMAC-localized myosin motors (which 'tug' on fibers, pulling them backward into the c-SMAC). A selective 'clutch' mechanism, perhaps provided by CD2-associated protein, which has been associated with TCR internalization69, may allow microclusters to attach to this moving 'radial fiber' and become localized in the central IS.

Figure 4. Five polarity systems in established T cell couples.
Figure 4 thumbnail

As in Figure 1, polarity can be viewed from the perspective of five different types of events. (a,b) The hypothesized 'radial fibers' of the actin cytoskeleton (a) and tubulin cytoskeleton (b) represent the profound changes in cytoskeletal reorganization that occur. (c) Integrins and signaling receptors are ultimately arrayed mainly in the IS as overlapping densities. (d) Many types of vesicles are transported toward the IS, and we suggest the existence of an additional recycling pool at or near the c-SMAC. (e) Polarity proteins are arrayed in patterns that presumably reinforce IS stability.



Full FigureFull Figure and legend (40K)
Integrins and the microtubule cytoskeleton are also repolarized after TCR engagement, and the MTOC faces the IS (Fig. 4b,c). The general mechanisms underlying MTOC movement are complicated and probably vary among cell types. For instance, in 3T3 fibroblasts initiating movement into a wound, the MTOC actually remains stationary while the nucleus is pushed backward by retrograde actin flow, thereby placing the MTOC in front of the nucleus. PAR-6 and aPKC are needed to hold the MTOC in position, whereas Cdc42, myotonic dystrophy–related kinase and myosin function are required for nuclear relocation70. Conversely, in astrocytes, the MTOC is actively pulled forward by microtubules by a mechanism that depends on Cdc42, PAR-6–aPKC and dynein and that involves capture of the microtubule 'plus' ends at the leading edge of the cell by adenomatosis polyposis coli protein and the polarity protein Dlg1 (refs. 68,71,72). The mechanism of MTOC reorientation in T cells remains to be elucidated.

Polarized endocytosis and exocytosis in the IS
Controlled internalization and delivery of vesicles between the cytoplasm and the plasma membrane is a key component regulating the polarity and function of motile as well as engaged T cells. For example, in cytotoxic T lymphocytes, secretory vesicles containing cytotoxic granules line up alongside the TCR in the IS73. Secretory vesicles bearing the cytokines interleukin 2 and interferon-gamma also line up facing the APC, although others (such as those containing tumor necrosis factor) do not demonstrate obvious directional 'preferences'11. Secretory vesicles bearing interleukin 2 and interferon-gamma localize together with vesicles defined by Rab proteins as well as by the v-SNARE syntaxin 6 (ref. 11).

Vesicular release is probably also important for the reinforcement or modulation of signaling at the IS. Studies of Lck74, Lat75, TCR10 and CTLA-4 (ref. 76) has shown that vesicles bearing those components of the proximal signaling cascade traffic toward the center of the IS, where they presumably fuse with the plasma membrane and deliver vesicular content. Cytokine receptors as well as 'housekeeping' proteins such as transferrin are similarly brought to the IS64, 77. The recycling of TCRs in vesicles may be essential for TCR accumulation at the IS10, although direct movement of the TCR into the IS along the plasma membrane3, 61 also occurs. SNAP-23 and syntaxin 4, both of which are components of t-SNAREs, are enriched in plasma membrane regions at or near the TCR accumulation in the IS, whereas vesicles bearing cellubrevin and v-SNAREs localize on vesicles inside the cytoplasm, juxtaposed to the IS10. In summary, these observations suggest the existence of an exocytic machine that delivers proteins into the IS.

Perhaps equally important to exocytosis is the uptake of proteins by endocytosis in regions adjacent to or in the IS. It is believed that internalization occurs at the center of the IS to facilitate TCR degradation69, 78. Alterations in CD2-associated protein, for example, result in decreased TCR internalization69, 79, and this protein has been associated with ubiquitin E3 ligases such as Cbl. However, more than simple degradation may be occurring at the IS. Continuous ruffling of membrane in the peripheral region as well as coalescing flow toward the central zone may require consistent reintroduction of membrane at the far outer domains. We thus suggest that a vesicular cycle (Fig. 4d) may serve to recycle proteins through the IS during serial receptor-ligand engagements.

