Increase in TNF-α and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a)

TNF/iNOS-producing dendritic cells (Tip-DCs) have been shown to arise during inflammation and are important mediators of immune defense. However, it is still relatively unclear which cell types contribute to their differentiation. Here we show that CD8 1 T cells, through the interaction with DCs, can induce the rapid development of human monocytes into Tip-DCs that express high levels of TNF-a and iNOS. Tip-DCs exhibited T-cell priming ability, expressed high levels of MHC class II, upregulated co-stimulatory molecules CD40, CD80, CD86, toll-like receptors TLR2, TLR3, TLR4, chemokine receptors CCR1 and CX3CR1 and expressed the classical mature DC marker, CD83. Differentiation of monocytes into Tip-DCs was partially dependent on IFN-c as blocking the IFN-c receptor on monocytes resulted in a significant decrease in CD40 and CD83 expression and in TNF-a production. Importantly, these Tip-DCs were capable of further driving Th1 responses by priming naive CD4 1 T cells for proliferation and IFN-c production and this was partially dependent on Tip-DC production of TNF-a and NO. Our study hence identifies a role for CD8 1 T cells in orchestrating Th1-mediating signals through the differentiation of monocytes into Th1-inducing Tip-DCs.Keywords: CD8 1 T cells . Cell differentiation . DCs . Monocytes . T-helper cells Supporting Information available online IntroductionDCs bridge innate and adaptive immunity by incorporating signals from environmental cues to drive the activation of T cells [1]. While DCs display a dendritic form and exhibit DC functions during steady state, inflammatory DCs, derived from CCR2 1 monocytes, only appear as a consequence of infection or inflammation [2]. Recent studies in mice have identified a subset of inflammatory DCs, known as TNF/iNOS-producing DCs (Tip-DCs), that are important for the clearance of Listeria monocytogenes bacteria [3]; influenza virus [4]; and regulation of IgA production in mucosal immunity [5]. Since the differentiation of monocytes into DCs or macrophages relies on the microenvironment, the presence of different T-cell types and cytokines is a critical feature in determining the differentiation outcome [6]. Besides their cytotoxic function [7], CD8 1 T cells have been shown to regulate allergic diseases by inhibiting the development of Th2 responses [8,9] and driving Th1 immunity in microbial infections [10][11][12]. CD8 1 T cells exert this pro-Th1 influence through a feedback mechanism during their interactions with DCs. CD8 1 T cells utilize a variety of factors, including IFN-g, GM-CSF, TNF-a and CD40L to activate DCs for the production of 13,14], the key cytokine for Th1 immunity [15]. Importantly, CD8 1 T cells were shown to interact with DCs in both lymph nodes [16] and peripheral tissue sites [4,17] where they exert their pro-Th1 influence.Previous studies have shown that CD8 1 T cells are able to infiltrate quickly into inflamed sites [18] that may facilitate their early interaction with DCs. In human psoriasis studies, the administration of alefacept, which ...

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“…Since they also expressed CD83 (Fig. 3C), TNF-a and iNOS, they could resemble Tip-DCs previously described in mice [3][4][5] and humans [22]. …”

supporting

confidence: 71%

“…T-cell and DC infiltration, resulted in decreased inflammation in the skin and a reduced number of Tip-DCs [22]. It is likely that reduced CD8 1 T-cell infiltration into skin can help to minimize monocyte recruitment and their inflammatory effects on monocyte differentiation.…”

Section: Discussionmentioning

confidence: 99%

Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

et al. 2011

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“…Thus, it is likely that anti-IL-12p40 effectively blocked the action of intracutaneous IL-12 and IL-23, from lesional APCs on lesional Th1 cells. According to recent reports, CD11c ϩ DCs are greatly increased in psoriatic skin compared with uninvolved skin, and the number of CD11c ϩ cells exceeds the number of CD3 ϩ T cells (53). In patients treated with efalizumab (anti-CD11a), CD11c ϩ cells in psoriatic skin significantly decreased at 2 wk posttreatment, probably because efalizumab directly inhibits the migration of these cells (53).…”

Section: Discussionmentioning

confidence: 99%

“…According to recent reports, CD11c ϩ DCs are greatly increased in psoriatic skin compared with uninvolved skin, and the number of CD11c ϩ cells exceeds the number of CD3 ϩ T cells (53). In patients treated with efalizumab (anti-CD11a), CD11c ϩ cells in psoriatic skin significantly decreased at 2 wk posttreatment, probably because efalizumab directly inhibits the migration of these cells (53). In our study, as shown in Table I, the number of CD11c ϩ cells in both responder groups decreased, but this decrease was not yet statistically significant at 2 wk posttreatment.…”

