CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector PERSPECTIVE Chemokine Receptors in T-Cell-Mediated Diseases of the Skin Anke S. Lonsdorf1, Sam T. Hwang2 and Alexander H. Enk1 The chemokine/chemokine receptor 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, chemokines 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-protein-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 proteins 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.