How does exocytosis coordinate with the other polarity participants present in the established IS? Lgl associates with syntaxin-4 in mammalian cells80 and may therefore influence the placement of t-SNARE on the plasma membrane in the peripheral IS, into which proteins may be recycled (Fig. 4e). Lgl protein may associate with cellular myosins, and such an interaction may influence the placement of adjacent t-SNAREs and thereby also influence the adhesiveness of integrins. Different t-SNAREs are required for the sorting of vesicles to distinct regions of the plasma membrane. For example, syntaxin-4 is involved in apical sorting, whereas syntaxin-3 is necessary for basolateral sorting. Distinct Rab proteins have also been associated with that. For example, Rab17 seems to be required specifically for apical sorting81. Rab13 has a specialized function in the recycling and delivery of transmembrane proteins that form the tight junctions of epithelial cells, such as occludin82. In cytotoxic T lymphocytes, the delivery of lytic granules to the IS depends on Rab27a, which is important for regulated secretion in several cell types73, and IS-localized secretory vesicles containing interleukin 2 are associated with Rab3d and Rab19 (ref. 11). Although syntaxin-4 accumulates along the IS near the TCR10, the specialized Rab proteins involved in recycling membranes at the IS are not yet known.

Future perspectives
Although re-establishing polarity during signaling remains a focus of ongoing work in this area, there is yet another arena in which polarity and its modification is likely to be potentially more clinically relevant. Underlying normal T cell surveillance is presumably a coordinated series of cues for the T cell to follow. Although the organization of those cues remains to be completely elucidated, it is certain that chemokine gradients into and throughout organs serve to orient T cell polarity (Fig. 1). The presence and density of integrin substrates provides a potential 'highway' on which T cells might 'crawl'. The presentation of chemokines together on an integrin receptor–bearing surface83 or to glycosaminoglycans on APCs84 may also influence T cell function. Two-photon imaging studies have suggested that T cells might travel along high endothelial venules85, perhaps 'entranced' by the unique combination of immobilized chemokines and a local high density of adhesion molecules.

A remaining issue is whether 'immune-privileged' sites, such as tumors or chronic inflammatory sites, might provide a defective series of motility cues that accounts in part for poor T cell surveillance and tolerance to antigens produced in these locations. Tumors, for example, co-opt both chemokine and matrix-remodeling mechanisms that influence the chemotactic and adhesive pathways discussed above. Might tumors create T cell disorder by overexpressing some cues while minimizing others? T cells are known to be much less reactive in their uropod46, and loss of polarity, such as by loss of Scrib, is associated with inhibition of signaling competence17. Notably, depletion of Dlg by means of short hairpin RNA results in overactive T cells in culture47, whereas for primary T cell blasts stimulated with APC plus antigen, loss of Dlg attenuates activation48. Perhaps the difference lies in the polarized cues that accompany the signals received in those disparate stimulation conditions. As future experiments examine tolerant environments in greater depth, it may be important to consider the possibilities that a T cell might well fail to become active or might remain tolerant precisely because of a disorganized array of conflicting polarity cues that effectively 'freezes' the T cell in a state of inactivity.

Received 7 August 2006; Accepted 14 September 2006; Published online: 19 October 2006.

