CCL1-CCR8 Interactions: An Axis Mediating the Recruitment of T Cells and Langerhans-Type Dendritic Cells to Sites of Atopic Skin Inflammation

Gombert, Michael; Dieu-Nosjean, Marie Caroline; Winterberg, Franziska; Bünemann, Erich; Kubitza, Robert; Cunha, Ludivine Da; Haahtela, Anna; Lehtimäki, Sari; Müller, Anja; Rieker, Juliane; Meller, Stephan; Pivarcsi, Andor; Koreck, Andrea; Fridman, Wolf‐Herman; Zentgraf, H.; Pavenstädt, Hermann; Amara, Ali; Caux, Christophe; Kemény, Lajos; Alenius, Harri; Lauerma, Antti; Ruzicka, Thomas; Zlotnik, Albert; Homey, Bernhard

doi:10.4049/jimmunol.174.8.5082

Cited by 184 publications

(157 citation statements)

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“…Recently, it was shown that the constitutive chemokine CXCL12 is also secreted by fibroblasts and its secretion is enhanced upon exposure to stress factors, such as hypoxia, irradiation, and burns [21][22][23][24][25]. CXCL12 secretion is not restricted to fibroblasts though, since endothelial cells and DC are also located in the dermis and also secrete CXCL12 [23,26,27]. Low expression of CXCR4, the CXCL12 receptor, was found on the surface of freshly isolated immature LC.…”

Section: Introductionmentioning

confidence: 99%

CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis

et al. 2008

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The initial step in Langerhans cell (LC) migration from the epidermis to the lymph node involves migration of maturing LC into the dermis. Here, we investigated the migration of LC out of the epidermis after exposure of the skin to contact allergens. Ex vivo intact human skin, epidermal sheets, and LC derived from the MUTZ-3 cell line (MUTZ-LC) were used to determine whether dermal fibroblasts play a role in mediating LC migration towards the dermis. Exposure of epidermal sheets or MUTZ-LC to allergens (nickel sulphate, 2,4-dinitrochlorobenzene, and cinnamaldehyde) or a cytokine maturation cocktail resulted in LC migration towards dermal fibroblasts. This was due to upregulation of CXCR4 on maturing LC and secretion of CXCL12/stromal derived factor-1 chemokine by fibroblasts. Neutralizing antibodies to either CXCL12 or CXCR4 completely blocked migration. Injection of CXCL12 neutralizing antibodies into intact human skin totally inhibited LC migration into the dermis. In contrast, neutralizing antibodies to CCL19/ CCL21 did not inhibit migration into the dermis. We describe a novel and essential role of dermis-derived CXCL12 in initiating migration of maturing human LC to the dermis thus permitting their further journey to the draining lymph nodes.Key words: Allergy . Chemotaxis . Cytokines . DC . Skin See accompanying commentary by Villablanca and Rodrigo IntroductionHuman skin is the external barrier to harmful environmental factors. Upon environmental assault (e.g. exposure to pathogens or allergens), Langerhans cells (LC) residing in the epidermis start to mature and migrate through the dermis [1,2]. Pathogenor allergen-exposed LC then migrate further into the afferent lymphatics towards the local lymph node where they are able to initiate a T-cell-mediated response [3]. LC migration is regulated by the sequential and differential expression of chemokines and their receptors [4,5]. Although migration to the lymph node is well documented, the chemokine ligands/receptors involved in the initial step of human LC migration out of the epidermis and into the dermis are as yet unknown.Several studies describe an essential role of CCR7 in mediating migration of mature LC towards the lymphatics [6][7][8][9][10]. CCR7 is highly expressed on fully mature, but not on immature LC, and is the chemokine receptor for the ligands CCL19 (MIP-3b) and CCL21 (6Ckine) [11][12][13]. Both of these chemokines are upregulated by lymphatic endothelial cells in response to allergen exposure [14]. Simultaneously, the chemokine receptor CCR6 on LC is downregulated upon maturation [15]. CCR6 is the receptor for CCL20 , which is mainly produced by keratinocytes (KC) in clinically normal human skin. CCR6/CCL20 is thought to 3050be of importance for epidermal homeostasis and homing of immature LC [16][17][18][19]. Taken together these reports show that loss of CCR6 and gain of CCR7 play important roles in the migration of mature LC out of the epidermis and into the lymphatic vessels. However, it is probable that other as yet unidentified sig...