Section: Discussionmentioning

confidence: 99%

An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

Toichi

Torres

McCormick

et al. 2006

The Journal of Immunology

188

126

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Psoriasis is characterized by activation of T cells with a type 1 cytokine profile. IL-12 and IL-23 produced by APCs are essential for inducing Th1 effector cells. Promising clinical results of administration of an Ab specific for the p40 subunit of IL-12 and IL-23 (anti-IL-12p40) have been reported recently. This study evaluated histological changes and mRNA expression of relevant cytokines and chemokines in psoriatic skin lesions following a single administration of anti-IL-12p40, using immunohistochemistry and real-time RT-PCR. Expression levels of type 1 cytokine (IFN-γ) and chemokines (IL-8, IFN-γ-inducible protein-10, and MCP-1) were significantly reduced at 2 wk posttreatment. The rapid decrease of these expression levels preceded clinical response and histologic changes. Interestingly, the level of an anti-inflammatory cytokine, IL-10, was also significantly reduced. Significant reductions in TNF-α levels and infiltrating T cells were observed in high responders (improvement in clinical score, ≥75% at 16 wk), but not in low responders. Of importance, the levels of APC cytokines, IL-12p40 and IL-23p19, were significantly decreased in both responder populations, with larger decreases in high responders. In addition, baseline levels of TNF-α significantly correlated with the clinical improvement at 16 wk, suggesting that these levels may predict therapeutic responsiveness to anti-IL-12p40. Thus, in a human Th1-mediated disease, blockade of APC cytokines by anti-IL-12p40 down-regulates expression of type 1 cytokines and chemokines that are downstream of IL-12/IL-23, and also IL-12/IL-23 themselves, with a pattern indicative of coordinated deactivation of APCs and Th1 cells.

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“…A key feature of psoriasis is the abnormal activation of dendritic cell (DC) subsets in the dermal compartment leading to the downstream T-cell-mediated autoimmune cascade [4]. A role for plasmacytoid DCs (pDCs) producing type I IFNs appears to be central in this process.…”

Section: Introductionmentioning

confidence: 99%

Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self‐DNA

et al. 2014

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Psoriasis is a T-cell-mediated skin autoimmune disease characterized by the aberrant activation of dermal dendritic cells (DCs) and the sustained epidermal expression of antimicrobial peptides. We have previously identified a link between these two events by showing that the cathelicidin antimicrobial peptide LL37 has the ability to trigger selfnucleic acid mediated activation of plasmacytoid DCs (pDCs) in psoriatic skin. Whether other cationic antimicrobial peptides exert similar activities is unknown. By analyzing heparin-binding HPLC fractions of psoriatic scales, we found that human beta-defensin (hBD)2, hBD3, and lysozyme are additional triggers of pDC activation in psoriatic skin lesions. Like LL37, hBD2, hBD3, and lysozyme are able to condense self-DNA into particles that are endocytosed by pDCs, leading to activation of TLR9. In contrast, other antimicrobial peptides expressed in psoriatic skin including elafin, hBD1, and psoriasin (S100A7) did not show similar activities. hBD2, hBD3, and lysozyme were detected in psoriatic skin lesions in the vicinity of pDCs and found to cooperate with LL37 to induce high levels of IFN production by pDCs, suggesting their concerted role in the pathogenesis of psoriasis.Keywords: Antimicrobial peptides r Plasmacytoid DC r Psoriasis r Skin r Toll-like receptor Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPsoriasis is a common T-cell-mediated inflammatory disease of the skin, which, in its most prevalent form, is characterized by the appearance of scaly erythematous plaques that may cover large Correspondence: Dr. Michel Gilliet e-mail: Michel.gilliet@chuv.ch areas of the patient's body [1][2][3]. A key feature of psoriasis is the abnormal activation of dendritic cell (DC) subsets in the dermal compartment leading to the downstream T-cell-mediated autoimmune cascade [4]. A role for plasmacytoid DCs (pDCs) producing type I IFNs appears to be central in this process. pDC-derived * These authors contributed equally to this work.www.eji-journal.eu 204Roberto Lande et al. Eur. J. Immunol. 2015. 45: 203-213 IFNs activate conventional DCs that stimulate autoimmune T cells to migrate into the epidermis [5]. Here, these T cells produce Th17 cytokines 7], which directly initiate keratinocyte proliferation and an abnormal epidermal differentiation pattern [8,9]. Another key feature of psoriasis is the excessive production of antimicrobial peptides (AMPs) and proteins by keratinocytes [10][11][12]. These AMPs are best known for their role in killing pathogenic microorganisms such as Gram-positive and Gramnegative bacteria, protozoa, fungi, as well as some viruses [13]. The antimicrobial activity of AMPs has been ascribed to their unique cationic and amphiphatic structure, which allows interaction with and disruption of microbial membranes containing a high degree of negative charges. Three major antimicrobial peptide classes found in psoriatic skin are the cathelicidin, β-defensins, or S100 proteins. ...

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Increase in TNF-α and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a)

Cited by 433 publications

References 33 publications

Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self‐DNA

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Increase in TNF-α and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a)

Cited by 433 publications

References 33 publications

Human CD8+ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

Human CD8+ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

An Anti-IL-12p40 Antibody Down-Regulates Type 1 Cytokines, Chemokines, and IL-12/IL-23 in Psoriasis

Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self‐DNA

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Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells