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Chemokine Receptors in T-Cell-Mediated Diseases of the Skin Anke S. Lonsdorf1, Sam T. Hwang2 and Alexander H. Enk1

The / network is an integral element of the complex system of homeostasis and immunosurveillance. Initially studied because of their role in coordinating tissue-specific migration and activation of leucocytes, have been implicated in the pathogenesis of various malignancies and diseases with strong inflammatory components. We discuss recent findings suggesting a critical involvement of chemokine receptor interactions in the immunopathogenesis of classical inflammatory skin disorders such as psoriasis and atopic dermatitis, as well as neoplastic diseases with a T-cell origin, such as mycosis fungoides. A deeper understanding of the underlying contribution of the chemokine network in the disease processes is key for the development of selective targeted immunotherapeutics that may meet the delicate balance between efficacy and safety. Journal of Investigative Dermatology (2009) 129, 2552–2566; doi:10.1038/jid.2009.122; published online 28 May 2009

INTRODUCTION dermatitis (AD), and mycosis fungoides or inducible production under homeo- In the past two decades, chemokine (MF), and discuss possible implica- static or inflammatory conditions, receptors have emerged as important tions in the development of novel chemokines can be further classified determinants for the directed trafficking targeted therapies. The structural orga- into inflammatory or homeostatic of T cells and their function in primary, nization of the skin allowing direc- chemokines. effector, and memory immune respon- tional migration of leucocytes within Chemokines interact with members ses (Sallusto et al., 2000). Although their the two defined compartments of the of the large family of seven-transmem- role in leukocyte activation and differ- epidermis and dermis, as well as its brane G--coupled receptors entiation is well established, it is becom- convenient accessibility, identifies the (Charo and Ransohoff, 2006). The ing increasingly clear that chemokine skin as an ideal model for in vivo C-terminal intracellular domain of the receptor/ligand interactions participate studies on chemokine involvement receptor is involved in receptor signal- in several other key biological processes in the pathogenesis of defined skin ing and internalization, whereas the such as apoptosis, tumorigenesis, and disorders. extracelluar acidic amino-terminal por- antimicrobial activity (Zlotnik et al., tion mediates ligand binding. To date, 1999; Rossi and Zlotnik, 2000). THE CHEMOKINE SYSTEM approximately 18 different chemo- A comprehensive discussion of the Chemokines are small (8–11kDa), kine receptors have been molecularly biology of chemokines has been the secreted that are predomi- defined (Mantovani et al., 2006). focus of several recent publications nantly involved in regulating leuko- Notably, there is considerable (Luster, 1998; Rossi and Zlotnik, cyte chemoattraction (Luster, 1998). redundancy in the chemokine network, 2000; Charo and Ransohoff, 2006; The approximately 50 identified mem- with chemokines binding to more than Bromley et al., 2008) and is beyond bers of the chemokine superfamily are one receptor and vice versa. the scope of this review. systematically subcategorized on the Instead, we aim to highlight the basis of the position and number of DIFFERENTIAL CHEMOKINE areas of chemokine biology with parti- conserved cysteine motifs in one out of RECEPTOR EXPRESSION ON cular impact on the immunopatho- four related families: C, CC, CXC, and T-CELL SUBSETS genesis of classical T-cell-mediated CX3C chemokines (Rossi and Zlotnik, Chemokine receptors have emerged as skin diseases, such as psoriasis, atopic 2000). On the basis of their constitutive important determinants for the pheno-

1Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany and 2Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Correspondence: Dr Anke S. Lonsdorf, Department of Dermatology, University Hospital Heidelberg, Voss-Strasse 2, Heidelberg D-69115, Germany. E-mail: [email protected] Abbreviations: AD, atopic dermatitis; APC, antigen-presenting cell; CD, cluster of differentiation; CLA, cutaneous lymphocyte-associated antigen; CTCL, cutaneous T-cell lymphoma; DC, dendritic cell; MF, mycosis fungoides; LC, Langerhans cells; SS, Se´zary syndrome; T-cell, T lymphocyte; TNF-a, tumor necrosis factor-alpha; Treg, regulatory T lymphocyte Received 15 December 2008; revised 4 March 2009; accepted 24 March 2009; published online 28 May 2009

2552 Journal of Investigative Dermatology (2009), Volume 129 & 2009 The Society for Investigative Dermatology AS Lonsdorf et al. Chemokine Receptors in T-Cell-Mediated Diseases

typical and functional characterization 1998; Sallusto et al., 1998a) and show TRADITIONAL FUNCTIONS AND of distinct T-cell subsets. The signifi- migration in response to CCL3-5 and NEW ASSIGNMENTS cance of a deeper insight into the role CXCR9-11. By contrast, Th2 cells have Chemokine interactions have been of the chemokine/chemokine receptor been found to preferentially express intensely studied for their significant network in the immunopathogenesis CCR4 (Bonecchi et al., 1998; Sallusto importance in the controlled regulation of T-cell-mediated skin diseases arises et al., 1998a), CCR8, and, to a lesser of immune cell trafficking and activa- essentially from the observation that extent, CCR3 (Sallusto et al., 1997), and tion. Recent studies indicate that distinct subsets of pathogenic effector can be selectively recruited by the chemokines may have additional roles leucocytes are preferentially recruited respective chemokines (CCL17, CCL22, and exert further key biological in different T-cell-mediated skin dis- CCL1, and CCL11). CCR6 has recently functions, with possible implications eases, three of which will be discussed been described as a marker for human for the immunopathogenesis of T-cell- as examples in this review. and murine Th17 cells, identifying the mediated skin diseases. Different subsets of T-helper cells vast majority of IL-17-producing T cells can develop from naive CD4 þ T cells in human peripheral blood (Acosta- Chemokine-mediated T-cell trafficking and may be characterized by a dis- Rodriguez et al., 2007; Annunziato to the skin crete pattern of cytokine production. et al., 2007; Singh et al., 2008). Molecular mechanisms controlling the Although IFN-g-producing Th1 cells CCR4 has been found to be abun- multistep process of directed migration are thought to primarily promote cell- dantly expressed on many systemic and tissue positioning are an area of mediated immune responses, Th2 cells, peripheral blood memory T cells, intense research. In response to antigen which secrete IL-4, IL-5, and IL-13, are which consequently respond to its encounter in secondary lymphoid mostly involved in humoral immunity, ligands, the chemokines, CCL17 and organs, activated T cells not only including allergic reactions. lL-17 and CCL22 (Campbell et al., 1999). Inter- acquire effector functions but also IL-22 have been described as the hall- estingly, these cells include essentially achieve the capacity to efficiently mark cytokines of Th17 cells, a newly all T cells with a skin-homing CLA þ migrate to extralymphatic tissues, such described T-helper subset with consid- phenotype, regardless of their Th1 or as the skin. The tissue-selective recruit- erable involvement in several inflam- Th2 polarization (Andrew et al., 2001). ment of naive and memory T lympho- matory and autoimmune diseases Further studies examining the T-cell cytes can largely be explained by the (Hirota et al., 2007; Pene et al., 2008). chemokine receptor expression in vivo joint expression of chemokine recep- In cutaneous T-cell lymphoma indicate that the patterns and regula- tors and adhesion molecules such as (CTCL), the malignant cell is thought tion of chemokine receptor expression selectins and integrins (Butcher and to typically derive from a Th2-polarized in vivo are more complex than those Picker, 1996). origin. In AD, Th2 cells are pre- suggested by present in vitro models Chemokine receptor engagement is dominantly implicated in the early of Th1 versus Th2 cell generation. Kim thought to facilitate transmigration by phase of the disease. In contrast, et al. (2001) reported that in vivo- permitting the firm adhesion of rolling chronic lesions of AD are characterized activated Th1 and Th2 cells display a lymphocytes to the luminal vascular by an accumulation of skin-homing remarkable heterogeneity with regard endothelium in an integrin-indepen- T cells with a Th1 phenotype (Grewe to their chemokine receptor expression. dent manner (Campbell et al., 1998; et al., 1998). By contrast, the inflam- Similarly, the IL-17-secreting subset of Campbell and Butcher, 2000; Fitzhugh matory infiltrate in psoriasis is predo- T-helper cells, as well as the population et al., 2000). Subsequently, chemokine minantly composed of Th1-polarized of antigen-specific Foxp3 þ regulatory gradients in the skin may guide recep- lymphocytes of a memory phenotype T cells, seems to be heterogeneous with tor-bearing subsets of T cells to distinct as well as neutrophils, macrophages, regard to chemokine receptor expres- sites within the tissue compartment and increased numbers of dendritic sion. T regulatory cells (Treg) and Th17 (Hwang, 2001). cells (DCs) (Prens et al., 1995). In cells share chemokine receptors with In humans, the expression of cuta- addition, Th17 cells have recently other T-cell lineages and might differ- neous lymphocyte antigen (CLA) been implicated in the pathogenesis entiate to have distinct chemokine defines a subset of skin-homing T cells of psoriasis and other autoimmune receptor expression profiles depending with specific carbohydrate-mediated inflammatory diseases (Lowes et al., on the microenvironment in which binding to E-selectin, an adhesion 2007; Steinman, 2007; Zaba et al., they are activated (Acosta-Rodriguez molecule highly expressed by endo- 2007). et al., 2007; Bromley et al., 2008). thelial cells under inflammatory condi- Over the past decade, the close Although the observed heterogeneity tions (Berg et al., 1991; Springer, 1994; association of chemokine receptor and flexible programing of chemo- Fuhlbrigge et al., 1997). expression with the functional pro- kine receptor expression might be an Although CLA þ T lymphocytes perties, differentiation, and maturation advantageous feature for the migratory represent only 10–15% of circulating status of T-cell subsets has been con- potential to diverse tissues in vivo, T cells in the peripheral blood, Clark vincingly documented. Th1 cells have these studies call the physiological et al. (2006) recently estimated that been reported to selectively express relevance of several in vitro observa- 90% of skin-resident T cells express CXCR3 and CCR5 (Loetscher et al., tions into question. CLA, and 80% of these cells are