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REFERENCES
  1. Gupton, S.L. et al. Cell migration without a lamellipodium: translation of actin dynamics into cell movement mediated by tropomyosin. J. Cell Biol. 168, 619–631 (2005). | Article | PubMed | ChemPort |
  2. Jacobelli, J. , Chmura, S.A. , Buxton, D.B. , Davis, M.M. & Krummel, M.F. A single class II myosin modulates T cell motility and stopping but not synapse assembly. Nat. Immunol. 5, 531–538 (2004). | Article | PubMed | ISI | ChemPort |
  3. Wülfing, C. & Davis, M.M. A receptor/cytoskeletal movement triggered by costimulation during T cell activation. Science 282, 2266–2269 (1998). | Article | PubMed | ISI | ChemPort |
  4. Smith, A. et al. A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes. J. Cell Biol. 170, 141–151 (2005). | Article | PubMed | ISI | ChemPort |
  5. Serrador, J.M. et al. CD43 interacts with moesin and ezrin and regulates its redistribution to the uropods of T lymphocytes at the cell-cell contacts. Blood 91, 4632–4644 (1998). | PubMed | ISI | ChemPort |
  6. del Pozo, M.A. et al. ICAMs redistributed by chemokines to cellular uropods as a mechanism for recruitment of T lymphocytes. J. Cell Biol. 137, 493–508 (1997). | Article | PubMed | ChemPort |
  7. Krummel, M.F. , Sjaastad, M.D. , Wülfing, C. & Davis, M.M. Differential assembly of CD3zeta and CD4 during T cell activation. Science 289, 1349–1352 (2000). | Article | PubMed | ISI | ChemPort |
  8. Tibaldi, E.V. , Salgia, R. & Reinherz, E.L. CD2 molecules redistribute to the uropod during T cell scanning: implications for cellular activation and immune surveillance. Proc. Natl. Acad. Sci. USA 99, 7582–7587 (2002). | Article | PubMed | ChemPort |
  9. Russell, S. & Oliaro, J. Compartmentalization in T-cell signalling: membrane microdomains and polarity orchestrate signalling and morphology. Immunol. Cell Biol. 84, 107–113 (2006). | Article | PubMed | ChemPort |
  10. Das, V. et al. Activation-induced polarized recycling targets T cell antigen receptors to the immunological synapse; involvement of SNARE complexes. Immunity 20, 577–588 (2004). | Article | PubMed | ISI | ChemPort |
  11. Huse, M. , Lillemeier, B.F. , Kuhns, M.S. , Chen, D.S. & Davis, M.M. T cells use two directionally distinct pathways for cytokine secretion. Nat. Immunol. 7, 247–255 (2006). | Article | PubMed | ChemPort |
  12. Roche, J.P. , Packard, M.C. , Moeckel-Cole, S. & Budnik, V. Regulation of synaptic plasticity and synaptic vesicle dynamics by the PDZ protein Scribble. J. Neurosci. 22, 6471–6479 (2002). | PubMed | ISI | ChemPort |
  13. Bilder, D. , Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000). | Article | PubMed | ISI | ChemPort |
  14. Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003). | Article | PubMed | ISI | ChemPort |
  15. Qin, Y. , Capaldo, C. , Gumbiner, B.M. & Macara, I.G. The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J. Cell Biol. 171, 1061–1071 (2005). | Article | PubMed | ChemPort |
  16. Lahuna, O. et al. Thyrotropin receptor trafficking relies on the hScrib-betaPIX-GIT1–ARF6 pathway. EMBO J. 24, 1364–1374 (2005). | Article | PubMed | ChemPort |
  17. Ludford-Menting, M.J. et al. A network of PDZ-containing proteins regulates T cell polarity and morphology during migration and immunological synapse formation. Immunity 22, 737–748 (2005). | Article | PubMed | ISI | ChemPort |
  18. Yamanaka, T. et al. Mammalian Lgl forms a protein complex with PAR-6 and aPKC independently of PAR-3 to regulate epithelial cell polarity. Curr. Biol. 13, 734–743 (2003). | Article | PubMed | ISI | ChemPort |
  19. Plant, P.J. et al. A polarity complex of mPar-6 and atypical PKC binds, phosphorylates and regulates mammalian Lgl. Nat. Cell Biol. 5, 301–308 (2003). | Article | PubMed | ISI | ChemPort |
  20. Betschinger, J. , Mechtler, K. & Knoblich, J.A. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 422, 326–330 (2003). | Article | PubMed | ISI | ChemPort |
  21. del Pozo, M.A. , Vicente-Manzanares, M. , Tejedor, R. , Serrador, J.M. & Sanchez-Madrid, F. Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur. J. Immunol. 29, 3609–3620 (1999). | Article | PubMed | ISI | ChemPort |