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Section: Introductionmentioning

confidence: 99%

CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis

et al. 2008

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“…26 and J. A. Gonzalo, Y. Qiu, J. M. Lora, A. AlGarawi, J. L. Villeval, J. Boyce, C. Martinez, G. Marquez, I. Goya, Q. Hamid, et al, submitted for publication) and by a recent study demonstrating CCL1 and CCR8 up-regulation in atopic dermatitis (21). There are also reports suggesting CCR8 expression by CD4 ϩ CD25 ϩ T REG cells, skin-homing CLA ϩ T cells, monocytes, NK cells, and dendritic cells (21,(27)(28)(29)(30)(31)(32).…”

Section: T He T Lymphocyte Pool Consists Of Naive T Cells and Agexpermentioning

confidence: 99%

CCR8 Expression Identifies CD4 Memory T Cells Enriched for FOXP3+ Regulatory and Th2 Effector Lymphocytes

Soler

Chapman

Poisson

et al. 2006

The Journal of Immunology

131

109

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CD4+ Th2 cells are important regulators of allergic inflammation. CCR8 is thought to play a role in Th2-mediated responses, however, expression of CCR8 in peripheral blood has not been fully characterized. Using a fluorescent form of the ligand selective for CCR8 (F-CCL1), we identified the leukocytes expressing CCR8 in human, monkey, and mouse peripheral blood. CCR8 expression is primarily restricted to a subset of human CD4 memory T lymphocytes (15%). Approximately 40% of CCR8+CD4+ T cells express Th2 cytokines IL-4 or IL-13 while 13% express the Th1 cytokine IFN-γ. In fact, 50% of all Th2, but only 5% of Th1, cells express CCR8. Upon anti-CD3/anti-CD28 mAb-mediated activation, CCR8+CD4+ T cells secrete 3- to 7-fold higher levels of IL-4, IL-5, IL-9, and IL-13 and 10- to 20-fold lower levels of IFN-γ or IL-17, compared with CCR8−CD4+ memory T cells. Two-thirds of CCR8+CD4 T cells express cutaneous lymphocyte-associated Ag while the majority lack gut-homing receptors. CCR8+CD4+ cells express CCR7 and CD62L and are present in spleen and lymph nodes of mice. Approximately 25% of CCR8+CD4 T cells express CD25high while 20% of CCR8+CD4+ express the T regulatory cell transcription factor FOXP3 accounting for 60% of all FOXP3-expressing CD4+ T cells. In conclusion, CCR8 marks a diverse subset of CD4 memory T cells enriched for T regulatory and Th2 cells which have the potential for recruitment into sites of allergic inflammation where they could participate in the induction and regulation of the allergic response.

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“…43 In addition, CCL1 is a potent anti-apoptotic factor. 44 The secretion of high amounts of CCL1 by BPA-exposed DCs might amplify certain immune responses by providing survival signals for Th cells and DCs and by recruiting more CCR8…”

Section: Bpa Induces Th2 Response Via Dcsmentioning

confidence: 99%

Bisphenol A in combination with TNF-α selectively induces Th2 cell-promoting dendritic cells in vitro with an estrogen-like activity

Guo¹,

Liu

Uemura

et al. 2010

Cell Mol Immunol

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Bisphenol A (BPA) is a monomer used in manufacturing a wide range of chemical products, including epoxy resins and polycarbonate. BPA, an important endocrine disrupting chemical that exerts estrogen-like activities, is detectable at nanomolar levels in human serum worldwide. The pregnancy associated doses of 17b-estradiol (E2) plus tumor-necrosis factor-a (TNF-a) induce distorted maturation of human dendritic cells (DCs) that result in an increased capacity to induce T helper (Th) 2 responses. The current study demonstrated that the presence of BPA during DC maturation influences the function of human DCs, thereby polarizing the subsequent Th response. In the presence of TNF-a, BPA treatment enhanced the expression of CC chemokine ligand 1 (CCL1) in DCs. In addition, DCs exposed to BPA/TNF-a produced higher levels of IL-10 relative to those of IL-12p70 on CD40 ligation, and preferentially induced Th2 deviation. BPA exerts the same effect with E2 at the same dose (0.01-0.1 mM) with regard to DC-mediated Th2 polarization. These findings imply that DCs exposed to BPA will provide one of the initial signals driving the development and perpetuation of Th2-dominated immune response in allergic reactions.

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CCL1-CCR8 Interactions: An Axis Mediating the Recruitment of T Cells and Langerhans-Type Dendritic Cells to Sites of Atopic Skin Inflammation

Cited by 184 publications

References 30 publications

CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis

CXCL12 is essential for migration of activated Langerhans cells from epidermis to dermis

CCR8 Expression Identifies CD4 Memory T Cells Enriched for FOXP3+ Regulatory and Th2 Effector Lymphocytes

Bisphenol A in combination with TNF-α selectively induces Th2 cell-promoting dendritic cells in vitro with an estrogen-like activity

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