Differential Regulation of Epidermal Langerhans Cell Migration by Interleukins (IL)-1α and IL-1β during Irritant- and Allergen-Induced Cutaneous Immune Responses

Cumberbatch, Marie; Dearman, Rebecca J.; Groves, Richard; Antonopoulos, Christos; Kimber, Ian

doi:10.1006/taap.2002.9442

Cited by 77 publications

(60 citation statements)

References 44 publications

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“…During the sensitization phase, they are responsible for Ag-specific T cell priming in LNs (34). Tregs can downregulate the expression of CD80 and CD86 on DCs (35, 36).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

Beidaq

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Hofmann

et al. 2016

The Journal of Immunology

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Contact hypersensitivity (CHS) of murine skin serves as a model of allergic contact dermatitis. Hapten-specific CD8 T cells and neutrophils represent the major effector cells driving this inflammatory reaction whereas Foxp3+ regulatory T cells (Tregs) control the severity of inflammation. However, whether in vivo expansion of endogenous Tregs can downregulate CHS-mediated inflammation remains to be elucidated. In this study, we addressed this issue by using injection of an IL-2/anti–IL-2 mAb JES6-1 complex (IL-2/JES6-1) as a means of Treg induction in 2,4,6-trinitrochlorobenzene–induced CHS. IL-2/JES6-1 injection before or after hapten sensitization led to a considerable reduction of skin inflammation, even when rechallenged up to 3 wk after the last treatment. Conversely, Treg depletion re-established the CHS response in IL-2/JES6-1–treated mice. IL-2/JES6-1 injection resulted in increased frequencies of natural and peripheral Tregs in spleen and draining lymph nodes (LNs), elevated IL-10 and TGF-β production by CD4 T cells, reduced CD86 expression by dendritic cells, and led to lower numbers of hapten-specific IFN-γ–producing CD8 T effector cells in LNs. Neutrophil and CD8 T cell infiltration was reduced in inflamed ear tissue, whereas CTLA-4+Foxp3+ Treg frequencies were augmented. Adoptive transfer of LN cells of sensitized mice into recipients treated with IL-2/JES6-1 showed impaired CHS. Our results show that in vivo Treg expansion results in a prolonged CHS suppression, a sustained reduction of hapten-specific CD8 T cells, and a decrease in effector cell influx in inflamed tissue.

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“…During the sensitization phase, they are responsible for Ag-specific T cell priming in LNs (34). Tregs can downregulate the expression of CD80 and CD86 on DCs (35, 36).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

Beidaq

Link

Hofmann

et al. 2016

The Journal of Immunology

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Section: Discussionmentioning

confidence: 99%

“…Exposure to contact allergens results in secretion of IL-1b by LC which in turn stimulates epidermal KC to secrete TNF-a, and also IL-18 [41][42][43]. Strong evidence shows that these epidermis-derived cytokines are essential for the migration of LC out of the epidermis [41][42][43]. Furthermore, these cytokines have been reported to increase secretion of many chemokines by fibroblasts [44,45] and this would explain the increased LC migration towards fibroblasts after allergen exposure.…”

Section: Discussionmentioning

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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“…This immunization strategy takes advantage of the professional antigen-presenting cells, known as Langerhans cells (LCs), found in the outer layer of the skin, the epidermis. LCs increase their baseline rate of migration out of the epidermis in response to stimuli such as contact sensitizers, inflammatory cytokines, and adjuvants (tumor necrosis factor alpha, interleukin-1␤ [IL-1␤]) (5,6,16,25,40) and travel to inductive sites of the immune system, which are primarily the draining lymph nodes (DLN). Adjuvants of the ADP-ribosylating exotoxin family, which includes heatlabile enterotoxin of Escherichia coli (LT), and their mutants have been used on the skin and have similar stimulatory effects on LCs (25,29).…”

mentioning

confidence: 99%

Immunostimulant Patch Enhances Immune Responses to Influenza Virus Vaccine in Aged Mice

Guebre‐Xabier

Hammond

Ellingsworth

et al. 2004

J Virol

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Improvement in the immune response to influenza virus vaccination in the elderly represents the primary unmet need in influenza virus vaccination. We have shown that topical application of immunostimulating (IS) patches containing heat-labile enterotoxin of Escherichia coli (LT) enhances immune responses to injected vaccines. We extend these findings and show that LT-IS patch application enhances the antibody responses to influenza virus vaccination in both young and aged mice. LT-IS patches markedly increased influenza virusspecific immunoglobulin G (IgG), hemagglutination inhibition antibody, mucosal antibody, and T-cell responses. The magnitude of the immune responses in aged mice receiving an LT-IS patch was equivalent to or greater than that of the immune responses in young mice given vaccine alone. These results suggest that addition of an LT-IS patch may compensate for the deficient immune function seen in the aged in response to influenza virus vaccination. Therefore, use of an LT-IS patch could be a new, safe, and simple immunization strategy that may significantly improve the outcome of influenza virus vaccination in the elderly.

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Differential Regulation of Epidermal Langerhans Cell Migration by Interleukins (IL)-1α and IL-1β during Irritant- and Allergen-Induced Cutaneous Immune Responses

Cited by 77 publications

References 44 publications

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

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

Immunostimulant Patch Enhances Immune Responses to Influenza Virus Vaccine in Aged Mice

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