  22. D'Souza-Schorey, C. , Boettner, B. & Van Aelst, L. Rac regulates integrin-mediated spreading and increased adhesion of T lymphocytes. Mol. Cell. Biol. 18, 3936–3946 (1998). | PubMed | ChemPort |
  23. Haddad, E. et al. The interaction between Cdc42 and WASP is required for SDF-1-induced T-lymphocyte chemotaxis. Blood 97, 33–38 (2001). | Article | PubMed | ISI | ChemPort |
  24. Snapper, S.B. et al. WASP deficiency leads to global defects of directed leukocyte migration in vitro and in vivo. J. Leukoc. Biol. 77, 993–998 (2005). | Article | PubMed | ISI | ChemPort |
  25. Weiner, O.D. et al. Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis. PLoS Biol. 4, e38 (2006). | Article | PubMed | ChemPort |
  26. Nolz, J.C. et al. The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr. Biol. 16, 24–34 (2006). | Article | PubMed | ChemPort |
  27. Yan, C. et al. WAVE2 deficiency reveals distinct roles in embryogenesis and Rac-mediated actin-based motility. EMBO J. 22, 3602–3612 (2003). | Article | PubMed | ISI | ChemPort |
  28. Laudanna, C. , Campbell, J.J. & Butcher, E.C. Role of Rho in chemoattractant-activated leukocyte adhesion through integrins. Science 271, 981–983 (1996). | PubMed | ISI | ChemPort |
  29. Constantin, G. et al. Chemokines trigger immediate beta2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow. Immunity 13, 759–769 (2000). | Article | PubMed | ISI | ChemPort |
  30. Volinsky, N. , Gantman, A. & Yablonski, D.A. Pak- and Pix-dependent branch of the SDF-1alpha signalling pathway mediates T cell chemotaxis across restrictive barriers. Biochem. J. 397, 213–222 (2006). | PubMed | ChemPort |
  31. Weiss-Haljiti, C. et al. Involvement of phosphoinositide 3-kinase gamma, Rac, and PAK signaling in chemokine-induced macrophage migration. J. Biol. Chem. 279, 43273–43284 (2004). | Article | PubMed | ISI | ChemPort |
  32. Leeuwen, F.N. et al. The guanine nucleotide exchange factor Tiam1 affects neuronal morphology; opposing roles for the small GTPases Rac and Rho. J. Cell Biol. 139, 797–807 (1997). | Article | PubMed | ChemPort |
  33. Lee, J.H. et al. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J. Cell Biol. 167, 327–337 (2004). | Article | PubMed | ChemPort |
  34. Palacios, F. , Price, L. , Schweitzer, J. , Collard, J.G. & D'Souza-Schorey, C. An essential role for ARF6-regulated membrane traffic in adherens junction turnover and epithelial cell migration. EMBO J. 20, 4973–4986 (2001). | Article | PubMed | ISI | ChemPort |
  35. Audebert, S. et al. Mammalian Scribble forms a tight complex with the betaPIX exchange factor. Curr. Biol. 14, 987–995 (2004). | Article | PubMed | ISI | ChemPort |
  36. Mathew, D. et al. Recruitment of scribble to the synaptic scaffolding complex requires GUK-holder, a novel DLG binding protein. Curr. Biol. 12, 531–539 (2002). | Article | PubMed | ISI | ChemPort |
  37. Lue, R.A. , Brandin, E. , Chan, E.P. & Branton, D. Two independent domains of hDlg are sufficient for subcellular targeting: the PDZ1–2 conformational unit and an alternatively spliced domain. J. Cell Biol. 135, 1125–1137 (1996). | Article | PubMed | ISI | ChemPort |
  38. Wang, H.R. et al. Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 302, 1775–1779 (2003). | Article | PubMed | ISI | ChemPort |
  39. Joberty, G. , Petersen, C. , Gao, L. & Macara, I.G. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat. Cell Biol. 2, 531–539 (2000). | Article | PubMed | ISI | ChemPort |
  40. Johansson, A. , Driessens, M. & Aspenstrom, P. The mammalian homologue of the Caenorhabditis elegans polarity protein PAR-6 is a binding partner for the Rho GTPases Cdc42 and Rac1. J. Cell Sci. 113, 3267–3275 (2000). | PubMed | ISI | ChemPort |
  41. Lin, D. et al. A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nat. Cell Biol. 2, 540–547 (2000). | Article | PubMed | ISI | ChemPort |
  42. Zhang, H. & Macara, I.G. The polarity protein PAR-3 and TIAM1 cooperate in dendritic spine morphogenesis. Nat. Cell Biol. 8, 227–237 (2006). | Article | PubMed | ChemPort |
  43. Chen, X. & Macara, I.G. Par-3 controls tight junction assembly through the Rac exchange factor Tiam1. Nat. Cell Biol. 7, 262–269 (2005). | Article | PubMed | ISI | ChemPort |
  44. Habets, G.G. et al. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell 77, 537–549 (1994). | Article | PubMed | ISI | ChemPort |
  45. Dustin, M.L. , Bromley, S.K. , Kan, Z. , Peterson, D.A. & Unanue, E.R. Antigen receptor engagement delivers a stop signal to migrating T lymphocytes. Proc. Natl. Acad. Sci. USA 94, 3909–3913 (1997). | Article | PubMed | ChemPort |
  46. Negulescu, P.A. , Krasieva, T.B. , Khan, A. , Kerschbaum, H.H. & Cahalan, M.D. Polarity of T cell shape, motility, and sensitivity to antigen. Immunity 4, 421–430 (1996). | Article | PubMed | ISI | ChemPort |
  47. Xavier, R. et al. Discs large (Dlg1) complexes in lymphocyte activation. J. Cell Biol. 166, 173–178 (2004). | Article | PubMed | ChemPort |
  48. Round, J.L. et al. Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells. J. Exp. Med. 201, 419–430 (2005). | Article | PubMed | ChemPort |
  49. Faure, S. et al. ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nat. Immunol. 5, 272–279 (2004). | Article | PubMed | ISI | ChemPort |
  50. Dulyaninova, N.G. , Malashkevich, V.N. , Almo, S.C. & Bresnick, A.R. Regulation of myosin-IIA assembly and Mts1 binding by heavy chain phosphorylation. Biochemistry 44, 6867–6876 (2005). | Article | PubMed | ISI | ChemPort |
  51. Campi, G. , Varma, R. & Dustin, M.L. Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J. Exp. Med. 202, 1031–1036 (2005). | Article | PubMed | ISI | ChemPort |
  52. Barda-Saad, M. et al. Dynamic molecular interactions linking the T cell antigen receptor to the actin cytoskeleton. Nat. Immunol. 6, 80–89 (2005). | Article | PubMed | ISI | ChemPort |
  53. Bunnell, S.C. , Kapoor, V. , Trible, R.P. , Zhang, W. & Samelson, L.E. Dynamic actin polymerization drives T cell receptor-induced spreading: a role for the signal transduction adaptor LAT. Immunity 14, 315–329 (2001). | Article | PubMed | ISI | ChemPort |
  54. Bubeck Wardenburg, J. et al. Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity 9, 607–616 (1998). | Article | PubMed | ChemPort |
  55. Hanada, T. , Lin, L. , Chandy, K.G. , Oh, S.S. & Chishti, A.H. Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes. J. Biol. Chem. 272, 26899–26904 (1997). | Article | PubMed | ChemPort |
  56. Hanada, T. , Lin, L. , Tibaldi, E.V. , Reinherz, E.L. & Chishti, A.H. GAKIN, a novel kinesin-like protein associates with the human homologue of the Drosophila discs large tumor suppressor in T lymphocytes. J. Biol. Chem. 275, 28774–28784 (2000). | Article | PubMed | ISI | ChemPort |
  57. Lee, K.H. et al. T cell receptor signaling precedes immunological synapse formation. Science 295, 1539–1542 (2002). | Article | PubMed | ISI | ChemPort |
  58. Phee, H. , Abraham, R.T. & Weiss, A. Dynamic recruitment of PAK1 to the immunological synapse is mediated by PIX independently of SLP-76 and Vav1. Nat. Immunol. 6, 608–617 (2005). | Article | PubMed | ISI | ChemPort |
  59. Yablonski, D. , Kane, L.P. , Qian, D. & Weiss, A.A. Nck-Pak1 signaling module is required for T-cell receptor-mediated activation of NFAT, but not of JNK. EMBO J. 17, 5647–5657 (1998). | Article | PubMed | ChemPort |
  60. Macara, I.G. Parsing the polarity code. Nat. Rev. Mol. Cell Biol. 5, 220–231 (2004). | Article | PubMed | ISI | ChemPort |
  61. Moss, W.C. , Irvine, D.J. , Davis, M.M. & Krummel, M.F. Quantifying signaling-induced reorientation of TCRs during immunological synapse formation. Proc. Natl. Acad. Sci. USA 99, 15024–15029 (2002). | Article | PubMed | ChemPort |
  62. Bunnell, S.C. et al. T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J. Cell Biol. 158, 1263–1275 (2002). | Article | PubMed | ISI | ChemPort |
  63. Wülfing, C. , Sjaastad, M.D. & Davis, M.M. Visualizing the dynamics of T cell activation: Intracellular adhesion molecule 1 migrates rapidly to the T cell/B cell interface and acts to sustain calcium levels. Proc. Natl. Acad. Sci. USA 95, 6302–6307 (1998). | Article | PubMed | ISI | ChemPort |
  64. Batista, A. , Millan, J. , Mittelbrunn, M. , Sanchez-Madrid, F. & Alonso, M.A. Recruitment of transferrin receptor to immunological synapse in response to TCR engagement. J. Immunol. 172, 6709–6714 (2004). | PubMed | ChemPort |
  65. Cullinan, P. , Sperling, A.I. & Burkhardt, J.K. The distal pole complex: a novel membrane domain distal to the immunological synapse. Immunol. Rev. 189, 111–122 (2002). | Article | PubMed | ISI | ChemPort |
  66. Yokosuka, T. et al. Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nat. Immunol. 6, 117–127 (2005). | Article |
  67. Cannon, J.L. et al. Wasp recruitment to the T cell:APC contact site occurs independently of cdc42 activation. Immunity 15, 249–259 (2001). | Article | PubMed | ISI | ChemPort |
  68. Etienne-Manneville, S. & Hall, A. Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta. Cell 106, 489–498 (2001). | Article | PubMed | ISI | ChemPort |
  69. Lee, K.H. et al. The immunological synapse balances T cell receptor signaling and degradation. Science 302, 1218–1222 (2003). | Article | PubMed | ISI |
  70. Gomes, E.R. , Jani, S. & Gundersen, G.G. Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating Cells. Cell 121, 451–463 (2005). | Article | PubMed | ISI | ChemPort |
  71. Etienne-Manneville, S. & Hall, A. Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. Nature 421, 753–756 (2003). | Article | PubMed | ISI | ChemPort |
  72. Etienne-Manneville, S. , Manneville, J.B. , Nicholls, S. , Ferenczi, M.A. & Hall, A. Cdc42 and Par6-PKCzeta regulate the spatially localized association of Dlg1 and APC to control cell polarization. J. Cell Biol. 170, 895–901 (2005). | Article | PubMed | ChemPort |
  73. Stinchcombe, J.C. , Bossi, G. , Booth, S. & Griffiths, G.M. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15, 751–761 (2001). | Article | PubMed | ISI | ChemPort |
  74. Ehrlich, L.I. , Ebert, P.J. , Krummel, M.F. , Weiss, A. & Davis, M.M. Dynamics of p56lck translocation to the T cell immunological synapse following agonist and antagonist stimulation. Immunity 17, 809–822 (2002). | Article | PubMed | ISI | ChemPort |
  75. Bonello, G. et al. Dynamic recruitment of the adaptor protein LAT: LAT exists in two distinct intracellular pools and controls its own recruitment. J. Cell Sci. 117, 1009–1016 (2004). | Article | PubMed | ISI | ChemPort |
  76. Egen, J.G. & Allison, J.P. Cytotoxic T lymphocyte associated antigen (CTLA-4) accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16, 23–35 (2002). | Article | PubMed | ISI | ChemPort |
  77. Maldonado, R.A. , Irvine, D.J. , Schreiber, R. & Glimcher, L.H. A role for the immunological synapse in lineage commitment of CD4 lymphocytes. Nature 431, 527–532 (2004). | Article | PubMed | ISI | ChemPort |
  78. Varma, R. , Campi, G. , Yokosuka, T. , Saito, T. & Dustin, M.L. T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25, 117–127 (2006). | Article | PubMed | ChemPort |
  79. Kirsch, K.H. et al. The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction. J. Biol. Chem. 276, 4957–4963 (2001). | Article | PubMed | ISI | ChemPort |
  80. Musch, A. et al. Mammalian homolog of Drosophila tumor suppressor lethal (2) giant larvae interacts with basolateral exocytic machinery in Madin-Darby canine kidney cells. Mol. Biol. Cell 13, 158–168 (2002). | Article | PubMed | ISI | ChemPort |
  81. Zacchi, P. et al. Rab17 regulates membrane trafficking through apical recycling endosomes in polarized epithelial cells. J. Cell Biol. 140, 1039–1053 (1998). | Article | PubMed | ISI | ChemPort |
  82. Terai, T. , Nishimura, N. , Kanda, I. , Yasui, N. & Sasaki, T. JRAB/MICAL-L2 is a junctional Rab13-binding protein mediating the endocytic recycling of occludin. Mol. Biol. Cell 17, 2465–2475 (2006). | Article | PubMed | ChemPort |
  83. Shamri, R. et al. Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat. Immunol. 6, 497–506 (2005). | Article | PubMed | ISI | ChemPort |
  84. Friedman, R.S. , Jacobelli, J. & Krummel, M.F. Surface-bound chemokines capture and prime T cells for synapse formation. Nat. Immunol. 7, 1101–1108 (2006). | Article | PubMed | ChemPort |
  85. Mempel, T.R. , Henrickson, S.E. & von Andrian, U.H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154–159 (2004). | Article | PubMed | ISI | ChemPort |
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Acknowledgments
We thank J. Gilden for critical reading of the manuscript, and C. Lin for assistance with graphics.

Competing interests statement:  The authors declare that they have no competing financial interests.

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