CCL21 chemokine axis in the adaptive immune system

Cytokine & Growth Factor Reviews 24 (2013) 269–283

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Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr

Survey

A myriad of functions and complex regulation of the CCR7/CCL19/ CCL21 chemokine axis in the adaptive immune system Iain Comerford *, Yuka Harata-Lee 1, Mark D. Bunting 1, Carly Gregor 1, Ervin E. Kara 1, Shaun R. McColl ** The Chemokine Biology Laboratory, School of Molecular and Biomedical Science, University of Adelaide, Australia

A R T I C L E I N F O

A B S T R A C T

Article history: Available online 12 April 2013

The chemokine receptor CCR7 and its ligands CCL19 and CCL21 control a diverse array of migratory events in adaptive immune function. Most prominently, CCR7 promotes homing of T cells and DCs to T cell areas of lymphoid tissues where T cell priming occurs. However, CCR7 and its ligands also contribute to a multitude of adaptive immune functions including thymocyte development, secondary lymphoid organogenesis, high affinity antibody responses, regulatory and memory T cell function, and lymphocyte egress from tissues. In this survey, we summarise the role of CCR7 in adaptive immunity and describe recent progress in understanding how this axis is regulated. In particular we highlight CCX-CKR, which scavenges both CCR7 ligands, and discuss its emerging significance in the immune system. ß 2013 Elsevier Ltd. All rights reserved.

Keywords: Chemokine CCR7 CCL19 CCL21 Immunity

Contents 1. 2. 3.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Overview of the CCR7/CCL19/CCL21 axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CCR7 and the development and organisation of the immune system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . CCR7 in the thymus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. CCR7 and secondary lymphoid organ development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. CCR7 and homeostatic lymphocyte recruitment and organisation of secondary lymphoid tissues 3.3. CCR7 and homeostatic DC recruitment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. CCR7 and regulatory T cell function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. CCR7 during the immune response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CCR7 and migration of DCs during inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. CCR7 and T cell activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. CCR7 and T-dependent antibody responses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. CCR7 in activated T cell recruitment to and egress from peripheral tissues . . . . . . . . . . . . . . . . . . 4.4. CCR7 and memory T cell recirculation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.

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Abbreviations: APC, antigen-presenting cell; BCR, B cell receptor; CCL, CC chemokine ligand; CCR, CC chemokine receptor; TCM, central memory T cell; CNS, central nervous system; CMJ, cortico-medullary junction; CXCL, CXC chemokine ligand; CXCR, CXC chemokine receptor; DN, double negative; EAE, experimental autoimmune encephalomyelitis; FRC, fibroblastic reticular cell; GPCR, G-protein coupled receptor; GAG, glycosaminoglycan; GC, germinal centre; HEV, high endothelial venule; LEC, lymphatic endothelial cell; KO, knock out; LN, lymph node; LCMV, lymphochorio meningitis virus; LTi, lymphoid tissue inducer; MAdCAM-1, mucosal addressin cell adhesion molecule 1; LT, lymphotoxin; MZ, marginal zone; MHC, major histocompatibility complex; PALS, periartiolar lymphoid sheath; PNAd, peripheral node addressin; PP, Peyer’s patch; plt, paucity of lymph node T cells; PGE2, prostaglandin E2; SLO, secondary lymphoid organ; SP, single positive; S1P1, sphingosine-1-phosphate receptor; SCS, subcapsular sinus; TCR, T cell receptor; TLO, tertiary lymphoid organ; TFH, T follicular helper cell; TREG, regulatory T cell; TEC, thymic epithelial cell; VV, vaccinia virus; VEGF, vascular endothelial growth factor; VSV, vesicular stromatitis virus. * Corresponding author at: Room 5.18, Molecular Life Sciences Building, School of Molecular and Biomedical Science, University of Adelaide, North Terrace Campus, Adelaide, SA 5005, Australia. Tel.: +61 883131127/883134630; fax: +61 883137532. ** Corresponding author at: Room 5.14, Molecular Life Sciences Building, School of Molecular and Biomedical Science, University of Adelaide, North Terrace Campus, Adelaide, SA 5005, Australia. Tel.: +61 883134259/883134630; fax: +61 883137532. E-mail addresses: [email protected] (I. Comerford), [email protected] (Y. Harata-Lee), [email protected] (M.D. Bunting), [email protected] (C. Gregor), [email protected] (E.E. Kara), [email protected] (S.R. McColl). 1 Tel.: +61 883131127; fax: +61 883137532. 1359-6101/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cytogfr.2013.03.001

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5.

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4.6. CCR7 in anti-tumour immunity . . . . . . . . . . . . . . . . . . Regulation of the CCR7 system . . . . . . . . . . . . . . . . . . . . . . . . Induction of CCL19/21 . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Regulation of CCR7 on T cells and DCs . . . . . . . . . . . . 5.2. Regulation of CCR7 by atypical chemokine receptors . 5.3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction As a system that depends entirely on stochastically improbable cellular encounters, adaptive immunity has evolved complex systems of control to facilitate the dynamic cellular interactions required for its function. Prominent amongst the molecular systems regulating immune cell migration are the chemokines; a superfamily of structurally related small cytokines that bind to chemokine receptors, G-protein coupled receptors (GPCRs) expressed on subsets of leukocytes. Eighteen signalling chemokine receptors have been identified to date and over 50 chemokine ligands are present in humans. Together, these receptors and ligands coordinate a vast array of the migratory events seminal for effective and robust immunity. One of the most prominent chemokine receptors in the adaptive immune system is CCR7, which has been established as an important component of lymphocyte-driven immune function. This receptor is expressed on various subsets of immune cells and promotes migration towards CCL19 and CCL21, the sole CCR7 ligands. These chemokines are generally considered ‘homeostatic’ as they are constitutively produced and, unlike the majority of chemokines, are not normally induced by inflammation. The main sources of CCL19 and CCL21 are a variety of stromal cells within primary and secondary lymphoid organs (SLOs) and, in the case of CCL21, also lymphatic endothelial cells (LECs) in peripheral tissues. The primary function of the CCR7/CCL19/CCL21 axis is to establish and propagate anatomical microenvironments conducive to cognate interactions between antigen-presenting cells (APCs) and antigen-specific lymphocytes, an important process in effective adaptive immune system function. Thus, the CCR7 axis plays a pivotal role in multiple aspects of development and execution of adaptive immunity. In this survey we review the many roles for CCR7 and explore the molecular mechanisms that control this axis, including those that induce CCL19/CCL21 expression, and those that potentiate or regulate the activity of the CCR7 system. In particular, we highlight the atypical chemokine receptor CCX-CKR, which also binds CCL19 and CCL21 without mediating cell migration, and discuss emerging evidence that this receptor acts as a key regulator of the CCR7 axis and hence adaptive immunity.

