A Th2 Chemokine, TARC, Produced by Keratinocytes May Recruit CLA+CCR4+ Lymphocytes into Lesional Atopic Dermatitis Skin

Vestergaard, Christian; Bang, Karen; Gesser, Borbala; Yoneyama, Hiroyuki; Matsushima, Kouji; Larsen, Christian Grónhøj

doi:10.1046/j.1523-1747.2000.00115.x

Cited by 321 publications

(266 citation statements)

References 47 publications

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“…These results contrast somewhat with Vestergaard et al (17) who concluded that CCL17/TARC was not in normal skin, but was expressed by keratinocytes but not endothelial cells in AD patients. Because both CCL27 and CCL17/TARC protein are present on inflamed cutaneous endothelium, trigger rapid adhesion of CLA ϩ memory T cells, and stimulate CLA ϩ memory T cell migration, CCR4 and CCR10 may provide redundant mechanisms to allow CLA ϩ /CCR4 ϩ /CCR10 ϩ memory T cell entry into inflamed cutaneous sites.…”

Section: Discussioncontrasting

confidence: 96%

Immune Surveillance and Effector Functions of CCR10+ Skin Homing T Cells

Hudak¹,

Hagen²,

Liu³

et al. 2002

The Journal of Immunology

108

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Skin homing T cells carry memory for cutaneous Ags and play an important sentinel and effector role in host defense against pathogens that enter via the skin. CCR10 is a chemokine receptor that is preferentially expressed among blood leukocytes by a subset of memory CD4 and CD8 T cells that coexpress the skin-homing receptor cutaneous lymphocyte Ag (CLA), but not the gut-homing receptor α4β7. Homing and chemokine receptor coexpression studies detailed in this study suggest that the CLA+/CCR10+ memory CD4 T cell population contains members that have access to both secondary lymphoid organ and skin compartments; and therefore, can act as both “central” and “effector” memory T cells. Consistent with this effector phenotype, CLA+/CCR10+ memory CD4 T cells from normal donors secrete TNF and IFN-γ but minimal IL-4 and IL-10 following in vitro stimulation. Interactions of CCR10 and its skin-associated ligand CC ligand 27 may play an important role in facilitating memory T cell entry into cutaneous sites during times of inflammation.

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Section: Discussioncontrasting

confidence: 96%

Immune Surveillance and Effector Functions of CCR10+ Skin Homing T Cells

Hudak¹,

Hagen²,

Liu³

et al. 2002

The Journal of Immunology

108

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“…After polarization into Th2 cells, CD4 + T cells express the chemokine receptors CCR3, CCR4 and CCR8, while Th1 cells preferentially express CXCR3 and CCR5 [14,15]. The CCR4 ligand TARC/ CCL17 has been shown to be strongly chemotactic for Th2 cells [6] and CLA + CD4 + T cells of the memory/ effector subtype [10,16].…”

Section: Introductionmentioning

confidence: 99%

“…TARC/CCL17-mediated recruitment of Th2 cells and CLA + CD4 + T cells was shown to play a major role in allergic diseases like atopic dermatitis [16,17], allergic asthma [18][19][20], allergic rhinitis [21] and allergic contact dermatitis [22].…”

