These data demonstrate that NK-cell subsets are able to modify their phenotype under certain conditions. Consequently, before performing functional assays of CXCR3− and CXCR3+ NK cells, sorting GPCR Compound Library of the two subsets was necessary. We previously reported that sorted human CD56dim and CD56bright NK-cell

subsets differ in IL-21-dependent proliferation 31. In order to investigate if this also holds true for murine NK-cell subsets, we determined the proliferation of sorted CXCR3− and CXCR3+ splenic NK-cell subsets in response to activation with IL-21 and/or IL-15 in [3H]thymidine and CFSE assays (Fig. 4). Upon stimulation, CXCR3+ NK cells displayed a stronger proliferative response than CXCR3− NK cells, regardless

of the combination of stimulating cytokines. Both IL-15 and IL-21 alone had comparable Trichostatin A solubility dmso effects on CXCR3+ NK cells, whereas CXCR3− NK cells proliferated poorly when stimulated with IL-21. In contrast, CXCR3− NK cells proliferated well in response to IL-15. As measured with [3H]thymidine, the combination of IL-15 and IL-21 resulted in drastically increased proliferation of both subsets, especially in CXCR3+ NK cells (Fig. 4B). This additive effect was not clearly detectable in CFSE assays where 7-AAD− NK cells were analyzed to exclude apoptotic cells. In contrast to CXCR3− NK cells, however, almost all CXCR3+ NK cells responded to stimulation with IL-15 and IL-21 alone or in combination. In order to investigate if murine CXCR3− and CXCR3+ NK cells display differential cytotoxic ability like human CD56dim and CD56bright NK cells, standard 4h 51Cr-release assays and CD107a assays were performed (Fig. 5). Cytotoxic

activity of CXCR3− NK cells against YAC-1 target cells was twice as high as CXCR3+ NK-cell-mediated cytotoxicity (Fig. 5A). Although CXCR3− NK cells also degranulated stronger than CXCR3+ NK cells, a relatively high proportion of the latter subset was also CD107a+ (Fig. 5B). We further analyzed degranulation of sorted CXCR3+ NK cells and discriminated neCXCR3− NK cells from NK cells that Sitaxentan maintained CXCR3 on their surface (stable; sCXCR3+), revealing that NK cells that downregulated CXCR3 expression displayed stronger degranulation than sCXCR3+ NK cells (Fig. 5C). Strongly reduced percentages of degranulating NK cells were measured when using negatively sorted NK cells that had no contact with anti-NKp46 antibody (data not shown). As human CD56bright NK cells are known to produce higher amounts of cytokines such as IFN-γ than CD56dim NK cells, cytokine production of sorted murine CXCR3− and CXCR3+ NK cells was determined both on mRNA and protein levels (Fig. 6) 14, 15. Upon stimulation with PMA/ionomycin or IL-12 and IL-18 (15 h), mRNA levels of MIP-1α, TNF-α, and IFN-γ were higher in CXCR3+ as compared with CXCR3− NK cells (Fig. 6A).

As the asymmetrical pattern seems to merge some features of the other two—with infants paying attention to the mother’s focus, as in symmetrical, while refraining from acting together, as in unilateral—it has been presumed to work as a transitional state between the unilateral and the symmetrical.

buy MI-503 With respect to the subcodes, we also expected symmetrical coregulation to change with advancing age, with affect sharing and action sharing occurring first and language sharing occurring later. In fact, the former patterns employ skills, like expressive and motor acts, that are already part of the infant’s repertoire at the beginning of the observational period, to communicate with others in person-focused interaction or to explore physical reality in object-focused interaction, respectively. By contrast, the latter pattern requires skills that infants still lack at the outset and that may be recruited for coregulation only in a subsequent period. Finally, as shown in previous studies on social play (Camaioni et al., 2003), we expected to see individual differences in the rate of developmental change. Because of the focus

on developmental change and individual differences, a multiple case study method (Camaioni et al., 2003; Fogel, 1990; Hsu & Fogel, 2001; Lavelli & Fogel, 2002) was used. This method implies a multiple timepoint design, providing a dual PD184352 (CI-1040) opportunity to make meaningful statements about the group and also to capture the rate and the shape of developmental trajectories for each case. Ten dyads were video-taped weekly at home, interacting with ACP-196 chemical structure a toy tea set (dishes, forks, knives, spoons, cups, etc.) brought by the observer. Four girls and six boys were observed, with the girls belonging to dyads 1, 4, 8, 9 and the boys to dyads 2, 3, 5–7, 10. All of the infants were full term at birth; five of them were first borns, four were second borns, and one was third born. All children belonged to biparental middle-class families,

living in a town of central Italy. The observations started when infants were 10-months-old (M = 10.7 months) and continued until they were 24-months-old (M = 24.9 months). Each session lasted about 5 min (M = 5 min 2 sec). Mothers were sitting with their infants at their favorite table with the toy tea set at their disposal. No other instruction was given to them than to play as usual and to ignore the observer as much as possible. All the mothers were informed about the general interest of our study and all of them agreed to participate. At the end of the study, they received an edited tape of the observational periods as a gift for their intensive participation in the project. The Relational Coding Scheme developed by Alan Fogel (1993) was employed to assess mother–infant coregulation.

5). Down-regulation of NO and H2O2 by eosinophils could be a mechanism for protecting neighbouring eosinophils from the high toxicity and lack of specificity of this species, as H2O2 is involved in the spontaneous apoptosis of eosinophils.8 Moreover, when performing as an APC there might be a benefit for individual eosinophils to down-regulate Epigenetics inhibitor toxic molecules in order to prolong survival and therefore function. We observed 85%

viability of eosinophils after culture for 24–48 hr with opsonized C. neoformans, similar to that observed for eosinophils in medium alone. In contrast, it has been demonstrated that live yeasts of C. neoformans inhibit NO production by Mφin vitro through efficient free-radical scavengers.42 Moreover, we have previously reported that FcγRII blockade up-regulates the production of NO by rat Mφ incubated with glucuronoxylomannan, the major component of Cryptococcus capsular polysaccharide.23 The present work demonstrates that MSCs and purified T cells isolated from spleens of infected rats and cultured with C. neoformans-pulsed eosinophils proliferate in an MHC class I- and MHC class II-dependent manner, producing a large quantity of Th1-type cytokines, such as TNF-α and IFN-γ, in the absence of Th2 cytokine synthesis. However, although naive T cells did not proliferate

or increase IFN-γ production, they did produce TNF-α in response Cyclopamine in vitro to C. neoformans-pulsed and unpulsed eosinophils. Therefore, fungally activated eosinophils induced the growth and activation of C. neoformans-specific CD4+ and CD8+ Th1 cells. In contrast, it has been IMP dehydrogenase previously demonstrated that antigen-loaded eosinophils present antigens to primed T cells and increase the production of Th2 cytokines.10,11 In this regard, eosinophils pulsed with Strongyloides stercoralis antigen stimulated antigen-specific primed T cells and CD4+ T cells to increase the production of IL-5.13,14 However, in a pulmonary cryptococcosis developed in BALB/c mice, Huffnagle et al.43 observed that

infiltrating T cells secreted significant amounts of Th2-type cytokines (IL-4, IL-5 and IL-10) in addition to Th1-type cytokines (IFN-γ and IL-2). These results suggest that the phenotype of CD4+ T cells recruited into the lungs included a combination of Th1, Th2 and/or T-helper 0 (Th0) cells. Nevertheless, recent studies have associated eosinophils with protective immunity to respiratory virus infections. In this regard, Handzel et al.44 has demonstrated that human eosinophils bind rhinoviruses (RV), present viral antigens to RV16-specific T cells, and induce T-cell proliferation and IFN-γ secretion. Moreover, Davoine et al.45 has shown that the concentration of both, IFN-γ and GM-CSF appeared to increase when human eosinophils were added to the co-culture of T cells, parainfluenza virus type 1 and dendritic cells. In addition, Phipps et al.

tropicalis secretes high levels of Saps in a medium containing

bovine serum albumin as the sole source of nitrogen.[41] Sap expression in C. tropicalis during colonization of the oral epithelium is not associated with invasion and tissue damage.[51] Sap production has been studied preferentially in C. albicans and few reports have been found on Sap production CB-839 chemical structure of non-albicans Candida spp. It is believed that there is a correlation between the expansion of SAP genes and the transition from commensal to pathogenic microorganisms. Non-pathogenic Candida spp. usually have fewer genes encoding Sap than opportunistic pathogenic species and this fact can be confirmed by gene sequencing these strains. However, this rule cannot be applied to species such as C. glabrata or C. krusei, which do not possess any SAP genes.[44] SAP genes are differentially involved in the development and maintenance of infections.[21] Expression of SAP1–SAP3 appears to be essential in mucosal infections and SAP4–SAP6 expression is essential in systemic infections.[21, 52, 53] The proteinases encoded by SAP9 and SAP10 appear to play a role in cell integrity, adhesion and cell separation after budding. In an infected host, Candida spp. are found in both hyphae and yeast forms. It is believed that hyphae formation is essential for fungal invasion, Selleck CP 690550 as it assists in

the escape from the macrophage after phagocytosis.[41, 54] Some studies Methane monooxygenase in vitro have reported that SAP1–SAP3 are expressed in the yeast phase, whereas SAP4–SAP6 are expressed only in the hyphal phase (Fig. 2).[41, 55-58] It is believed that SAP2 has a functional role in invasion and spread of systemic infections.[52, 58, 59] The expression of these genes and the development of hyphae are not strictly linked, but are governed

by the same factors.[41] A further study on substrate specificity of Sap isoenzymes conducted by Aoki et al. [61] showed similar specificity among them. They were clustered into three groups according to substrate specificity. Sap7 and Sap10 showed high substrate specificity, whereas other Sap isoenzymes had broad substrate specificity. Interestingly, Sap4 to Sap6, which are coproduced in the hyphal form, may target similar host proteins. According to Ortega et al. [44], the pattern of SAP gene expression can be modified depending on the exposure conditions of the isolates. Physiological stress seems to promote increased secretion of Sap. Gene expression is variable and may be influenced by environmental conditions in vivo and by experimental conditions in vitro. Results of a study by White and Agabian [20] suggest that the cellular type controls the expression pattern of Sap isoenzymes. Studies on SAP gene expression identified seven genes as being differentially regulated in vitro (Fig.

OVA, complete, and incomplete Freund’s adjuvant (CFA and IFA, respectively) were purchased from Sigma-Aldrich. Tissue culture media Dulbecco’s-Modified Eagle’s Medium (DMEM) was supplemented with 10% heat-inactivated fetal bovine serum (FBS), 2 mM L-glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin (all

from Gibco). Mice were immunized s.c. under ether anesthesia at two sites (base of the tail and along the back) with 100 μg of OVA in 100 μL of 1:1 PBS:CFA. Three weeks later, they were boosted s.c. with 50 μg of OVA in IFA. Arthritis was induced 2 wk after the boost, by intra-articular (i.a.) injection of 100 μg OVA in 25 μL PBS in one paw (day 1). The paw thickness was measured every day during the course of the AIA using a caliper calibrated with 0.01-mm graduations. Adoptive transfer experiments for AIA development

were performed as follows: LNCs from OVA-immunized MEK inhibitor WT mice were isolated and stimulated in vitro in the presence of OVA (20 μg/mL). To overexpress miR-21, cells were transfected with 150 nM pre-miR21 miRNA precursor (cat no. PM10206, Ambion, Austin, TX, USA) using siPORT NeoFX transfection agent (cat no. AM4511, Ambion) for the entire period of antigenic stimulation. As a negative control, OVA-stimulated cells were treated with the transfection reagent alone. After 72 h of stimulation, cells were washed and adoptively transferred (day 0) into syngeneic naïve recipients (5×106 cells/mouse). Subsequently, see more mice were immunized s.c., with OVA in incomplete Freund’s adjuvant (day 1) and 6 days later (day 7) were intra-articularly injected with OVA/PBS. The development of AIA was monitored on a daily basis as mentioned above. Mice were immunized s.c. with OVA (100 μg) in CFA as described above, and 9–10 days later, draining LNs were collected. A single-cell suspension was prepared and cells were adjusted at 4×106 cells/mL. LNs were then cultured in the presence or absence of Ag in flat-bottomed 96-well plates for 72 h at 37°C in a 10% CO2 90% air-humidified incubator. Eighteen hours before harvesting, 1 μCi of [3H]-thymidine (Amersham Biosciences) was added to each well. The cells were harvested and incorporated

radioactivity was measured using Selleck Ponatinib a Beckman β counter. Stimulation index (S.I.) is defined as (cpm in the presence of Ag/cpm in the absence of Ag). LN cells from WT and PD1−/− mice were isolated at days 9 and 10 after OVA immunization and restimulated in vitro with OVA (50 μg/mL). After 72 h, cells were collected and analyzed for the expression of CD4 (RM4-5), CD44 (Pgp-1, Ly24), and CD3e (145-2C11) (all from BD Pharmingen) by flow cytometry. Antibody staining was performed for 20 min at 4°C in PBS/5% FCS. Cells were acquired on a FACSCalibur (BD Biosciences) and the analysis was performed with the FlowJo software (Tree Star). Cytokine production was determined in culture supernatants harvested following 48 h stimulation of Ag-primed LNCs with OVA (20 μg/mL).

Sections were then either stained with haematoxylin & eosin (H&E) to estimate the tumour mass and infiltrate or subjected to immunohistochemistry to identify neutrophils and Treg cells. The length (l) and width (w) of tumour mass plus infiltrate on each section was measured

on a calibrated microscope. An estimate was made of the total tumour volume based on the area of tumour mass and infiltrate (πlw) on adjacent sections and the distance between sections (h): i.e. hπ(√lw + √LW + (√lw * √LW))/3. It was assumed that the tumour mass and infiltrate terminated at the mid-point between the last section in which it was observed and the next. The sum of these CHIR-99021 cell line volumes resulted in an estimation of the tumour mass and infiltrate. For staining of neutrophils, sections were dehydrated then microwaved in 10 mm citrate buffer pH 6. Sections were equilibrated selleck kinase inhibitor in PBS before blocking of peroxidase activity with 1% H2O2. Non-specific antibody binding was blocked by incubation with PBS supplemented with 1% bovine serum albumin and 2% rabbit serum. Neutrophils were detected using rabbit anti-mouse interleukin-8 receptor B (IL-8RB; K-19; Santa Cruz Biotechnology, Santa Cruz, CA) followed by incubation with biotinylated swine anti-rabbit abs (Dako, Glostrup, Denmark). Neutrophils were then visualized

by incubation with horseradish peroxidase-conjugated Extravidin (Sigma-Aldrich) followed by development with diaminobenzidine (DAB) substrate kit (VectorLabs, Burlingame, CA) according to the manufacturer’s instructions and counterstaining with haematoxylin. For staining of Foxp3, sections were dehydrated and microwaved in 50 mm Tris–HCl, 2 mm

EDTA, pH 9. Endogenous biotin was blocked by incubation in avidin followed by biotin (VectorLabs). Non-specific binding sites were subsequently blocked with horse serum. Foxp3 cells were stained using rat anti-Foxp3 antibodies (FJK-16; eBioscience, San Diego, CA, USA), then biotinylated anti-rat abs (BDBiosciences, San Jose, CA, USA) and stained cells were visualized by incubation with horseradish peroxidase-conjugated Extravidin and DAB as described above. The ID-8 peritoneal lavage cells were collected by injecting 6 ml PBS with 2 mm EDTA and 0·5% bovine serum albumin into the peritoneum of killed mice with 6 ml fluid recovered in every case. Cytofunnels were assembled as described in the manufacturer’s instructions. A 240-ml sample of lavage fluid was spun for 10 min at 112.9 g. Slides were then air dried and stained using a Wright–Giemsa stain, rinsed in deionized water and allowed to air dry. Bone marrow (BM) was collected from naive mice and neutrophils were isolated by density centrifugation. Briefly, BM cells were layered on top of 72%, 64% and 52% Percoll solutions, with the cells at the lower interphase constituting mainly mature neutrophils after centrifugation.

85–23, revised 1985) and the national laws on Protection of Animals were followed. A total of 109 female NOD mice were analysed. First, 62 female NOD mice were litter-matched and randomized after weaning into four groups (groups A1–D1; Fig. S1). As

a control group, female NOD mice in group A1 (n = 16) were not mated. In the remaining groups, female NOD were mated at age 10 weeks to male NOD mice (group B1, n = 15) representing MHC identical mating, male CByB6F1/J mice (group C1, n = 16) representing MHC haploidentical mating or male C57BL/6J mice (group D1, n = 15), representing fully MHC mismatched mating. For pairings, two male mice were used in each group. To analyse the effect of later gestation, a second set of 47 female NOD mice were litter-matched and randomized after weaning into three groups: control unmated females (n = 16, group A2); females mated at

age 13 weeks to three male Selisistat cell line NOD mice (n = 16, group B2); and females mated at age 13 weeks to three male CByB6F1/J mice (n = 15, group C2). For the mating, two female and one male mouse were housed together in one cage for a median time of 14 days [interquartile range (IQR), 14–17 days]. Subsequently, 45 of 46 females mated at 10 weeks of age and 29 of 31 females mated at 13 weeks of age delivered altogether 610 pups. The number of pups per litter ranged between four and 13 (median, 9; IQR, 7–10), and the offspring numbers were distributed equally between the different mating groups (Fig. S1). All pups remained with their dam for the weaning period of median 21 days (IQR, 21–23 days). All female AUY-922 solubility dmso NOD mice were followed to overt diabetes or until the age of 28 weeks. Diflunisal Urine glucose levels were measured twice weekly using urine glucose sticks (Diastix, Bayer HealthCare LLC, Mishawaka, IN, USA), beginning at 10 weeks of age. The diagnosis of diabetes was defined as two consecutive urine glucose values > 5·5 mmol/l and blood glucose levels > 13·9 mmol/l (Glucometer Elite,

Bayer Diagnostics GmbH, Munich, Germany). Venous blood was obtained at age 10 weeks (prior to the mating) and 16 weeks (after weaning), and diabetes onset or 30 weeks for the measurement of insulin autoantibodies. In group C1, splenocytes from two diabetic mice at diabetes onset and two non-diabetic mice at the end of observation were collected to look for lymphocyte chimerism. Antibodies to insulin were detected using a radiobinding assay, as described previously [14]. All measurements were performed on coded samples that were operator-blinded. The upper limit of normal was determined from the 99th centile values obtained in sera from BALB/c and C57BL/6 female mice. The assay is represented as laboratory B in the animal models of Diabetes Workshop [15]. In order to analyse if cells with paternal genome alleles migrated during gestation from the fetus to the dam and persisted, staining and flow cytometry for MHC class I molecules was performed on the collected splenocytes.

Stimulatory effects of progesterone and estrogen hormones together with a higher basal metabolic rate increase maternal ventilatory sensitivity to chemosensory stimuli and raise Ibrutinib chemical structure ventilation by 25% [53]. The greatest changes, however, are those occurring in the uteroplacental circulation, where an even greater fall in vascular resistance preferentially directs some 20% of total cardiac output to this vascular bed by term, amounting to a >10-fold or greater increase over levels present in the nonpregnant state such that, by term, uteroplacental flow may approach 1 L/min [61]. Many of these changes are complex, distinctive,

and subject to particular, local control. The purpose of this review is to describe the remodeling process that enables the progressive and substantial increase in uteroplacental blood flow required for normal fetal growth and development. Most broadly, the remodeling process can be viewed as a combination of changes in vascular structure, which result in increased vessel diameter and length, and concurrent changes in vascular function, i.e., altered vasoreactivity (including NVP-AUY922 order myogenic tone). Ultimately, this combination of passive structure and superimposed

active tone regulate arterial lumen diameter, the primary physiological determinant of vascular resistance and, hence, blood flow to the uteroplacental circulation. With the exception of the endometrium, the vascular system of the adult is largely quiescent. Structural changes that do occur with age, such as arterial stiffening and plaque formation, are generally pathological in nature as they may lead to the development of hypertension and atherosclerosis, respectively. Endometrial changes are cyclic with each menstrual cycle and involve only the microcirculation. Hence, the significant growth of the maternal vessels

during pregnancy represents a unique physiological event whose understanding can be approached from the standpoint of underlying processes and associated events, signals and pathways (Figure 1). Much of this review is focused on the structural changes that occur in arteries and veins, i.e., true structural ifoxetine remodeling, whose pattern is most often referred to as being outward (or expansive) and hypertrophic [59]. The latter term derives from the fact that the most common pattern is one of luminal enlargement with little or no change in wall thickness (with the exception of the mouse [81, 82]). Without any change in wall thickness, cross-sectional area will increase secondary to the larger lumen and result in a greater overall tissue mass. Put differently, eutrophic lumenal expansion requires a reduction in wall thickness to maintain a constant cross-sectional area whereas hypertrophic expansion accomplishes an increase in diameter without any change in wall thickness (although total cross-sectional area is still increased).

CD11c-DTR (where DTR stands for diphtheria toxin receptor) mice carry a transgene encoding a DTR-GFP fusion Selleckchem Paclitaxel protein under the control of a murine CD11c promoter [1]. Our results demonstrate a minimal if any effect if mDCs are deleted prior or during the first 10 days after induction of EAE by MOG immunization. CD11c-DTR mice on C57BL/6 genetic background were immunized with MOG protein in CFA and pertussis toxin to induce EAE. First, the efficiency of DC depletion was assessed after DTx injection

of CD11c-DTR mice. An analysis of DC depletion in the skin, skin-draining inguinal LN and spleen was performed both before and after MOG immunization. All results are presented in Supporting Information Table 1 and the most relevant results are PLX4032 presented in Figure 1. Dermal Langerin− DCs were efficiently depleted for at least 4 days after DTx injection and subsequent MOG immunization (Fig. 1A and Supporting Information

Table 1). CD11chi MHC II+ mDCs from skin-draining LNs and spleen were also efficiently depleted whereas around 50% of CD11cintermediate MHC II+ inflDCs were depleted by the DTx injection (Fig. 1B and C). Finally, the frequency of PDCA-1+ B220+ CD11clo pDCs was not affected by the DTx injection (data not included). Thus, dermal DCs and mDCs but not pDCs, were depleted by the DTx injection in CD11c-DTR mice, which is in concordance with previous studies [1]. To test for any unspecific effects of DTx on EAE, DTx-treated C57BL/6 mice were included in all experiments. No differences between PBS-treated CD11c-DTR control mice and DTx-treated C57BL/6 control mice were observed in terms of EAE severity or observed

immune reactivity (Table 1; and data not included). This suggests that DTx does not affect the clinical signs of EAE or immune reactivity toward MOG. In EAE, DCs upregulate their IL-6 and IL-23/IL-12p40 expression, and primed and differentiated pathogenic Th cells can be detected 4–10 days after MOG immunization [12, 14]. To assess the role of DCs during inititation of EAE, DCs were Rutecarpine depleted in vivo after MOG immunization. For inducible, short-term in vivo ablation of DCs, CD11c-DTR mice that carry a transgene encoding a DTR-GFP fusion protein under the control of the murine CD11c promoter were used. Conditional depletion is induced by injection of DTx, which leads to a 5- to 6-day ablation of DCs [1]. DCs were depleted in vivo on the day before — or 8 days after — EAE induction. DC depletion in CD11c-DTR mice by DTx injection 1 day before MOG immunization did not alter the incidence but reduced the mean maximum clinical EAE score compared with that of PBS-treated control CD11c-DTR mice (p = 0.05; Table 1; Fig. 2A) or DTx-injected C57BL/6 mice (Table 1).

In addition, the cytokine imbalance of psoriasis is clearly illustrated by therapeutic response IDH tumor to IL-4 [56]. Patients treated with recombinant human IL-4 showed a reduction of clinical scores, lesional Th1 cells, and the IFN-γ/IL-4 ratio, whereas the number of circulating Th2 cells was increased [56]. This study clearly highlights the adjustment

of the disease-specific cytokine imbalance as an important therapeutic tool. In contrast to psoriasis, the skin of atopic eczema patients is frequently colonized by staphylococci, in particular S. aureus (reviewed in [57]). This phenomenon is due to a tissue-restricted immune deficiency that relates to the Th2-dominated cytokine microenvironment typically observed in atopic eczema. In vitro, both, IL-4 and IL-13, have been shown to inhibit Th1- [47] and Th17-mediated [8] induction of antimicrobial Ibrutinib peptides in epithelial cells via STAT6 and SOCS molecules [58]. The clinical relevance of these two opposing T-cell cytokine signatures has been shown in vivo in a rare population of patients suffering from both psoriasis and atopic eczema in parallel [50]. In such patients, only eczema

lesions, but not psoriasis plaques, were colonized by S. aureus [50]. Beyond insufficient epithelial immunity, a second hallmark of atopic eczema is an impaired epidermal barrier with consequent transepidermal water loss and dryness of the skin (reviewed

in [59]). While mutations in genes of the epidermal differentiation complex, such as filaggrin, are strongly associated with atopic eczema, a Th2-dominated microenvironment also damages the epidermal barrier by downregulating filaggrin and other genes of the epidermal differentiation complex [60-62]. Thus, Th2 cytokines antagonize Th1 and Th17 immunity in the skin and largely explain the phenotype of atopic eczema [57]. A third cutaneous model disease is ACD. Here, small and harmless molecules (haptens) such as nickel elicit an acute eczematous immune response characterized by T-cell cytotoxicity and keratinocyte apoptosis [63, 64]. The clinical phenotype Glycogen branching enzyme of ACD is largely explained by the cytokine content of the local microenvironment. Depending on the eliciting hapten, a mixed T-cell infiltrate is observed with dominating Th1 cytokines. In such a microenvironment, IL-17 functions as an amplifier of nonspecific T-cell apoptosis mediated by IFN-γ [36] and enhances the cytotoxic immune response typical for ACD. In summary, the function of T-cell cytokines strongly varies depending on the cytokine content of the local microenvironment. Therefore, the function of Th-cell subsets has to be interpreted within the context of the microenvironment and disease setting.