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are structurally and functionally distinct and differentially regulated. CCL21 has an unusual extended C-terminal tail for a chemokine [4], facilitating high affinity binding to glycosaminoglycans (GAGs) and other elements of the extracellular matrix, which is thought to result in CCL21 being a predominantly matrixand endothelial cell-bound chemokine. Conversely, CCL19 lacks this extension and may be more readily available locally in a soluble form. Recent studies have shown that matrix-bound CCL21 promotes both chemotactic migration of cells and induces cell adhesion [5] particularly under shear forces [6], which is important in the extravasation process. However, matrix-bound CCL21 can also be cleaved and when present in a soluble form behaves more like CCL19 in that it induces chemotaxis but not adhesion [5]. In mice, two isoforms of CCL21 differing in a single amino acid are differentially expressed from distinct genes [7]. CCL21a is mainly expressed by medullary thymic epithelial cells (mTECs) and, in secondary lymphoid organs (SLOs) by blood vessel high endothelial venules (HEVs) and fibroblastic reticular cells (FRCs) in the T cell areas, while CCL21b is expressed in peripheral tissues, predominantly by LECs. In contrast, CCL19 is restricted to the thymus and SLOs and is expressed by mTECs, FRCs and by activated DCs (Fig. 2). Notably, in humans CCL21 is not detectably produced by HEVs [8] but studies have demonstrated that both CCL19 and CCL21 produced by other LN stromal cells can be transcytosed across HEVs and thereby influence lymphocyte recruitment from the blood [9,10]. Interestingly, CCL19 and CCL21 differentially

CCR7 and its ligands CCL19

CCL21 C

C

N

N

K(d) = 1nM

K(d) = 1nM

2. Overview of the CCR7/CCL19/CCL21 axis Understanding of the biological function of CCR7 proceeded substantially and rapidly following its identification 20 years ago as the first lymphocyte-specific GPCR [1]. The identification of CCR7’s ligands [2,3] as the lymphocyte migration-inducing chemokines, CCL19 and CCL21, which were abundant in lymphoid organs, provided the first clues to what we now understand the functions of this receptor/ligand axis to be. Significantly, no other CCR7 ligands have since been identified and the vast majority of the biological functions of CCL19 and CCL21 shown to date are mediated through CCR7. However, CCL19 and CCL21 appear not to serve completely overlapping and thus redundant functions (Fig. 1). Despite both binding CCR7 with similar affinities and generally being expressed in lymphoid organs, CCL19 and CCL21

Cell migration CCR7 phosphorylation ERK/arrestin activation CCR7 internalisation/desensitization

Intracellular calcium mobilization Actin polymerization

Fig. 1. CCR7 and its ligands. Schematic of interaction between CCR7/CCL19/CCL21. CCL19 and CCL21 interact with CCR7 with similar affinities. Both chemokines induce chemotactic responses through CCR7. CCL19 and not CCL21 induces CCR7 receptor desensitisation and internalisation by differentially activating signal transduction through CCR7.

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Fig. 2. Expression of CCR7 and its ligands in the immune system. Schematic showing the various major subsets of leukocytes that express CCR7 and the various cellular sources of CCL19 and CCL21.

stimulate CCR7 [11,12]. Ligation with CCL21 does not induce barrestin recruitment and subsequent receptor desensitisation and internalisation, while CCL19 does [11–13]. One explanation for this may be that CCL21, while supporting migration of CCR7+ cells into lymphatic vessels or within SLOs, will not render these cells subsequently unable to respond to CCL19 produced locally in the T cell areas, allowing for CCR7+ cells to sequentially follow two migratory cues mediated through the same receptor. Using mathematical modelling and in vitro physiological chemokine gradient conditions recent studies have suggested peripheral blood T cells preferentially migrate towards CCL21, and owing to the differential abilities of CCL19 and CCL21 to compete for and desensitise CCR7, CCL19 provides a chemorepulsive signal when CCL21 is present [14]. Similarly, Haessler and colleagues recently reported that DCs migrate much more efficiently in 3-dimensional chemokine gradients to CCL21 than CCL19 [15], although another study indicated that CCL19 was the dominant ligand for DCs in competitive migration experiments [16]. While these findings regarding ligand dominance for CCR7 are intriguing and controversial, they remain to be formally tested in relevant in vivo settings. However, it is notable that CCL21 seems to be capable of mediating the majority of the migratory effects through CCR7 in vivo and, as will be described in more detail later, CCL19 may play a supplementary role and provide non-migratory signals such as promoting cell survival [17]. Cells of the immune system that express CCR7 encompass subsets of thymocytes, T cells, B cells and DCs (Fig. 2). Specifically, CCR7 is expressed on double negative (DN) thymocytes [18], single positive (SP) thymocytes [18], naı¨ve T cells [19–21], a subset of memory T cells termed central memory T cells (TCM) [19,22], naı¨ve B cells [23] and semi-mature and mature DCs [24–26]. A common feature of these CCR7+ cells is their requirement for migration to, and within, lymphoid organs. DN and SP thymocytes migrate within the thymus, the site of T cell selection and production; DCs migrate from tissues to SLOs, while mature T cells and B cells circulate through SLOs in search of congnate interactions required to initiate adaptive immune responses. In addition to these cells, CCR7 expression has also been detected on macrophages [27] and neutrophils [28], and CCR7 also appears to contribute to the entry and positioning of these cells within SLOs. The principal tools that have been used to dissect the biological functions of the CCR7 axis are the Ccr7 / mouse [29] and the paucity of lymph node T cells (plt) mouse – a naturally occurring mouse mutant that lacks CCL19 and CCL21a expression [7]. More recently the Ccl19 / mouse has also been generated [17]. Along with other reagents such as neutralising antibodies and antagonists that allow for individual blocking of CCR7, CCL19 or CCL21,

these tools have allowed insight into the overall functions and the significance of the constituent parts of this receptor ligand axis. As we shall describe below, these reagents have provided, and continue to provide, the means to demonstrate that CCR7 and its ligands have a plethora of functions in adaptive immunity. 3. CCR7 and the development and organisation of the immune system 3.1. CCR7 in the thymus Self-MHC restricted, non-self reactive T cells are critical for adaptive immunity and these cells develop from bone marrowderived precursors in the specialised environment of the thymus. Chemokine-induced migration is required for developing thymocytes to journey through successive compartmental niches, thus providing exposure to sequential thymic environments essential for T lineage differentiation and clonal selection on the basis of antigen receptor specificity [30]. T cell development in the thymus initiates following importation of BM-derived precursors at the CMJ. These cells then differentiate in the medulla and are termed DN1 cells (CD4 CD8 double-negative). Outward migration into the cortex then occurs simultaneously with differentiation to DN2 cells. TCR recombination begins at the DN3 stage, in the outercortex and subcapsular zone and continues during the last stage of precursor differentiation, termed DN4. Developing thymocytes now begin to up-regulate both CD4 and CD8 and undergo positive selection for successful TCR rearrangement. Passage through this stage results in the CD4 vs CD8 lineage decision and migration towards to medulla where both CCL19 and CCL21 are expressed by mTECs. Once in the medulla, negative selection of self-reactive TCRs occurs, mediated by mTECs and DCs, followed by emigration into circulation as functional naı¨ve T cells. Both early precursors and late stage thymocytes are exposed to and respond to CCL19/ CCL21 and as a result CCR7 operates at multiple stages of thymocyte development. Numerous single gene-knock out (KO) and multiple gene-KO studies have demonstrated that CCR7 expression, synergising with CCR9 and CXCR4, enables efficient immigration of circulating bone marrow-derived precursors into the thymus [31–33]. Subsets of DN1/DN2 cells express CCR7 which appears to be required for outward migration of DN2 cells to the cortex, as plt and Ccr7 / mice exhibit accumulation of DN2 cells at the CMJ, and DN3 cells, the next stage of development, are reduced in number [18]. Upon successful passage through positive selection for expression of a T cell receptor (TCR) that is selfMHC restricted and the CD4 vs CD8 lineage decision, CCR7 is required for migration of CD4 and CD8 SP thymocytes back to the