Section: Introductionmentioning

confidence: 99%

IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites

et al. 2006

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A cardinal feature of allergic disorders and immune responses is enhanced leukocyte trafficking. This is largely orchestrated by chemokines. The CC chemokine thymus-and activation-regulated chemokine (TARC/CCL17) selectively attracts Th2 cells via the G protein-coupled chemokine receptor CCR4. We show here that TARC/CCL17 is expressed by human T cells upon stimulation with IL-4. Mapping of the transcriptional start site revealed the presence of two putative STAT6 binding motifs in proximity to the start position. EMSA and chromatin immunoprecipitation experiments demonstrated that STAT6 was able to bind to both motifs. A fragment of the TARC/CCL17 promoter containing both sites was tested in reporter gene assays for IL-4 inducibility. The promoter was inducible in a STAT6-deficient cell line only after introduction of functional STAT6. When mutations were inserted into one of the STAT6 motifs, IL-4-induced promoter activation was reduced. With both sites mutated, inducibility was completely abrogated. These data demonstrate collectively that T cells serve as a source of TARC/CCL17 when stimulated with IL-4 and that STAT6 is essential for this. IntroductionChemokines are structurally related 8-12-kDa chemoattractant cytokines that regulate leukocyte trafficking and inflammatory diseases. Depending on the motif displayed by the first or first two of their conserved cysteines, they have been classified into C, CC, CXC or CX3C chemokine subfamilies. Chemokines have been shown to not only regulate hemopoietic cell migration but also to be involved in a number of other physiological and pathological processes [1]. The 8-kDa thymus-and activation-regulated chemokine (TARC/CCL17) was first isolated from phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMC) by Imai et al. in 1996 [2] by means of a signal sequence trap method [3]. The TARC/CCL17 gene is located on chromosome 16q13 in a cluster with MDC/ CCL22 and Fractalkine/CX3CL1 [4]. It encodes a highly basic 94 amino acid residues long preprotein with a cleavage site between Ala23 and Ala24. The mature TARC/CCL17 protein is 71 amino acid residues in length and was shown to be constitutively expressed in thymus [2] and, upon activation with different inducers, in several cell types including PBMC [5], monocytes [6], dendritic cells [7], endothelial cells, and bronchial epithelial cells [8].Leukocytes are activated by chemokines through seven-transmembrane G protein-coupled receptors. Based on the subfamily of chemokines they bind, chemokine receptors are named XCR1, CCR1-9, CXCR1-5 and CX3CR1 [9]. The specific functional high-affinity receptor for TARC/CCL17 is the CC chemokine receptor 4 (CCR4), which has also been shown to serve as receptor for CCL22/MDC (macrophage-derived chemokine). CCR4 is predominantly Interleukin-4 (IL-4), mainly produced by Th2 T cells, mast cells, basophils and eosinophils, appears to be a crucial factor in allergic responses. IL-4 induces differentiation of allergen-specific Th2 cells and class switching towards IgE produc...

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“…These CCR4 + cells also express the cutaneous lymphocyte antigen (CLA), a ligand for E-selectin [12,17,18]. This suggests that T cell homing to inflamed skin is governed by tissue-specific interactions mediated by CLA and CCR4 on T cells interacting with E-selectin and CCL17 on endothelium [19,20]. CCR10 binding to CCL27 can also mediate T cell migration to dermal inflammation.…”

Section: Introductionmentioning

confidence: 99%

CXCR3 is required for migration to dermal inflammation by normal andin vivo activated T cells: differential requirements by CD4 and CD8 memory subsets

et al. 2005

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Lymphocytes in inflamed tissues express numerous chemokine receptors. The relative importance of these receptors for migration in inflammation is unclear. The role of CXCR3 in T cell subset migration was examined using monoclonal antibodies developed to rat CXCR3. CXCR3 was expressed on sixfold more CD8 + (*30%) than CD4 + (*5%) T cells in spleen, lymph nodes and blood, and on *10% of CD4 + CD45RC -(memory) and *50% of CD8 + CD45RC + spleen T cells. After immunization, CXCR3 increased tenfold on CD4 + lymph node lymphoblasts (*55%), and >90% of inflammatory exudate T cells were CXCR3 + . CXCR3 + T cells migrated significantly better than CXCR3 -T cells to all dermal inflammatory stimuli tested in vivo, even though these T cells are a minority of the memory T cells. Blocking CXCR3 inhibited recruitment of 60-85% of unstimulated T cells and up to 90% of CD8 + CD45RC + effector T cells, but caused <50% inhibition of CD4 + and CD8 + memory (CD45RC -) T cells. About 90% of T lymphoblast migration to IFN-c, IFN-c plus TNF-a, polyinosinic polycytidylic acid, lipopolysaccharide, and delayed-type hypersensitivity (DTH)-induced inflammation was inhibited. Blockade also reduced DTH-induced induration. Thus, CXCR3 has a nonredundant role in T cell migration to dermal inflammation and is critical for activated T lymphoblast recruitment, but memory T cells are less dependent on CXCR3 for their infiltration.

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A Th2 Chemokine, TARC, Produced by Keratinocytes May Recruit CLA+CCR4+ Lymphocytes into Lesional Atopic Dermatitis Skin

Cited by 321 publications

References 47 publications

Immune Surveillance and Effector Functions of CCR10+ Skin Homing T Cells

Immune Surveillance and Effector Functions of CCR10+ Skin Homing T Cells

IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites

CXCR3 is required for migration to dermal inflammation by normal andin vivo activated T cells: differential requirements by CD4 and CD8 memory subsets

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