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effector memory T cells (Picker et al., an analogous scenario for chemokines The skin contains two major subsets 1993). However, as E-selectin is not expressed in the skin compartment are of DCs: dermal DCs and Langerhans exclusively expressed by the cutaneous eagerly awaited. cells (LCs) in the epidermis (Loser vascular complex but also on endo- and Beissert, 2007; Udey and Nagao, thelium in various tissues under inflam- T-cell differentiation 2008). A complex interplay between matory conditions, other skin-specific The role of chemokine receptor expres- cytokines, adhesion molecules, matrix factors seem to contribute to the hom- sion as a determinant for the functional metalloproteinases, and lipid media- ing of CLA þ T cells. CCR4 and CCR10 properties and lineage commitment of tors, as well as chemokines and their expression in particular seems to be T-cell subsets has been the focus of receptors, orchestrates the in situ posi- associated with a CLA þ skin-homing intense research efforts. Chemokines tioning of DC and directs their reloca- phenotype of circulating T cells may influence T-cell differentiation tion from peripheral tissues to the (Homey et al., 2000a, 2002; Schaerli indirectly by stimulating antigen- draining lymph nodes (Moser and et al., 2004) and has been found to presenting cells to induce or repress Willimann, 2004; Adema et al., 2005). be critical for T-cell recruitment to polarizing cytokines, such as IL12 During maturation, DCs undergo a the skin in two different inflammation (Braun et al., 2000). Alternatively, rapid and coordinated switch in their models (Reiss et al., 2001; Campbell chemokines have been shown to regu- chemokine receptor profile (Sallusto et al., 2007). late T-cell polarization by acting et al., 1998b). Immature DCs have The majority of CLA þ lymphocytes directly on activated T cells (Karpus been reported to express a distinct in the peripheral blood co-expresses et al., 1998). Experimental evidence subset of chemokine receptors, includ- CCR4 (Campbell et al., 1999), with from several studies indicates that ing CCR1, CCR2, CCR5, CCR6, CCR8, subsets (30–40%) showing additional CCR5–CCL3 and CCL2 interactions in and CXCR1 (Villablanca et al., 2008), expression of CCR10 (Hudak et al., particular might be alternate or com- enabling them to migrate to inflamed 2002). The CCR10 ligand, CCL27, is plementary pathways to IL-12 and tissues, including the skin (Gombert exclusively produced by epidermal IL-4 in dominating T-cell polarization et al., 2005). Conversely, CXCR4 and keratinocytes (Morales et al., 1999; (reviewed by Luther and Cyster, 2001). CCR7 are expressed at very low levels Homey et al., 2002) and CCL17—a With immunotherapeutics targeting on immature DCs, but are markedly CCR4 ligand—is synthesized by acti- the chemokine network forthcoming, upregulated once DCs undergo matu- vated keratinocytes, DCs, and endo the disease-related contribution of ration after antigen capture (Sallusto thelial cells in the skin (Campbell chemokine/chemokine receptor inter- et al., 1998b). et al., 1999; Campbell and Butcher, actions in Th1 and Th2-cell polariza- Although identifying CCR7 as an 2000). Although CCL17 expression is tion and effector functions is evolving indispensable regulator for the entry not skin-specific, Reiss et al. (2001) (Kim et al., 2001). of dermal DCs and LCs into afferent have suggested a model in which CCR4 dermal lympathics, studies from Ohl and CCR10 share partly redundant or Chemokine-mediated effects on et al. (2004) propose that CCR7 may be overlapping roles in the recruitment of skin-resident DCs dispensable for the initial step of LC leukocytes to the skin. Chemokine/chemokine receptor inter- mobilization within the epidermis, that Apart from supporting immune actions are not limited to targeting is, migration from the epidermis toward cell recruitment to tissues, chemo- naive, memory, and effector lympho- the dermis. Correspondingly, studies kines are thought to play an active cytes but extend to all subsets of leuco- using human skin explants revealed role in the positioning of distinct cytes, including mature leucocytes of that CXCR4 and its ligand, CXCL12, T-cell subsets within different tissue the innate , as well as expressed by dermal endothelial cells, compartments. their hematopoietic precursors (Moser are crucial factors for LC migration Notably, a high binding affinity of and Willimann, 2004). from the epidermis to the dermis, CCL27 to proteins of the extracellular Dendritic cells represent an integral whereas CCR7 is not essential (Avniel matrix has been documented, suggest- link between components of the innate et al., 2006; Ouwehand et al., 2008). In ing a possible mechanism for the and the adaptive immune system. As addition, Kabashima et al. (2007a) maintenance of chemokine gradients professional antigen-presenting cells, have confirmed an important role for within the skin compartment (Homey they possess the unique ability to take CXCR4 expression of mature DCs in et al., 2002). In addition, the accumu- up and process antigen in peripheral their migration to skin-draining lymph lation of epidermal CCL27 in skin- tissues to activate resting lymphocytes nodes. draining lymph nodes may influence in secondary lymphoid organs and In light of these findings, a two-step the homing of CCR10 þ T cells (Huang elicit an adaptive immune response. model for LC migration to skin-draining et al., 2008). Worbs et al. (2007) Thus, the directed migration of DC lymph nodes has recently been pro- recently reported that CCR7 ligands from the skin to the skin-draining posed by Villablanca and Mora (2008). present within secondary lymphatic lymph nodes is an essential factor in Under homeostatic conditions, imma- tissue stimulate the intranodal motility their immunostimulatory function and ture LCs that do not express CXCR4 and positioning of T cells in vivo. pathogenetic involvement in T-cell- and CCR7 remain mostly confined to Conclusive in vivo studies investigating mediated skin diseases. the epidermis. In a first step, the

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upregulation of CXCR4 in response to et al. (2003) reported that CCR10 et al. (2003), reporting broad anti- inflammatory stimuli is thought to engagement by locally produced microbial activity of high concentra- enable the maturing LCs to enter CCL27 in the skin allows melanoma tions of CCL28 on mucosal surfaces. the dermal compartment of the skin, cells to escape the host’s immune For CCL27, the CCR10 ligand expres- following a chemokine gradient of antitumor killing mechanisms, possibly sed in the skin, the current data are enhanced CXCL12 expression by through the activation of PI3K/Akt. more controversial. In this regard, it is dermal endothelial cells in inflamed Similar mechanisms might contribute noteworthy that most antimicrobial skin. TNF-a, expressed at elevated to the survival and maintenance of assays are performed in vitro under levels in the skin under inflammatory pathogenic T cells in the skin in other non-physiological conditions. A high conditions such psoriasis or AD, neoplastic or inflammatory skin dis- concentration of chemokines, low pH, contributes to the disconnection eases, in which selected chemokines and salt-free conditions as used in between LCs from the keratinocytes are abundantly expressed. many assay systems are unlikely to of the epidermis by downregulating occur in vivo. However, the observa- CCR6 expression on maturing LCs Microbicidal activity tion that chemokines, such as CCL27, and thus rendering them insensitive In addition to providing a physical may reach high local concentrations to keratinocyte-derived CCL20 barrier, keratinocytes of the human due to their high binding affinity to (Randolph et al., 2005; Villablanca epidermis constitutively or inducible proteins of the extracelluar matrix et al., 2008). Once in the dermis, high express a number of molecules with (Homey et al., 2002) indicates that levels of CCR7 expression on their cell bactericidal or bacteriostatic proper- chemokine measurements from bio- surface subsequently permit the mature ties, such as human beta-defensins, logical fluids may significantly under- LCs and dermal DCs to exit the tissue LL-37, psoriasin (S100A7), and cystatin estimate the levels reached in tissue and migrate to skin-draining lymph A (Harder et al., 1997; Schittek et al., compartments, such as the skin. nodes, where the CCR7 ligands, 2001; Zaiou and Gallo, 2002; Harder Comprehensive screening showed CCL19 and CCL21, are readily ex- et al., 2004; Glaser et al., 2005). The that about two-thirds of the 30 human pressed (Forster et al., 1999; Saeki protein family of these so called anti- chemokines tested have antimicrobial et al., 1999). microbial peptides is a fundamental activity under the specific experimental Along these lines, it is noteworthy element of the innate defense system conditions (Yang et al., 2003). that besides the most extensively stud- of epithelial and endothelial tissues, It is persuasive to speculate that ied chemotactic effects, recent reports including the skin. different chemokine levels in diseased have pointed toward new functions of Accumulating evidence indicates skin may partially account for an chemokine receptor interactions in DC that the members of the chemokine altered susceptibility to cutaneous bac- biology. Analogous to effects described family and antimicrobial peptides not terial infections, such as in AD. on T cells, CXCR4–CXCL12 interactions only share structural similarities but However, the relative importance of might also affect LC survival and also exert substantially overlapping the antimicrobial activity of chemo- maturation (Kabashima et al., 2007b), functions (Yang et al., 2002, 2003). kines in vivo remains a field of much whereas CCR7 engagement seems to Although a number of antimicrobial controversy and emphasizes the need be involved in the regulation of cyto- peptides are chemotactic for selected for testing in appropriate animal model architecture and endocytosis, survival, classes and subsets of leukocytes (Yang systems. maturation, and the migratory speed of et al., 2004), many chemokines have DCs (Sanchez-Sanchez et al., 2006). a substantial antimicrobial activity Decoy receptors against a broad range of microorgan- In addition to the traditional functions Survival pathways isms (Yang et al., 2003). Human of the signaling chemokine receptors Several chemokines have been b-defensins exhibit chemotactic activ- delineated above, a new group of non- reported to trigger downstream pro- ity by sharing the chemokine receptor, signaling chemokine-binding receptors survival signals. In particular, activa- CCR6, with its sole chemokine ligand, has recently been characterized by tion of the intracellular downstream CCL20, expressed in the skin by epi- virtue of their failure to initiate conven- effector molecules, phosphatdylinositol- dermal keratinocytes and activated tional signaling cascades or mediate 3-kinase (P13K) and prokinase B (Akt), endothelial cells (Yang et al., 1999). chemoattraction. has been shown to lead to increased Correspondingly, data from recent Three of these so-called decoy resistance to apoptosis on chemokine studies suggest that CCL20 also or scavenger receptors have been receptor engagement (Youn et al., has antimicrobial activity, predomi- described so far: D6, DARC (duffy 2002; Murakami et al., 2003). CCL1 nantly against Gram-negative bacteria antigen receptor for chemokines), and has been described as a potent anti- (Hoover et al., 2002). CCX–CKR (ChemoCentryx chemokine apoptotic factor for thymocytes, and For CCL28, an additional role in receptor). Their unique structural and CCL1–CCR8 interactions have been mucosal immunity beyond being a functional properties, distinct specifi- shown to provide survival signals to chemoattractant for CCR10- and/or city and tissue distribution, as well malignant T cells in adult T-cell lym- CCR3-expressing immune cells is being as their pivotal role in modulating phoma (Ruckes et al., 2001). Murakami implicated by studies from Hieshima immune responses have been

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comprehensively discussed in a recent infiltration and psoriasiform changes late with disease activity, have been review (Mantovani et al., 2006). of the epidermis (Jamieson T, Nature reported (Morales et al., 1999; Homey The best-characterized decoy recep- Immunol 2005). Conversely, a trans- et al., 2002; Kakinuma et al., 2003a). tor, D6, is a promiscuous seven-trans- genic D6 expression in keratinocytes The constitutive expression of CCL27 membrane-domain G-protein-coupled was found to dampen cutaneous by keratinocytes in the skin can be receptor, typically expressed on lym- inflammation and bestow substantial upregulated by inflammatory mediators phatic vessels in the skin, gut, and lungs protection from the development of (IL-1 and TNF-a), and is found at (Nibbs et al., 2001). D6 binds most chemically induced skin tumors in elevated levels not only in psoriatic inflammatory, but not homeostatic, CC different animal models (Nibbs et al., lesions but also in Th2-dominated chemokines and is subsequently inter- 2007). An expanded appreciation of inflammatory skin diseases, such as nalized in a ligand-independent way the complex biological activities and AD (Homey et al., 2002). Thus, from the plasma membrane to endocy- functions of this newly identified group CCL27–CCR10 interactions seem to be tic compartments, wherein chemokines of atypical chemokine receptors will involved in the recruitment of memory are targeted for degradation (Weber significantly contribute to a more T cells to the skin regardless of their et al., 2004; Martinez de la Torre comprehensive understanding of the Th1 or Th2 polarization, and a CCL27 et al., 2005). pathophysiology of inflammatory and gradient in the skin has been postulated Similar to D6, DARC shares struc- neoplastic diseases. to contribute to the epidermal position- tural similarities with a conventional ing of CCR10 þ T cells (Morales et al., chemokine receptor but lacks the seq- THE CHEMOKINE NETWORK 1999; Homey et al., 2000b) (Figure 1). uence motif required for signal trans- IN THE PATHOGENESIS OF In addition to CCR10, CCR4 is duction. DARC expression has been T-CELL-MEDIATED SKIN DISEASE highly expressed on a subset of mem- reported on erythrocytes and endothe- Psoriasis ory T cells with a CLA þ skin-homing lial cells in tissues under steady state The fundamental contribution of che- phenotype, and both receptors seem to and inflammatory conditions, including mokines in skin-specific leukocyte cooperate in the recruitment of mem- the skin (Rot, 2005). Although binding homing and inflammation is shown ory T cells to the skin under inflamma- of homeostatic chemokines to DARC impressively in the pathogenesis of tory conditions (Reiss et al., 2001) has not been reported yet, DARC psoriasis. Psoriasis, one of the most (Figure 1). Although the expression of interacts in a promiscuous manner with common chronic inflammatory skin the CCR4 ligand, CCL17, is not skin several inflammatory chemokines of disorders, is characterized by hyper- specific, its expression by the dermal both the CXC- and CC subfamilies proliferation of basal keratinocytes and vascular endothelium under inflamma- (Gardner et al., 2004). Data from a prominent cutaneous inflammatory tory conditions may collaborate with multiple studies indicate complex roles infiltrate. keratinocyte-derived CCL27 in mediat- of DARC in inflammation, tumorigen- The inflammatory infiltrate of psori- ing leukocyte migration into inflamed esis, and , and a lack of atic skin is predominantly composed skin. DARC expression has been associated of Th1- and Th17-polarized lympho- Recent research has drawn attention with greater susceptibility to certain cytes of a memory phenotype, as well to the involvement of CCL20 and its tumors and inflammatory diseases as neutophils, macrophages, and only known receptor, CCR6, in the (Segerer et al., 2003; Bandyopadhyay increased numbers of DCs (Prens pathogenesis of psoriasis (Figure 1). In et al., 2006; Wang et al., 2006). et al., 1995). An early cellular event lesional psoriatic skin, both CCL20 and Recently, Pruenster et al. (2009) re- in the development of a psoriatic lesion CCR6 have been detected at signifi- ported that, unlike other known non- is the influx of activated T cells into cantly elevated levels (Homey et al., signaling chemokine receptors, DARC the affected skin, the proinflammatory 2000a). CCL20, primarily expressed by does not act as a decoy but instead cytokines of which trigger a cycle of epidermal keratinocytes and activated supports chemokine transcytosis and cutaneous inflammation and epidermal endothelial cells, is a highly potent chemokine-induced leukocyte migra- hyperplasia, resulting in the psoriatic chemoattractant for CCR6 þ epithelial tion in vitro and in vivo. phenotype (Bata-Csorgo et al., 1995). Langerhans-type DCs and memory Nevertheless, studies from several The complex cellular events leading T cells (Liao et al., 1999; Dieu-Nosjean animal models have highlighted the to psoriatic skin inflammation require a et al., 2000). Skin-homing CLA þ importance of chemokine scavenging controlled interplay between circulat- memory T cells express high levels in the regulation of inflammatory and ing leukocytes and resident skin cells of CCR6, and both CCL20 and CCR6 antitumor immune responses in the and seem to be vitally coordinated by have been reported to colocalize with skin (Bonecchi et al., 1998; Shenoy chemokine interactions (Table 1). epidermal T cells in psoriatic skin and Lefkowitz, 2003; Martinez de la Studies from Homey et al. (2000b) (Fitzhugh et al., 2000; Homey et al., Torre et al., 2005; Nibbs et al., 2007). identified CCL27 as a new skin-specific 2000a). CLA þ T cells isolated from D6-deficient mice show exacerbated chemokine, exclusively produced by psoriatic skin respond to lower con- inflammatory responses in a model of epidermal keratinocytes (Morales et al., centrations of CCL20 as compared with phorbol ester-induced skin inflamma- 1999). In psoriatic patients, elevated T cells from healthy donors, whereas tion, with prominent cutaneous T-cell serum levels of CCL27, which corre- CCL20 production by keratinocytes

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Table 1. Synopsis of main chemokine/chemokine receptor interactions reported to be involved in the pathogenesis of psoriasis, atopic dermatitis and/or mycosis fungoides/Se´zary syndrome Ligand(s) expressed Chemokine in the skin (alternate Preferential expression receptor acronym) on T-cell subsets Disease connection References

CCR4 CCL17 (TARC) Skin-homing CD4+ CLA+ Mycosis fungoides Fierro et al. (2006); Sokolowska-Wojdylo et al. (2005); CCL22 (MDC) T cells Se´zary syndrome Campbell et al. (1999); Kakinuma et al. (2001); Th2 cells Atopic dermatitis Ishida et al. (2003) Th17 cells Psoriasis Treg CCR6 CCL20 (MIP-3a, LARC) Th17 cells Psoriasis Homey et al. (2000a); Kleinewietfeld et al. (2005); Treg Hedrick et al. (in press) CCR8 CCL1 (1309) Th2 cells, Atopic dermatitis Gombert et al. (2005) gd T cells Treg CCR10 CCL27 (CTACK) Skin-homing CLA+ CD4+, Psoriasis Hudak et al. (2002); Morales et al. (1999); and CD8+ T cells Atopic dermatitis Homey et al. (2000b); Homey et al. (2002); Mycosis fungoides Notohamiprodjo et al. (2005); Sokolowska-Wojdylo et al. (2005); Kakinuma et al. (2003a, b) ? CCL18 Receptor unknown, Atopic dermatitis Pivarcsi et al. (2004); Park et al. (2008) CCL18 induces migration of CLA+ memory T cells into the skin CXCR3 CXCL9 (MIG) CD4+ CD45RO+ T cells Psoriasis Flier et al. (1999); Kallinich et al. (2003) CXCL10 (IP-10) Low-grade mycosis CXCL11 (IP-9, I-TAC) fungoides CXCR4 CXCL12 (SDF-1) CD4+ CD45RO+ T cells Mycosis fungoides Kallinich et al. (2003)

can be induced by proinflammatory expression, further investiga- matory infiltrate, predominantly con- cytokines (that is, IL-1 and TNF-a) tion surprisingly revealed that CCR6 sisting of CLA þ CD4 þ memory commonly found in psoriatic skin is mainly required for the recruit- T cells (Leung and Bieber, 2003). (Homey et al., 2000a). Interestingly, ment and/or function of a non- Clinical and experimental evidence CCR6 has lately been described as a T-cell source of IL-22 in this model points toward a crucial role of the marker for human and murine Th17 (Hedrick et al., in press). composition of the T-cell infiltrate cells, and their hallmark cytokines in the immunopathogenesis of the IL-17 and IL-22 have been implicated Atopic dermatitis disease (Woodward et al., 2001; Leung to be critically involved in the Atopic dermatitis, or atopic eczema, is and Bieber, 2003). pathogenesis of several autoimmune a common pruritic and chronically Chemokines have complex func- inflammatory diseases, including relapsing inflammatory skin disease tions regarding the development and psoriasis (Murphy et al., 2003; Langrish with a steadily increasing prevalence composition of the inflammatory infil- et al., 2005; Acosta-Rodriguez et al., (Leung and Bieber, 2003; Asher et al., trate in AD (Table 1). Homey et al. 2007; Annunziato et al., 2007; 2006). The pathogenesis of AD is (2006) recently suggested an amplifica- Blauvelt, 2008; Singh et al., 2008). generally multifactorial and may tion cycle of atopic skin inflammation A recent study assessed the role of involve both genetic and environ- in which chemokine interactions play a CCR6 in an IL-23-induced mouse mental factors (Palmer et al., 2006; critical role. Patient scratch is thought model of psoriasiform dermatitis in Weidinger et al., 2007). Acute lesions to induce mechanical injury and facili- which the psoriatic phenotype has emerge as erythematous macules or tate superinfection of atopic lesions, previously been reported to be predo- papules with a typical distribution resulting in the production of proin- minantly meditated by the Th17 cyto- pattern and severe pruritus, whereas flammatory cytokines and chemokines, kine, IL-22 (Chan et al., 2006; Zheng chronic lesions show characteristic which are thought to orchestrate the et al., 2007). Interestingly, CCR6- lichenification or thickening and recruitment of pathogenic leukocytes deficient mice were resistant to IL-23- hypertrophy of the epidermis. into the skin. Although multiple induced psoriatic skin inflammation In addition to acanthosis and homeostatic and inflammatory chemo- in this model. Although the pathology hyperkeratosis, AD skin lesions show kines have been shown to relate to the was absolutely dependent on CCR6 histopathologically a marked inflam- AD phenotype (reviewed by Homey

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Injury

Proinflammatory cytokines IL-1 CCL27 TNF-α CCL20 IFN -γ CCL17 Epidermis Th17 CCR6 Th1 IL-17 IL-22 DC CCR10 Th1 IL-23 CLA CCR4

CCR4 CLA

E-selectin

Dermal blood vessel CCR10 CCR4 CLA

Figure 1. Roles for chemokines and their receptors in psoriasis. Common events in lesional psoriatic skin include activation of skin dendritic cells and keratinocytes, recruitment and activation of predominantly Th1- and Th17-polarized T cells, followed by keratinocyte damage. Inflammatory mediators (TNFa, IL-1, and so on) enhance the production of CCL27 by keratinocytes, as well as endothelial cell-derived CCL17, and may collaborate in mediating the homing of CCR10 þ CCR4 þ skin-homing memory T cells to the site of cutaneous inflammation. In addition, elevated levels of CCL20 may further contribute to the homing and in situ positioning of CCR6 þ memory Th17 cells in psoriatic skin.

et al., 2006), the roles of CCR10 and but little or no CXCR3 (Campbell et al., specific association of the chemo- CCR4 in AD have been particularly 1999; Biedermann et al., 2002). Corre- kine, CCL18, with an AD phenotype well documented (Figure 2). spondingly, high levels of the CCR4 (Pivarcsi et al., 2004). The CCL18 Both CCR10 and its ligand, CCL27, ligands, CCL17 and CCL22, have been mRNA expression in lesional skin from exhibit strong immunohistochemical detected in the lesional skin of AD AD patients was found to be more than staining in skin biopsies from AD patients and in the skin of a mouse 100-fold higher than levels of CCL17. patients (Vestergaard et al., 2003). model of AD (NC/Nga model) (Galli An additional DNA microarray analysis CCL27, constitutively expressed by hu- et al., 2000; Vestergaard et al., 2003). revealed the strongest association of man keratinocytes, can be upregulated Similar to CCL27, the plasma levels of CCL17 with AD, compared with DNA by proinflammatory cytokines (that is, the CCR4 ligands, CCL17 and CCL22, isolated from skin of psoriasis patients IL-1 and TNF-a) present in inflamed show an elevated level in AD patients or from healthy controls. In addition, a tissue (Morales et al., 1999; Homey compared with those in healthy con- recent study showed an increased et al., 2002), and serum levels of trols, and seem to correlate closely with protein expression of CCL18 in the CCL27 show a significant correlation disease activity (Kakinuma et al., 2001; serum of patients with extrinsic AD, with disease severity (Kakinuma et al., Wakugawa et al., 2001). Although the compared with patients with non-aller- 2003a). In mouse models mimicking contribution of both CCL17 and CCL27 gic type of AD (intrinsic AD), with a AD and allergic contact dermatitis, for the recruitment of memory T cells to significant decrease after specific neutralization of CCL27 resulted in a sites of skin inflammation is well immunotherapy (Park et al., 2008). significantly impaired memory T-cell established, a specific association with Although the receptor for CCL18 has recruitment to the skin and a decreased an AD phenotype has not been demon- yet to be identified, CCL18 has been tissue inflammation (Homey et al., strated (Figure 2). reported to bind to CLA þ memory 2002). By contrast, a comprehensive study T cells in the blood of AD patients Th2 clones derived from the lesional of the expression of chemokines in vitro and induce their migration into skin of AD patients have been found to in various chronic inflammatory or human skin in vivo (Gunther et al., highly express CCR4 on their surface, autoimmune skin diseases revealed a 2005).

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Allergen Injury Bacterial superantigen

CCL22 Proinflammatory cytokines CCL17

Epidermis TNF-α IL-1 CCL27 Th2

CCL18 CCR4 CCR10

? Th2 CCL1 DC

MC CCL1 CCR8 ? E-selectin CCR8 CLA

CCR4 Dermal blood vessel CLA CCR10

Figure 2. Roles for chemokines and their receptors in atopic dermatitis. Mechanical injury, such as patient scratch, and superinfection trigger atopic skin inflammation by the induction of inflammatory cytokines and chemokines. CCL17–CCR4 and CCL27–CCR10 interactions contribute to the extravasation and homing of CLA þ memory T cells to the site of cutaneous inflammation. CCL18 production by skin-resident DC can be strongly induced by allergen exposure as well as by staphylococcal superantigens, and is thought to further sustain the migration of CLA þ memory T cells from the peripheral blood to atopic skin lesions. In addition, CCL1 production by endothelial cells and mast cells during atopic skin inflammation may contribute to the recruitment of CCR8-expressing T cells and DC, as well as sustaining their maintenance and survival at the site of cutaneous inflammation (MC: mast cell; ?: unknown receptor).

In light of these findings, it is CCL18, CCL1 expression can be Mycosis fungoides and Se´zary syndrome noteworthy that CCL18 was reported significantly induced by S. aureus Mycosis fungoides is the prototypic to be produced mainly by dermal DCs superantigens and by allergen and most frequent form within the in close proximity to infiltrating T cells exposure. CCR8, the sole receptor for broad group of CTCLs, accounting for in atopic skin and to be strongly CCL1, was abundantly expressed on approximately 72% of reported CTCL induced by allergen exposure and subsets of DCs in vitro, as well as on a cases (Weinstock and Gardstein, 1999; staphylococcal superantigens (Pivarcsi small subset of circulating T cells Criscione and Weinstock, 2007). In et al., 2004). Interestingly, 90% of AD (Bonecchi et al., 1998). Interestingly, MF, the neoplastic T cells display a patients show a colonization of lesions CCL1 has been previously described strong epidermotropism and preferen- with Staphylococcus aureus, and anti- as a potent antiapoptotic factor for tially localize to the skin. staphyloccocal therapy frequently sup- thymocytes (Ruckes et al., 2001). Although a de novo presentation of ports a clinical improvement (Breuer CCR8 interactions may thus not only the advanced stages of the disease are et al., 2000, 2002) (Figure 2). contribute to immune cell recruitment possible, MF classically presents itself In addition to CCL18, CCL1 has but also to their maintenance and with a slow, indolent course that may recently been found to be another survival at sites of atopic skin inflam- progress over years from patches and chemokine that is specifically and mation. plaques to tumor stages, and with a selectively upregulated in AD com- The specific association of CCL18 possible subsequent involvement of pared with other inflammatory skin and CCL1 with an AD phenotype, in lymph nodes and the peripheral blood. disorders and healthy skin (Gombert conjunction with its regulation by aller- The Se´zary syndrome (SS), which was et al., 2005) (Figure 2). Gombert et al., gen exposure and microbial products, is previously often categorized as a var- identified mast cells and endothelial suggestive of a significant involvement iant of MF, has now been classified as cells as the major source of CCL1 of CCL18 and CCL1/CCR8 interactions a separate entity by WHO and EORTC during atopic skin inflammation and in the induction and/or augmentation of (Willemze et al., 2005). According demonstrated that, analogous to atopic skin inflammation. to ISCL (International Society for

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Cutaneous Lymphoma), the diagnosis proteolytically cleaves and inactivates display a CLA þ skin-homing pheno- of SS is based on the verification of an the CXCR4 ligand, CXCL12. Given the type. In addition to CLA interactions, extensive, clonal population of abnor- abundant CXCR4 expression that has the unique expression pattern of che- mal T cells with hyperconvoluted, recently been reported on malignant mokine receptors can in part explain cerebriform nuclei in the peripheral T cells in MF patches (Kallinich et al., the cutaneous tropism of the malignant blood in addition to erythroderma. 2003), the loss of CD26 expression T cells (Figure 3). Supporting the notion Histologically, patches and plaques strongly suggests a potential role for of a Th2 origin of malignant cells, high of MF are characterized by the often CXCR4 in the skin-homing of Se´zary levels of CCR4, but not of CCR5 and band-like accumulation of lympho- cells (Sokolowska-Wojdylo et al., CXCR3 expressions, have recently been cytes in the upper dermis and fairly 2005; Narducci et al., 2006) (Table 1). demonstrated on skin-infiltrating T cells specific Pautrier microabscesses, con- The inactivation of CD26 has been in SS (Fierro et al., 2006). Serum levels sisting of aggregates of malignant shown to enhance the migratory po- of the related chemokines, CCL17, T cells clustering around LCs in the tential of cell lines derived from pa- CCL22, and CXCL10, are significantly epidermis (Pimpinelli et al., 2005). tients with SS in response to CXCL12, increased in both SS patients and However, an early disease of MF and whereas the presence of soluble CD26 patients suffering from erythroderma SS may not show the entirely devel- is inhibitory (Narducci et al., 2006). due to inflammatory dermatoses. How- oped typical histopathological changes CXCR4 engagement has previously ever, the results from these studies and can clinically mimic benign been reported to result in the upregula- support the perception of SS being a inflammatory skin disorders such as tion of the key prosurvival kinases, Th2 disorder with a selective expres- psoriasis and AD, often impeding an PI3K and Akt, with relevance in the sion of CCR4, whereas inflammatory early diagnosis. progression of solid malignancies such erythroderma shares overexpression of Although development and disease as melanoma (Lee et al., 2006). Given both Th1-and Th2-related chemokine activity seem to be controlled by a the constitutive expression of CXCL12 receptors (Fierro et al., 2006). population of tumor-specific CD8 þ in the skin, the loss of CD26 on Se´zary In addition to the predominant Th2 Tcells, the malignant cells are thought cells might sustain their chemokine- profile of malignant cells in MF and SS, to originate from CD4 þ CD45RO þ driven, cutaneous migration, and acti- Berger et al. (2005), recently reported memory T cells, which frequently lack vation of downstream effectors of this the in vitro conversion of malignant the expression of certain T-cell surface antiapoptotic pathway contributes to T cells to cells with a Treg pheno- markers, such as CD26, CD49d, and their survival in the skin compartment type after stimulation with cryptic CD7 (Vowels et al., 1994; Berger et al., (Hwang et al., 2008). self-antigens that might be uncovered 1996; Bernengo et al., 2001). CD26, In line with characteristic epidermo- during apoptosis. The adoption of Treg- also known as dipeptidylpeptidase IV, tropism, the malignant T cells typically suppressor functions by CTCL may offer

CXCR4 CXCL12 CXCL12 Epidermis CXCR4 CXCR4 CCL17 CCR4 CCL27 Treg CCR4 Th2 CXCR3 CCR10 CCR4 CCR10 DC

E-selectin CCR7 Skin-draining CLA

CCL21 Dermal blood vessel CCL19

Figure 3. Roles for chemokines and their receptors in mycosis fungoides and Se´zary syndrome. Chemokine receptors such as CCR10 and CCR4 permit skin-specific homing of malignant T cells and support the efficient engagement of DC and the subsequent release of pro-inflammatory cytokines. Apart from a role in cutaneous homing of Se´zary cells, CXCR4 might sustain their chemokine-driven survival in the skin compartment by activating intracellular key pro-survival signals. During disease progression, changes in the expression pattern of selected chemokine receptors such as CCR4 and CXCR3 seem to correlate with reduced epidermotropism of the malignant T cells. The directional migration of CCR7-expressing malignant T cells from the skin to the draining lymph nodes is effectively supported by the release of CCL19 and CCL21 by stromal cells of the lymphatic vessels and the lymph node.

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a possible explanation for the immuno- to the reduced epidermotropism of fully controlled CCR4-expressing suppressive nature of the disease and malignant T cells generally observed malignant T-cell clones by eliciting increased susceptibility of MF and SS in skin biopsies from advanced stage antibody-dependent natural killer- patients to opportunistic infections MF and SS. Kallinich et al., (2003) mediated cytotoxicity (Niwa et al., (Axelrod et al., 1992). compared the chemokine receptor 2004; Ishida et al., 2004b). CCR4 and CCR10 in particular expression in different stages of MF However, a distinct chemokine are frequently present on malignant and reported decreased expression receptor expression has not only been T cells in MF and SS and play a levels of CCR4 and CXCR3 lesional documented on subsets of pathogenic potential role in their homing to the skin of tumor-stage patients with MF, T cells in various disease but also on skin (Notohamiprodjo et al., 2005; whereas levels of the lymph-node- immune cells exerting regulatory func- Sokolowska-Wojdylo et al., 2005) homing receptor, CCR7, were remark- tion, such as Treg cells (Kleinewietfeld (Figure 3). CCL17—a major CCR4 ably increased. Moreover, a recent et al., 2005). Notably, the antibody ligand expressed by activated keratino- report revealed that the addition of used in the described study did not cytes, DC, and endothelial cells—is CXCL13 to CCL19 or to CCL21, the only lyse malignant CCR4 þ T-cells increased in the serum of MF patients, selective CCR7 agonists responsible for in vitro but also reduced the expression with levels correlating with disease lymph node homing, strongly enhances of Foxp3 mRNA, suggesting a possible activity (Kakinuma et al., 2003b). Simi- the migration of CCR7 þ Se´zary cells effect in depleting regulatory T cells larly, the CCR10 ligand, CCL27, is (Picchio et al., 2008). Although a (Ishida et al., 2004a, b). Although the found at elevated levels in patients prognostic implication has not yet inhibition of Treg functions by means with MF and SS and might serve as an been validated, these findings corre- of chemokine receptor antagonism has indicator for disease activity (Fujita late with the clinical enlargement of been demonstrated to be favorable et al., 2006; Kagami et al., 2006). peripheral lymphnodes and greater for tumor control, the disruption of CCR10–CCL27 interactions are pro- leukemic burden seen in patients with normal endogenous immune regulatory posed to play an early role in the advanced stage MF. mechanisms may result in broader, pathophysiology of MF from the patch unfavorable effects, such as increased stage. Fujita et al., (2006) reported NEW TOOLS—NEW QUESTIONS inflammatory responses and risk for significantly higher numbers of circu- During the past decade, we have infection (Unsoeld et al., 2007). lating CCR10 þ CD4 þ cells in the observed the development of potent A new approach takes advantage peripheral blood of MF patients com- immunotherapeutics directed against of the physiological endocytosis of pared with those in healthy controls or surface molecules that are involved chemokine receptors after ligation, patients with AD and an accumulation in the migration and/or function of eventually enhancing the presentation of CCR10 þ skin-infiltrating tumor immune cells. The diversity of chemo- of tumor-derived peptides on the cell cells in MF lesions. By contrast, serum kine receptors and their preferred surface (Biragyn et al., 2004). Data levels of CCL27, although considerably expression on distinct leukocyte sub- from a recently published animal elevated compared with those in sets that have been implicated in the study provided proof-of-principle that healthy controls, showed no significant pathogenesis of different inflammatory chemokine receptor-expressing tumors differences in comparison with patients or neoplastic diseases offer the oppor- can be successfully controlled by the with AD. In patients with MF and SS, tunity for their selective targeting. delivery of toxins through their chemo- an unfavorable outcome of the disease Monoclonal antibodies that target kine receptors (Baatar et al., 2007). was associated with an overexpression inflammatory cytokines or adhesion Biragyn and colleagues have gener- of CCR4 by malignant CD4 þ T cells molecules, such as the anti-a4-integrin ated chemokine-toxin fusion proteins, (Ishida et al., 2003, 2004b). mAb, Natalizumab, have been suc- chemokines fused with toxic moieties Chemokines may not only facili- cessfully used for the treatment of that are nontoxic unless delivered tate the recruitment of tumor cells inflammatory and autoimmune dis- into the cell cytosol. Treatment to certain tissues like the skin but eases (von Andrian and Mackay, with CCL17-expressing chemotoxin may also induce tissue infiltration 2000). However, given the consider- efficiently eradicated CCR4-expressing by various immunosuppressive cells, able promiscuity in the chemokine CTCL established in NOD-SCID mice such as Tregs, leading to an escape network, with multiple chemokines (Baatar et al., 2007). While strengthen- from immunosurveillance and an often sharing the same receptor, strate- ing the concept that the targeting of unfavorable outcome in malignant gies favoring the selective targeting chemokine receptors such as CCR4 or diseases. Suppressive CCR4-expressing and inactivation of chemokines by CCR10 permits the control of growth CD4 þ CD25 high Tregs are being blocking antibodies seem to be less and dissemination of certain tumors, recruited to sites of cutaneous lym- promising. this study on the whole showcases phoma that express high levels of Conversely, agents that block che- the complexity and challenges in CCL17 or CCL22 (Ishida et al., 2003). mokine receptors expressed on distinct the field. Despite the initial tumor A change in the expression patterns leucocyte subsets are expected to be control by CCL17-chemotoxin treat- of selected chemokine receptors during more specific. In preclinical studies, ment, the malignancy eventually disease progression seems to correlate mAbs directed against CCR4 success- relapsed. Importantly, after tumor

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relapse, the malignant cells seemed particularly effective and reasonable in order to therapeutically control the resistant to additional and repeated combination with established systemic homing of pathogenic T cells to the treatment with the chemokine toxin. It therapies targeting Th1-related cyto- cutaneous compartment has proven remains to be seen whether such a kines, such as the anti-TNF-a mAbs to be challenging. Over the years, highly specific treatment in hetero- (Eternacept, Infliximab). the close association of chemokine genous malignancies selects for tumor Another noteworthy level of com- receptor expression with the func- variants and thus supports the out- plexity is added by the finding that tional properties of T-cell subsets has growth of tumors with an aberrant some chemokines may naturally exert been convincingly documented and receptor expression. either agonistic or antagonistic effects. the key molecules have been well During the last decade, particular An emerging concept in the field defined. However, several key concep- attention has been paid to the devel- is the regulation of Th1 and Th2 tual issues based on the experimental opment of small molecule antagonists responses by natural chemokine anta- evidence outlined above have risen directed against chemokine receptors. gonism. The Th2-type associated in recent years and future studies will As synthetic small-molecule anta- chemokine, CCL26, an agonist for need to address these key challenges. gonists directed against G-protein- CCR3, has been found to be an coupled receptors have been used antagonist for CCR2, thus, negatively CONFLICT OF INTEREST effectively in the treatment of various regulating the migration of human The authors state no conflict of interest. diseases, the finding that chemokines monocytes (Ogilvie et al., 2003), and signal through this large class of recep- in a model of allergen-induced airway ACKNOWLEDGMENTS tors has raised hope for their thera- inflammation, the CXCR3 ligand, ASL was supported by a DFG – NIH Research peutic application in targeting specific CXCL9, which is generally asso- Career Transition Award of the German Research Foundation (Deutsche Forschungsgemeinschaft, chemokine receptors. ciated with Th1-responses, evolved DFG). We apologize to colleagues whose work Nevertheless, despite intense as a negative regulator of eosinophil we were unable to cite due to space constraints. research efforts and promising results recruitment by the antagonism of CCR3 from animal studies more than (Fulkerson et al., 2004). The demon- two decades after the discovery of stration that a chemokine can function REFERENCES chemokines and their receptors, only both as an agonist for one and as an Acosta-Rodriguez EV, Rivino L, Geginat J, few synthetic receptor antagonists antagonist for a different chemokine Jarrossay D, Gattorno M, Lanzavecchia A have found their way into a clinical receptor has added another level to et al. (2007) Surface phenotype and antigenic specificity of human interleukin application. the regulation of Th1/Th2-mediated 17-producing T helper memory cells. 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