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Fig. 3. The role of CCR7 and its ligands in the thymus. Schematic representation of the various processes involving CCR7 during T cell development in the thymus. (1) CCR7+ thymocyte precursors cross blood vessels at the cortico-medullary junction to enter the thymus. This process involves CCR7 but is partially redundant with CCR9 and CXCR4. (2) DN1 cells and DN2 cells express CCR7 and use this receptor to migrate out to the subcapsular zone. However, CCL19 and CCL21 are predominatly expressed in the thymic medulla. CCR7 is lost on developing thymocytes during the DN3 and DN4 stage but (3) is re-expressed during the DP stage during positive selection. Positively selected SP thymocytes use CCR7 to migrate back towards the medulla, where CCL19 and CCL21 are abundant. (4) Mature SP thymocytes that survive negative selection in the medulla also express CCR7 and this is involved in a partially redundant manner for egress of mature thymocytes from the thymus.

medulla [34–39] where they undergo negative selection to delete cells expressing self-reactive TCRs. Furthermore, in the absence of CCR7, thymocytes have impaired TCR signalling required for optimal negative selection [34]. The reliance SP cells have for CCR7 and its ligands to migrate to the medulla and undergo negative selection contributes to the increased incidence of spontaneous autoimmunity in Ccr7 / and plt mice [35,40,41]. A role for CCL19, but not CCL21, in emigration of fully differentiated T cells has also been identified in the neonatal thymus [42]. However, removal of CCR7 does not lead to a complete block in thymocyte development, suggesting overlapping roles with other thymic chemokine axis. As such, roles for both CCR9 and CXCR4 have been identified in DN2/ DN3 and DN3/DN4 differentiation, respectively [43,44]. Together, it is clear that CCR7 contributes at multiple stages of T cell development in the thymus and plays a crucial role in generating a non-self reactive peripheral T cell pool. These many functions for CCR7 and its ligands in the thymus are summarised in Fig. 3. 3.2. CCR7 and secondary lymphoid organ development As the site of antigen accumulation and lymphocyte priming, SLOs are essential for the induction of adaptive immune responses. CCR7 has been shown to have a role in the development of these organs, alongside the CXCR5/CXCL13 chemokine system. Ccr7 / mice go on to develop most SLOs including spleen, Peyer’s Patch (PP) and most LNs, although the occasional absence of inguinal, popliteal and parathymic LNs has been documented [45]. Although present in Ccr7 / mice, these organs display disrupted architecture with defects in lymphocyte compartmentalisation

(see below). CCR7 plays an overlapping role with CXCR5 in LN development, as Ccr7 / Cxcr5 / mice often lack cervical, facial and brachial LNs, which are present in singly deficient mice [45,46]. These chemokine receptors exert their effects on lymphoid organogenesis, at least in part, through their expression on lymphoid tissue inducer (LTi) cells [46]. The current paradigm for secondary lymphoid organogenesis involves recruitment of CD4+CD3 IL-7Ra+ LTi cells, which also express CCR7, to sites of lymphoid organ development. Lymphotoxin (LT) a1b2 expressed by LTi cells ligates the LT receptor on stromal ‘organiser’ cells, which invokes clustering of these cells and induces expression of CCL19, CCL21 and CXCL13 along with various adhesion molecules, promoting further lymphocyte recruitment and compartmentalisation [47]. Thus, expression of CCR7 is involved in both initial recruitment of LTi cells and subsequent recruitment of lymphocytes, although its function here is partially redundant with CXCR5 [46]. During chronic inflammation, including rheumatoid arthritis and multiple sclerosis, highly organised lymphocytic infiltrates resembling SLOs often develop in diseased tissue, termed tertiary lymphoid organs (TLOs). The evidence regarding the importance of CCR7 in formation of TLOs is somewhat contradictory. Ccr7 / mice spontaneously develop TLOs at mucosal sites including the stomach and salivary glands [40,48]. Additionally, Ccr7 / mice develop bronchus-associated lymphoid tissue in lung tissue, which is abrogated by adoptive transfer of Ccr7+/+ TREGS [49]. Conversely, ectopic expression of CCL21 in the pancreas and thymus has been shown to be sufficient to induce TLO formation in these tissues [50–52]. Ectopic expression of CCL21 in human liver was also

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associated with TLO formation [53]. Furthermore, deletion of CCR7 inhibits development of TLOs in a mouse model of chronic antigeninduced arthritis [54]. Therefore, it seems clear that although TLO formation can occur in a CCR7-independent manner, expression of CCR7 ligands can also be a sufficient signal to induce formation of these structures. These apparently conflicting findings may be reconciled by the finding that Ccr7 / mice exhibit defects in negative selection, TREG function and effector cell egress from tissues that culminates in spontaneous chronic inflammatory infiltrates in multiple tissues where CCR7-independent TLO formation occurs. 3.3. CCR7 and homeostatic lymphocyte recruitment and organisation of secondary lymphoid tissues Once SLOs develop, they recruit lymphocytes; a process that occurs continuously throughout life with an estimated 2.5  1010 lymphocytes passing through each human LN each day. CCR7 and its ligands play an important role in lymphocyte recruitment to LNs and PPs. In contrast to the spleen where lymphocyte entry appears to be chemokine independent, naı¨ve lymphocyte entry to LNs and PPs occurs almost entirely through HEVs found in the cortex of LNs and PPs and additionally in PP follicles. Lymphocytes

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roll along HEVs of LNs via interactions between CD62L on lymphocytes and its ligand, peripheral node addressin (PNAd), on the endothelium. In PP, a4b7 integrin-expressing lymphocytes roll on PP HEVs, which express the mucosal addressin cell adhesion molecule 1 (MAdCAM-1). In both PPs and LNs, these rolling naı¨ve lymphocytes express CCR7 to detect CCL21, and/or CCL19, presented on the luminal surface of HEVs. CCR7 signals induced by ligation cause integrin activation, firm adhesion and subsequent extravasation into the LN or PP (Fig. 4, top right panel shows lymphocyte entry to the LN). T cells in particular are dependent upon CCR7 for efficient entry into LN and PP [10]. T cells in the peripheral blood express high levels of CCR7 that, relative to T cells within LNs, is highly receptive to ligand triggering [55]. LNs and PPs of plt mice and Ccr7 / mice show severe reductions in the number of T cells and elevated numbers of T cells in peripheral blood [7,29]. Following intravenous transfer of Ccr7 / CD4+ and CD8+ T cells into mice, recruitment of these cells to LN and PP is markedly impaired [29]. CCL21, but not CCL19, appears to be the CCR7 ligand essentially involved in this process as Ccl19 / mice do not have reduced frequencies of T cells in LN [17]. B cells also use CCR7 to gain entry to LN and PP across HEVs, although they are less dependent on this axis than T cells. While blood-borne B cells have recently been shown to predominantly use CCR7 to adhere to HEVs

Fig. 4. CCR7 and recruitment and migration of cells in LN. Schematic showing the structure and cellular composition of the LN indicating various CCR7-dependent processes in the LN. (Top left segment) Tissue DCs enter the LN first by entering lymphatic vessels in peripheral tissues. CCL21 expressed on LECs provides an entry signal to the lymphatic vessels, which then drain into the LN SCS. CCR7 is also involved in migration of DCs from the SCS into the LN paracortex. (Top right segment) Naı¨ve lymphocytes enter LN from the blood across HEVs in the paracortex. CCR7 induces arrest of lymphocytes on HEVs, and these cells subsequently enter the LN. (Bottom right segment) Within the LN paracortex, T cells and DCs migrate along CCL21 and CCL19 expressing FRC networks facilitating antigen scanning and APC-T cell interactions. (Bottom left segment) Following antigen activation, B cells in the cortex induce CCR7 expression and migrate towards the T cell rich paracortex. Antigen activated TFH cells lose CCR7 expression and also migrate towards the T-B cell border. These interactions are critical for the initiation of the GC reaction and high affinity antibody responses.

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in LN [56] and PP [57] and transferred Ccr7 / B cells have compromised capacity for LN recruitment [29], CCR7/CCL19/CCL21 are not absolutely required for B cell entry to the LN, as resting B cell frequencies in LNs are normal in Ccr7 / mice [29] and CXCR4/ CXCL12 interactions appear sufficient to support extravasation of B cells in plt mice [58]. In addition, B cells are also able to cross LN and PP HEVs via CXCR5/CXCL13 interactions [59]. Once naı¨ve lymphocytes enter SLOs, they segregate into distinct T cell and B cell areas. This is also controlled to a large extent by CCR7, which provides the homing signal to the T cell area where FRCs are abundant sources of CCL19 and CCL21 [17,60]. This contrasts with the follicular areas, where CXCL13 is instead produced. Thus, the starkly differential expression of CCR7 and CXCR5 between naı¨ve T and B cells dictates whether they locate to the T cell areas or the follicles respectively. As lymphocyte entry to the spleen is largely chemokine independent, this organ has proved useful to examine the role of chemokine receptors in compartmentalisation of lymphocytes within SLOs. Lymphocytes enter the spleen from blood at the marginal zone (MZ) and migrate into the periartiolar lymphoid sheath (PALS) at MZ bridging channels where FRCs traverse the marginal sinus [61]. Various studies have revealed the importance of CCR7 and its ligands in the organisation of the T area of the SLOs. In Ccr7 / and plt mice, severely impaired T cell migration into the splenic PALS is apparent and there is no discernable T cell zone in LN paracortex [29,62,63]. In addition to providing the signal for naı¨ve T cell homing to the PALS or LN paracortex, CCR7 and its ligands also play various other important roles in T cell recirculation through SLOs. Real-time imaging and two-photon microscopy has enabled assessment of the contribution of CCR7 and its ligands to lymphocyte motility within LNs. Non-antigen engaged T cells must remain in a constant state of locomotion to effectively sample presented antigens within LNs and recirculate from one LN to the next. This intranodal T cell motility has been shown to involve CCR7. T cells deficient in CCR7, or WT cells in plt LN, show reduced motility in LN and move with reduced velocities [64,65]. This ability of CCR7 ligands to promote motility, rather than adhesion, appears to be a characteristic of CCL19 and CCL21 signalling in T cells that occur under shear stress-free conditions such as those encountered in the LN T cell zone [6]. Furthermore, CCR7 also contributes to signalling that enhances T cell survival within LNs. Specifically, CCL19 produced by FRCs has been shown to operate in concert with IL-7 to promote T cell survival in LNs, and this is one of the few functions of CCL19 that does not seem to overlap with that of CCL21 in T cell biology, although the molecular mechanisms underpinning this have yet to be resolved [17]. Following antigenscanning without cognate engagement in SLOs, T cells make their way to efferent lymphatic vessels or, in spleen, to blood vessels to re-enter circulation. The essential receptor for lymphocyte egress from SLOs is the sphingosine-1 phosphate receptor 1 (S1P1). CCR7 has been shown to counteract this egress signal and contributes to T cell retention within SLOs [66]. Therefore the relative expression of CCR7 or S1P1 determines whether T cells remain within or leave secondary lymphoid tissue. Recently, a feedback mechanism, which may control the relative abundance of these receptors on T cells was uncovered. CCL19 signalling through CCR7 in T cells was reported to induce expression of S1P1 [67]. Therefore, it is likely that sustained CCR7 signalling in response to ligands encountered by T cells in SLOs will promote T cell motility, survival and retention within SLOs, but also ultimately leads to CCR7 becoming refractory to further signals [55] and promotes expression of factors required for T cell exit, following which T cells re-enter the circulation and CCR7 reacquires its capacity for recruitment to the next SLO [55] and the process will be repeated for the life of the cell until antigen receptor engagement.

3.4. CCR7 and homeostatic DC recruitment In addition to recruiting lymphocytes, LNs are also the destination of migratory APCs, such as DCs, from peripheral tissues. This occurs constitutively in the absence of inflammation but is massively increased following tissue infection or damage. Migration of DCs in the absence of inflammation is required for optimal peripheral tolerance induction as tolerogenic DCs provide antigen-specific signals to ensure self-reactive T cell anergy or TREG priming occurs. Migrating CCR7+ DCs leave peripheral tissues and enter afferent lymphatic vessels, which drain into the subcapsular sinus (SCS) of LNs (Fig. 4, upper left panel). From here, migrating DCs move along FRCs networks to the LN paracortex where they interact with T cells. Analyses of plt, Ccl19 / and Ccr7 / mice have revealed an important role for CCR7 and CCL21, but not CCL19, in regulating homeostatic trafficking of DCs to the LNs. In plt and Ccr7 / mice, severe defects in abundance of CD11cintMHC IIhi skin-derived DCs, CD11b+ DCs, CD8+ DCs and plasmacytoid DCs are apparent [29,63,68–71]. Accordingly, the induction of peripheral tolerance to antigen delivered via the respiratory or gastrointestinal tract is defective in Ccr7 / mice [72,73]. Interestingly, CCR7dependent homeostatic trafficking of DCs was also recently shown to feedback on lymphocyte recruitment from the blood to LN. Constitutively migrating DCs support HEV formation by providing LT [74] and vascular endothelial growth factor (VEGF) [70] that promotes endothelial cell mitosis required for optimal HEV development and T cell recruitment from peripheral blood. Furthermore, constitutively migrating DCs also induce CCL21 production by FRCs and provide a cell surface binding site for this chemokine, which subsequently also promotes T cell retention in LNs [70]. 3.5. CCR7 and regulatory T cell function Peripheral tolerance to self and harmless antigen is also exerted by a subset of CD4+ T cells that express the transcription factor FoxP3, termed regulatory T cells (TREGS) [75]. This subset of T cells express high levels of CCR7 [76,77] and numerous studies have indicated that TREGS require CCR7 and its ligands for their effective function. Although not required for natural TREG differentiation in the thymus, nor for TREG-mediated suppression in vitro, CCR7 mediates TREG homing to the T cell zone of the LN [78] and therefore is essential for TREG-APC interactions that mediate effective immune suppression [76]. Co-transfer of T helper cells with Ccr7 / TREGS into SCID mice leads to increased gastrointestinal pathology compared with transferred WT TREGS [76]. However, this requirement for CCR7 in order for TREGS to exert their regulatory function appears to be confined to the LN-homing subset of TREGS that do not express CD103. In response to subcutaneous ovalbumin challenge, antigen-specific Ccr7 / TREGS were unable to exert suppression over other TCR transgenic cells in the LN. In contrast, Ccr7 / CD103+ TREGS accumulate in tissues such as the skin and exert increased local suppression compared with WT [77]. Thus, CCR7 plays a dual role in TREG biology: for inducible TREGS, CCR7 is essential for efficient priming of these cells in LN; while ‘effector’ TREGS appear to use CCR7 to exit tissues and therefore CCR7 limits their abundance in peripheral tissues. 4. CCR7 during the immune response The importance of the CCR7/CCL19/CCL21 chemokine axis in the generation of adaptive immune responses has been tested in a wide variety of models. In most models of immunity, mice deficient in CCR7 or its ligands exhibit reduced or delayed adaptive immune responses, particularly when antigen is limited. Following immunisation with a single protein antigen, Ccr7 / and plt mice

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have markedly fewer interactions between DCs and T cells in LN paracortex and delayed T cell and humoral immune responses of altered magnitude [29,79]. However, in scenarios where replicating antigen is present and/or where B cells can provide sufficient antigen presentation to prime T cells, the requirement for CCR7 and its ligands appears to be redundant. Thus, in various models of viral infection such as vesicular stromatitis virus (VSV), lymphochorio meningitis virus (LCMV) or vaccinia virus (VV), CCR7 is not required for protective immunity [80,81], although in the case of LCMV, decreased CTL responses have been documented in Ccr7 / mice [80]. However, depending on the precise nature of the infection, effective immune responses to various pathogens can be CCR7-dependent. For example, plt mice have increased susceptibility to murine hepatitis virus [63], and Ccr7 / mice are more

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susceptible to infection with Listeria monocytogenes, Mycobacterium tuberculosis, Leishmania donovani and Toxoplasma gondi [82– 85]. The reported effects of interference or deletion of the CCR7/ CCL19/CCL21 axis in model immune/inflammatory responses or models of infection [29,40,80–105] are summarised in Table 1. In the following section the role of the CCR7 axis in the generation of adaptive immune responses shall be described in more detail. 4.1. CCR7 and migration of DCs during inflammation Following antigen capture in peripheral tissues and exposure to inflammatory cytokines such and IL-1b and TNFa, DCs enter a maturation programme involving up-regulation of CCR7 [24,26,106], MHC and co-stimulatory molecules, which enables

Table 1 The effect of manipulation of the CCR7 axis on immune/inflammatory responses and infectious disease. Model

Method

Hypersensitivity Allergic asthma

Phenotype/effect

Mechanism

Reference

Ccr7

Impaired migration of tolerising DCs to LN

[72]

plt

CCR7 required for tolerance to inhaled antigen Enhanced inflammation

Allergic asthma

[86]

Allograft rejection Allograft rejection Allograft rejection

CCL19 antagonist Ccr7 / Ccr7 /

Inhibits graft rejection Prolonged graft survival Graft survival

DTH (DNP-KLH) Graft versus host disease Graft versus host disease Experimental asthma OVA-induced asthma

Ccr7 / Ccr7 / chimaera CCR7 antagonist Ccr7 / plt

Nephrotoxic serum nephritis

Ccr7

/

Lack of DTH response Induces GVHD Prevents GVHD Enhanced inflammation Inflammation not resolved as readily as WT Exacerbated disease

Increased number of leukocytes at the site of inflammation, and increased TH2 activity and IL-4 levels CD8+ T cell priming relies on CCL19 Delayed cellular infiltration to graft Impaired generation of allospecific CTL response Not demonstrated Impaired TREG expansion Decreased donor T and B cell activation Increased effector cytokines in BAL CCL19/21 required for resolution of inflammation in airway TREG cells not recruited to SLOs effectively

Autoimmunity EAE EAE

Ccr7 Ccr7

/

EAE Experimental autoimmune thyroiditis Multiorgan autoimmunity

/

, plt

/

Anti-CCL21 NODx Ccr7

/

Ccr7

/

Bacterial infection Aspergillus conidia Listeria monocytogenes

Ccr7 Ccr7

/

Mycobacterium tuberculosis Pseudomonas aeruginosa

Ccr7 Ccr7

/

Viral infection Influenza infection

Ccr7

/

Influenza infection

Ccr7

/

LCMV

plt

LCMV

Ccr7

/

g-Herpes infection

Ccr7

/

Parasitic infection Leishmania donovani Toxoplasma gondii

plt Ccr7

Other inflammatory models Atherosclerosis in ApoE / Atherosclerosis

Anti-CCL19/21 Ccr7 /

chimaera

/

/

/

Resistant to disease Normal disease. Altered site of immune priming to the spleen Delayed disease onset 100% development of the disease (0% in WT mice) Increased susceptibility, disease onset and severity

Enhanced fungal clearance Increased bacterial burden in liver More susceptible to infection Infection more efficiently cleared

Defective activation of Ag-specific CD8+ T cell response Impaired CD8+ T cell egress from lung CD8+ T cell response and production of anti-viral Abs comparable to heterozygous (plt/wt) mice Reduced clonal expansion but comparable CTL activities to heterozygous (Ccr7 /+) mice More severe inflammation, higher viral load

[87] [88] [89] [29] [90] [91] [92] [93] [94]

Decreased IL-23 production by DCs Not demonstrated

[95] [96]

Decreased frequency of TH17 cells in spleen Increased lymphocyte infiltration into the thyroids and autoantibody in the serum Increased lymphocyte infiltration into periphery of pancreatic islets

[97] [98]

More DC activation Impaired priming of CD8+ T cells due to lack of CCR7 on CD8+ T cells and DCs Impaired DC migration to DLN Enhanced anti-microbial immune response

[99] [82]

Impaired ability of Ag transport to DLN by DCs

[101]

+

Inability of CD8 T cells to respond to CCL21 expressed by LECs during infection Contact between virus-loaded DCs and T cells occurred in splenic MZ, not the PALS

[40]

[83] [100]

[102] [81]

Weak recruitment of CTLs to SLOs and impaired co-localisation and interaction between DCs and CTLs Reduced and delayed T cell activation

[80]

Increased susceptibility to infection Fatal

Impaired migration of DC from MZ to PALS CCR7 on T cells required for IFNg production

[84] [85]

Prevented regression of lesion Attenuates plaque development

Monocyte emigration from plaques requires CCR7 Reduced infiltration of T cells into aorta and reduced TH1 response

[104] [105]

[103]

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priming of naı¨ve T cells in LNs. Responsiveness to CCL21 is required for antigen-laden Langerhan’s cells and dermal DCs to migrate through the dermal stroma to lymphatic vessels, and this has been shown to increase massively during inflammation [107]. Recent imaging studies have revealed that CCL21 is bound to lymphatic vessels [108,109] adjacent to ‘portals’ consisting of flexible junctions between the basement membrane and LECs [109,110]. After CCR7/CCL21 dependent entry into the lymphatic vessel, DCs travel with lymph flow and arrive at the LN SCS. Here, CCR7 is again required to facilitate entry of DCs into the LN paracortex, as was recently demonstrated in an elegant study by Forster and colleagues utilising intralymphatic injection of WT and Ccr7 / DCs. By 12 h post-injection, WT DCs were present in the paracortex while Ccr7 / DCs remained within the SCS [111]. The process of inward migration from the SCS to the paracortex involves DCs following a haptotactic gradient formed by production and immobilisation of CCL21 on the surface of FRCs [5,112]. CCL21 signalling induced up-regulation of integrins enabling DC attachment to the extracellular matrix, and soluble CCL19 was found to influence the direction of DCs undergoing haptotaxis [5]. Thus, the CCR7 chemokine axis plays a key role at multiple steps of DC migration from peripheral tissues to SLOs during inflammation where they can interact with cognate T cells to initiate adaptive immunity. In addition to promoting DC migration, non-migratory functions have also been attributed to CCR7 ligands by modulating particular aspects of DC function. Exposure of DCs to CCL19 has been reported to enhance DC production of IL-1b, IL-12 and TNFa together with increased expression of the co-stimulatory molecules CD40 and CD86 [113]. Furthermore, CCL19 and CCL21 have been shown to induce rapid endocytosis of antigen by DCs [114], promote survival of mature DCs [115,116] and CCL19 has been reported to induce, while CCL21 inhibits, extension of DC dendrites [117] that facilitate interactions with T cells. However, a more recent study revealed that dendrite probing by DCs was also CCR7independent [111]. Collectively, it is clear that, similar to the case with T cells, CCL19 and CCL21 act at multiple stages of DC function, stimulating not only recruitment but also co-stimulating multiple pathways required for DC function. 4.2. CCR7 and T cell activation During immune priming, APCs present antigenic peptides on MHC molecules to cognate T cells within the paracortex of LNs (Fig. 4, lower right panel) and the PALS of the spleen. Antigenspecific interactions lead to stable cell-cell contacts and if appropriate co-stimulatory factors are present, T cell priming, proliferation and activation occur. It has been postulated that production of CCL19 by DCs [118,119] will contribute to attraction of CCR7+ T cells to facilitate antigen-specific interactions, however defects in T cell priming by DCs are not apparent in Ccl19 / mice [68]. In contrast, it is clear that CCR7 and CCL21 are required for DC-T cell interactions within the LN paracortex or splenic PALS. In the absence of CCR7 or in plt mice, antigen-specific interactions between DCs and T cells still occur, but the efficiency of these interactions is diminished and these events occur in the splenic MZ bridging channels or LN superficial cortex [29,63]. In addition to ensuring that DCs and T cells encounter one another in the appropriate micro-anatomical compartment with sufficient frequency, CCR7 and its ligands also play supplementary roles in T cell activation by acting as co-stimulatory factors during T cell priming. Studies by Gollmer and colleagues revealed that CCL21 lowers the activation threshold for T cell activation in vitro and that GPCR signalling stimulates T cell activation within LNs [120], while another in vitro study revealed that CCL21 stimulation acted directly on naı¨ve T cells to bias towards a TH1 profile and supported

their proliferation during TCR activation [121]. In line with this, a recent study indicated that priming of TH2 cells in vivo was favoured in Ccr7 / mice [122]. However, contrasting findings have also been reported. Ziegler and colleagues reported that addition of CCL21 or CCL19 during T cell activation inhibited T cell proliferation and cytokine production [123]. Given that similar in vitro activation systems and similar chemokine concentrations were used in these studies clarification of the direct effect of CCR7 ligands on T cells during activation that can reconcile these disparate findings are required. In addition to the direct effects on T cells, T cell differentiation can also be influenced indirectly through the effects of CCR7 ligands on DCs. CCL19 and CCL21 are reported to induce production of DC-derived cytokines that assist in priming T cells including IL-12 and IL-23, promoting TH1 and TH17 responses, respectively [95,113]. Thus, CCR7 ligands appear to play a complex role in stimulating T cell activation. 4.3. CCR7 and T-dependent antibody responses Collaborative interactions between antigen-specific T cells and B cells are required for the processes of somatic hypermutation, affinity maturation and isotype switching that characterise effective high affinity humoral immune responses [124]. These interactions occur in specialised structures that form in the follicular areas of SLOs known as germinal centres (GCs). A prominent role for the CCR7 axis in the T and B cell interactions required to initiate the GC reaction has been described. Importantly, Ccr7 / and plt mice display impaired T-dependent antibody responses [29,125], although these responses still occur in the absence of this chemokine axis. Following B cell receptor (BCR)-mediated activation, antigenspecific B cells undergo multiple changes in chemokine receptor expression, facilitating their progression through the GC reaction via migration to appropriate micro-anatomical niches within the SLO. Specifically, antigen-inexperienced B cells bear a CXCR5+CCR7lo cell surface phenotype, which attracts and retains these cells within CXCL13-rich B cell follicles [23]. Shortly after activation, antigen-engaged B cells up-regulate expression of CCR7 [23,126], which, in collaboration with the oxysterol receptor EBI2, facilitates their migration to and distribution along the T-B border [127–129], where CCL21 emanates from T cell zone FRCs [17,130,131]. CCR7dependent positioning of B cells at the T-B border occurs rapidly (within 6 h of antigen engagement) [23,131], and these cells can be retained in this area for several days where they receive survival and proliferative signals through interactions with cognate helper T cells (Fig. 4, lower left panel). These helper T cells with B cell helper function are now recognised as a distinct lineage referred to as T follicular helper (TFH) cells [132], and govern the quality and magnitude of the GC reaction by providing crucial signals that regulate B cell selection, differentiation and proliferation. Modulation of CCR7 expression is also required for antigen-activated TFH cell recruitment to the T-B border. Differentiation of TFH from naı¨ve precursors is coupled with the loss of CCR7 and induction of CXCR5, which together facilitates their migration into B cell follicles and subsequently GCs [126,133–135]. Various studies have shown that forced expression of CCR7 on T cells prevents their migration to the follicular zones following immunisation [135,136], strongly indicating that modulation of CCR7 is an essential process allowing re-localisation of TFH cells and subsequent CXCR5-driven homing into B cell follicles. Therefore, it is evident that reciprocal antigen-activated B cell induction of CCR7 and TFH downregulation of CCR7 plays a key role in facilitating interactions between these cells required for optimal high affinity protective antibody responses.

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4.4. CCR7 in activated T cell recruitment to and egress from peripheral tissues As discussed above, the role of the CCR7 axis in recruitment of lymphocytes to LNs is well established but evidence also suggests that CCR7-dependent entry of effector lymphocytes to peripheral tissues is of importance. CCL21, and to a lesser extent CCL19, are also expressed in non-lymphoid tissues including the skin [137], lung [138] and the central nervous system (CNS) [97,139,140], and, contrary to their standard classification as homeostatic chemokines, these can also be induced in inflammatory circumstances. Further, although CCR7 expression is reduced on most T cells following activation, it is generally still expressed to some extent on these cells. In addition, subsets of memory T cells retain highlevel expression of CCR7, and CCR7+ T cells are observed within peripheral autoimmune lesions [137]. While much more attention has focused to date on the inflammatory chemokines in regulating homing of effector T cells to peripheral tissues, blocking CCR7 or CCL21 reduces adoptively transferred early effector T cell recruitment to the lung in a model of airway challenge [138] and CCR7 has been shown to be an essential entry signal to the CNS for T cell leukaemias [141]. The contribution made by the CCR7 axis in other models of effector T cell recruitment remain to be determined in detail, but it is likely that this receptor system plays a more substantial role than has been identified to date in these processes. An important step in the resolution of peripheral inflammation and development of immune memory is egress of effector T cells from tissues. Here, a key role for CCR7 has been demonstrated. In the absence of CCR7, effector T cells accumulate in peripheral tissues including the skin [142,143], the asthmatic lung [144] and the peritoneal cavity [145]. This accumulation is caused by defective emigration of effector T cells into CCL21 rich afferent lymphatic vessels, a process that relies upon CCR7 expression [144], at least during acute inflammation [142]. In the absence of this CCR7-dependent drainage of effector T cells from peripheral tissues, impaired resolution of peripheral immune responses occurs that can culminate in autoimmune lesions. 4.5. CCR7 and memory T cell recirculation Two subsets of memory T cells have been defined on the basis of their trafficking pattern which is determined by homing receptor expression: effector memory T (TEM) cells (CCR7loCD62L ) and central memory T (TCM) cells (CD62L+CCR7hi) [19] TEM traffic through peripheral tissues protecting against secondary infection at the sites of pathogen entry, while TCM migrate through SLOs in search of reactivating antigen [19,146]. Perhaps unsurprisingly, a role for CCR7 has been documented for optimal LN accumulation of TCM cells in mice [147,148]. However, compared with naı¨ve T cells, TCM cells are less reliant on CCR7. In the absence of CCR7 ligands, TCM recruitment to the LN is reduced by only 20%, whereas naı¨ve T cell homing is almost completely abrogated [148]. It appears that other chemokine receptors, including CXCR4, operate alongside CCR7 in TCM recruitment to the LN [148]. In line with this, an absolute requirement of CCR7 for memory T cell responses is not apparent. Indeed, Kursar and colleagues reported that memory T cell responses to the intracellular bacteria L. monocytogenes were independent of CCR7 [82]. Likewise, following LCMV infection, effective memory CTL responses are generated in the absence of CCR7, although these cells tend to reside in non-lymphoid tissues in Ccr7 / mice [80]. Therefore, it appears that multiple trafficking receptors dictate the function of memory T cells and that, while CCR7 and its ligands play a role in memory T cell biology, this axis is not an absolute requirement for adaptive immune memory.

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4.6. CCR7 in anti-tumour immunity The role of CCR7 and its ligands in tumour immunity has also been highlighted during the last decade. The importance of the CCR7 axis in tumour immunity was first investigated by Sharma and colleagues, who demonstrated that intratumoural administration of recombinant CCL21 resulted in eradication of subcutaneous lung cancers, associated with enhanced T cell and DC infiltration leading to enhanced CTL responses [149]. Numerous studies have since demonstrated that induced expression of CCL19 [150,151] or CCL21 [150,152–155] in tumour tissue results in inhibition of tumour growth or complete rejection of established tumours associated with increased infiltration by T cells and/or DCs in various cancer models. However, expression of CCR7 on tumour infiltrating cells was not demonstrated in these studies and, therefore, the CCR7-dependency of the observed effect was not directly demonstrated. Nevertheless, these studies strongly suggested that CCL19 and CCL21 have the capacity to recruit antitumour lymphocytes and APCs to tumour tissue, leading to inhibition of tumour growth or rejection of established tumours. More recently, a clinical study has shown that better prognosis of patients with advanced colorectal carcinoma was associated with increased infiltration of CCR7+ T cells [156]. Middel and colleagues have also shown that expression of CCL19 or CCL21 by human renal cell carcinoma was associated with accumulation of CCR7+ DCs in the tumour margin [157]. In addition, in a mouse model of lung cancer, intratumoural delivery of CCL21 also resulted in enhanced infiltration of CD3+CCR7+ T cells, while the frequencies of TREG cells and myeloid derived suppressor cells were decreased, leading to inhibition of tumour growth [158]. In contrast, Shields and colleagues demonstrated that expression of CCL21 by mouse melanoma cells results in enhanced infiltration of TREG cells and myeloid derived suppressor cells into tumours and also drives lymphoid neogenesis of an immunosuppressive nature at the tumour site, leading to melanoma outgrowth [159]. These effects are abrogated in mice lacking CCR7, indicating the dependency on host CCR7. Together, while the majority of current literature indicates the potential involvement of the CCR7 axis in anti-tumour immunity, which promotes this axis as a tractable target for cancer therapies, existing data also dictate caution as activation of adaptive tumour immunity through CCR7 may also lead to induction of tolerance to tumour antigens. 5. Regulation of the CCR7 system Given the importance of CCR7 and its ligands to the numerous immune processes described above, it is vital that this system is tightly regulated to ensure appropriate responses. This is achieved in a variety of ways, including highly regulated production of CCL19 and CCL21 in defined cellular and anatomical niches in response to various cues; regulation of expression and sensitivity of CCR7 on immune cells; and regulation of CCR7 ligand abundance and location at a post-translational level by regulatory chemokine binding receptors. These shall be explored in turn in the next section. 5.1. Induction of CCL19/21 Despite their classification as homeostatic chemokines CCL19 and CCL21 can be induced in certain inflammatory circumstances. Given the dramatic effects that can result from inappropriate production of these chemokines, such as TLO formation when these chemokines are expressed in tissue-specific transgenic mice [50,51,53], tight regulation is exerted over the production of these chemokines. Two main pathways for CCL21 production are apparent: LT-dependent and LT-independent [138], and CCL19

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expression appears to be LT-dependent. In lymphoid stroma, LTinduced CCL19 and CCL21a predominate. In mice that lack membrane LT or TNFa, both CCL19 and CCL21a are absent in SLOs [160] due to impaired induction of these chemokines following interactions between LTi cell and stromal organisers. Constitutive expression of CCL21b in peripheral tissues however is LT-independent [138]. CCL21b expressed by LECs, which appears to be an essential signal for steady state DC entry into lymphatic vessels, is maintained in mice lacking membrane LT. However, both CCL19 and CCL21 may be induced following inflammatory signalling in peripheral tissues in an LT-dependent manner. Inflammatory signalling that induces MAPK cascades has been shown to result in production of CCL21 in LECs in the skin [161] and LT-dependent inflammatory signalling involving NFkB induces CCL21 expression in the lung [138]. In addition, inflammatory cytokines have also been shown to induce CCL21 in LECs. For example, subcutaneous injection of IL-1b or TNFa increased mRNA for CCL21 in LECs and potentiated the migration of subsequently injected BM-DCs [107]. A recent study has also implicated the surface molecule CD137 on LECs as playing a role in CCL21 induction [162], and crosslinking this receptor on LECs led to CCL21 expression, although how this depends on the essential LT-mediated signal for CCL21 induction in LECs is not yet clear. While CCL21 has been more widely reported to be inducible under inflammatory circumstances than CCL19, expression of LT-dependent CCL19 at sites of peripheral inflammation has also been reported, including during CNS inflammation, in the salivary gland during experimental Sjogren’s syndrome and in the rheumatoid joint [140,163,164]. 5.2. Regulation of CCR7 on T cells and DCs While CCR7 expression is another level at which the activity of the CCR7 axis is regulated, this remains poorly understood. Recently the transcription factor Foxo1 was shown to be responsible for driving high level CCR7 expression in naı¨ve T cells [165] and interferon regulatory factor 4 was shown to be an essential molecule for CD11b+ DC CCR7 expression [166]. In addition, TCR stimulation attenuates CCR7 expression in T cells and a variety of cytokines and inflammatory mediators have been shown to modulate CCR7 expression in T cells and DCs. Despite this, a clear picture of how this receptor is regulated has not yet emerged. Various post-translational mechanisms have also been described that either potentiate or regulate the activity of CCR7 on both T cells and DCs. A recent study by Schaeuble and colleagues demonstrated that TCR signalling cross-talks with that of CCR7 to alter the sensitivity to CCL21 [167]. Short-term TCR activation profoundly increases CCR7 sensitivity, presumably to enable continued antigen sampling in LN, whereas long-term TCR activation suppressed the activity of CCR7, inhibiting further cell migration. Similarly, recent studies have shown that signalling through receptors that work alongside CCR7, such as CD62L or CXCR4 for T cell LN entry, increase CCR7-mediated migratory signals in T cells [168,169]. In addition, crosstalk with other chemokine receptors involved in DC migration, such as CCR4 in Langerhan’s cells, promotes CCR7-dependent LC migration [170]. Other mechanisms are also in play that potentiate or regulate the function of CCR7 in DCs. Most prominently, the inflammatory mediator prostaglandin E2 (PGE2) has been shown to be a key factor in CCR7 function in DCs. PGE2 induces CCR7 expression on maturing DCs and is an essential signal for DC migration by potentiating CCR7 activity via lowering the signalling threshold in these cells required for migration [171–173]. Conversely, recent evidence has implicated the liver-X receptor in attenuating CCR7mediated DC migration [174,175], although this can reportedly be over-ridden by PGE2 signalling [176].

5.3. Regulation of CCR7 by atypical chemokine receptors Atypical chemokine receptors are a subfamily of chemokine receptors that do not appear to mediate cell migration, are generally expressed by stromal cells and have been proposed to regulate chemokine biology either by scavenging or transporting their ligands [177]. The best studied of these receptors are DARC and D6, which regulate the biology of multiple inflammatory chemokines. However, the atypical chemokine receptor CCX-CKR, coded by the gene Ccrl1, has particular significance in the context of CCR7 biology, as this receptor specifically binds both CCL19 and CCL21, in addition to the CCR9 ligand CCL25 [178,179]. We have previously shown that CCX-CKR efficiently mediates CCL19 uptake and that this chemokine is subsequently degraded in transfected cells, conferring a specialised capacity for chemokine scavenging by CCX-CKR compared with CCR7 [180]. Expression of CCX-CKR appears to be mainly restricted to LECs in LN [60,181], cTECs in the thymus [182], although it is detectable by RT-PCR from a widerange of peripheral and mucosal tissues [179]. Expression of CCXCKR by hematopoietic cells is more controversial, with one study suggesting expression by BM-DCs [178] but analysis of a CCX-CKRGFP reporter mouse indicating expression only in stromal lineages [181]. Our own analysis of CCX-CKR expression indicates that DCs do not express this receptor. We find that stromal cells and highly restricted subpopulations of bone marrow-derived cells are the only cells to express this molecule (Comerford et al., unpublished). Importantly, in the absence of CCX-CKR, CCL19 and CCL21 protein levels in tissues and LNs are increased [97], consistent with a scavenging function of CCX-CKR for CCR7 ligands. Notably, in Ccrl1 / mice there is a large increase in soluble CCL21 protein in the serum, perhaps indicating that CCX-CKR functions to prevent chemokine entry into the bloodstream. Likely as a result of these defects in regulation of levels of CCR7 ligands, defects in steadystate DC migration from skin to LN have been identified in Ccrl1 / mice [181] (and Bunting et al., unpublished) and resting LNs tend to be smaller in Ccrl1 / mice [181] (and Bunting et al., unpublished). In addition, following subcutaneous immunisation, Ccrl1 / mice have reduced immune responses in draining LN [97] and enhanced responses in spleen, a phenotype with similarities to the plt mouse [63]. Therefore, it appears that in the peripheral immune system, lack of regulation of CCR7 ligands caused by deletion of CCX-CKR actually leads to some similar phenotypes to that caused by deletion of CCR7 ligands. However, exceptions to this are also apparent. In contrast to Ccr7 / and plt mice, segregation of T and B cells in LN and spleen appears intact in Ccrl1 / mice [97,181], apparently ruling out a role for this receptor in regulating chemokine localisation and lymphocyte compartmentalisation in SLOs. Further, following immunisation for experimental autoimmune encephalomyelitis (EAE), Ccrl1 / mice display exacerbated symptoms with earlier disease onset and skewing of the T cell response towards TH17 [97]. This is in contrast to that reported in Ccr7 / and plt mice where reduced disease is apparent [95]. The reasons for this may lie in the effect of overabundance of CCL19 and CCL21 and their impact on T cell priming. CCL21 has been reported to lead to IL-23 production in DCs, and Ccrl1 / mice have elevated CCL21 and IL-23 alongside the increase in pathogenic TH17 cells [97]. Thus, a complex interplay appears to exist between CCX-CKR and the CCR7 axis in the peripheral immune system. Regulation appears to be exerted over CCL19 and CCL21 by CCX-CKR, but determining the overall impact of this on the multiple CCR7-dependent immune processes will take significant further investigation. We have also recently examined the role of CCX-CKR in the thymus. Like Ccr7 / mice (see above), Ccrl1 / mice develop spontaneous autoimmune-like pathology resembling Sjogren’s syndrome [182], pointing towards an important role for CCX-CKR

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Fig. 5. Regulation of CCR7 ligands by CCX-CKR. A schematic of CCX-CKR-mediated regulation of the CCR7 axis is shown. CCR7 is generally expressed on leukocytes, binds CCL19 and CCL21 and promotes migration and activation of cells in response to these chemokines. Conversely, CCX-CKR is expressed by stromal cells and binds CCL19 and CCL21 with lower affinity and does not mediate cell migration. CCX-CKR is likely to play a role in regulating the availability of CCR7 ligands either by binding, internalising, degrading or transporting CCL19 and CCL21. Alternative signal transduction mechanisms are also possible downstream of CCX-CKR.

in the development and maintenance of tolerance. While an earlier study had revealed that overexpression of CCX-CKR in the thymus inhibited progenitor seeding of the embryonic thymus, but reported no major effects of deleting this receptor on thymocyte development [181], our analysis revealed that deletion of CCX-CKR impacted on the thymic stroma, thymic chemokine localisation and impaired negative selection of thymocytes [182]. The disparity between these two studies will require future clarification but it seems evident that post-translational control over chemokines exerted through CCX-CKR can have a major impact on signalling chemokine receptors such as CCR7 that are important for fundamental processes such as immune tolerance. Thus, while the overall impact of CCX-CKR on the biology of the CCR7 axis has not yet been fully explored, increasing evidence implies that this atypical chemokine receptor forms a key regulatory component of the system. The potential functions of CCX-CKR and how this might interplay with the CCR7 axis are summarised in Fig. 5. Another atypical chemokine receptor that may also have some relevance to the CCR7 axis is a molecule known as CRAM-B. This receptor has also been shown to bind to and internalise CCL19 without mediating cell migration [183]. Intriguingly, CRAM-B expression is reported to be highest on pre- and pro-B cells and has been postulated to play a role in regulating B cell migration. Importantly, expression of CRAM-B appears to attenuate responses through CCR7 in cells of B cell origin [184]. While the overall impact of CRAM-B on regulation the CCR7 axis is not yet clear, analysis of CCR7-dependent immune functions in CRAM-B deficient mice should yield further insights. 6. Summary Nearly 20 years worth of accumulated data have demonstrated the importance of the CCR7 axis in adaptive immunity. Primarily by mediating migration of DCs and T cells to SLO niches, this system plays a fundamental role in the organisation of the immune system; central and peripheral tolerance; triggering adaptive

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Dr Iain Comerford completed his doctoral studies at the University of Glasgow in 2005. He performed postdoctoral studies at the University of Adelaide and is currently a research fellow at the University of Adelaide funded by Multiple Sclerosis Research Australia.

Dr Yuka Harata-Lee is a recent PhD graduate at the University of Adelaide under the supervision of Dr Iain Comerford and Professor Shaun McColl.

Dr Mark Bunting is a recent PhD graduate at the University of Adelaide under the supervision of Dr Iain Comerford and Professor Shaun McColl.

Ms Carly Gregor is current post-graduate student under the supervision of Dr Iain Comerford and Professor Shaun McColl.

Mr Ervin Kara is current post-graduate student under the supervision of Dr Iain Comerford and Professor Shaun McColl.

Professor Shaun McColl completed his doctoral studies in 1988 at the University of Adelaide and then performed postdoctoral studies at the University of Laval, Canada, before taking up an academic position at the University of Laval in 1989. In 1993, Professor McColl moved to the John Curtin School of Medical Research before returning to the University of Adelaide in 1995. Professor McColl is currently a Professor of Immunology at the University of Adelaide. He is a leader in the field of chemokine biology, has published more than 100 manuscripts in this area and has been recipient of numerous prizes and fellowships for his research.