Cells In Psoriasis Patients Research Articles

Dysregulated Peripheral Invariant Natural Killer T Cells in Plaque Psoriasis Patients.

Background: Psoriasis is a common immune-mediated skin disease that involves T-cell-mediated immunity. Invariant natural killer T (iNKT) cells are a unique lymphocyte subpopulation that share properties and express surface markers of both NK cells and T cells. Previous reports indicate that iNKT cells regulate the development of various inflammatory diseases. IL-17 is a key cytokine in the pathogenesis of psoriasis and a key therapeutic target. Secukinumab is a fully human IgG1κ antibody that targets IL-17A, thereby antagonizing the biological effects of IL-17. Objective: To explore the expression of iNKT cells in psoriasis patients and the effect of secukinumab on them. Methods: We examined the frequencies of iNKT cells, Tregs, naïve and memory CD4+and CD8+T cells in the PBMCs as well as their cytokine production in a cohort of 40 patients with moderate-to-severe plaque psoriasis and 40 gender- and age-matched healthy controls. We further collected peripheral blood of another 15 moderate-to-severe plaque psoriasis patients who were treated with secukinumab and evaluated the proportion of iNKT cells in the PBMCs at baseline and week 12. Results: The frequencies of conventional CD4+ T cells, CD8+ T cells, and Tregs in the PBMCs were comparable between psoriasis patients and healthy controls, but the frequencies of Th17 cells, Tc1 cells and Tc17 cells were increased in psoriasis patients. The frequency of peripheral iNKT cells and CD69+ iNKT cells was significantly decreased in psoriasis patients. Both iNKT2 cells and iNKT17 cells were increased in psoriasis patients, but the ratio of iNKT2 cells vs iNKT17 cells was significantly reduced in psoriasis patients. After receiving secukinumab, the proportion of iNKT cells in the PBMCs of patients was increased, while the proportion of iNKT17 cells was decreased. Conclusion: Dysregulated iNKT cells may be involved in the pathogenesis of psoriasis and secukinumab may play a regulatory role on iNKT cells.

Characterizing memory T helper cells in patients with psoriasis, subclinical, or early psoriatic arthritis using a machine learning algorithm

BackgroundPsoriasis patients developing psoriatic arthritis (PsA) are thought to go through different phases. Understanding the underlying events in these phases is crucial to diagnose PsA early. Here, we have characterized the circulating memory T helper (Th) cells in psoriasis patients with or without arthralgia, psoriasis patients who developed PsA during follow-up (subclinical PsA), early PsA patients and healthy controls to elucidate their role in PsA development.MethodsWe used peripheral blood mononuclear cells of sex and age-matched psoriasis patients included in Rotterdam Joint Skin study (n=22), early PsA patients included in Dutch South West Early Psoriatic Arthritis Cohort (DEPAR) (n=23) and healthy controls (HC; n=17). We profiled memory Th cell subsets with flow cytometry and used the machine learning algorithm FlowSOM to interpret the data.ResultsThree of the 22 psoriasis patients developed PsA during 2-year follow-up. FlowSOM identified 12 clusters of memory Th cells, including Th1, Th2, Th17/22, and Th17.1 cells. All psoriasis and PsA patients had higher numbers of Th17/22 than healthy controls. Psoriasis patients without arthralgia had lower numbers of CCR6-CCR4+CXCR3+ memory Th cells and higher numbers of CCR6+CCR4-CXCR3-memory Th cells compared to HC. PsA patients had higher numbers of Th2 cells and CCR6+CCR4+CXCR3- cells, but lower numbers of CCR6+CCR4+CXCR3+ memory Th cells compared to HC. The number of CCR6+ Th17.1 cells negatively correlated with tender joint counts and the number of CCR6+ Th17 cells positively correlated with skin disease severity.ConclusionsUnsupervised clustering analysis revealed differences in circulating memory Th cells between psoriasis and PsA patients compared to HC; however, no specific subset was identified characterizing subclinical PsA patients.

Infliximab modifies regulatory T cells and co-inhibitory receptor expression on circulating T cells in psoriasis

BackgroundPsoriasis is a T cell–mediated autoimmune skin disease. Accumulating evidence has demonstrated that co-inhibitory receptors (CIRs) play a vital role in regulating T cell–mediated immune response, especially in neoplasm and autoimmunity. However, the immuno-function of CIRs in the development of psoriasis remains unclear. ObjectiveWe investigated the expression of CIRs on the circulating T lymphocytes of psoriasis patients before and after anti–tumor necrosis factor-α (TNF-α) therapy. MethodsWe enrolled 17 patients with moderate-to-severe plaque psoriasis, 17 patients with mild plaque psoriasis, and 18 healthy controls in this study. Fourteen of the moderate-to-severe psoriasis patients were treated with infliximab, a monoclonal antibody against TNF-α. Peripheral blood was collected, and peripheral blood mononuclear cells were extracted. The proportion of T cell subsets along with their expression of CIRs, namely T cell immunoreceptor with Ig and ITIM domains (TIGIT), lymphocyte activating gene 3 (LAG-3), cytotoxic T–lymphocyte associated protein 4 (CTLA-4), B and T lymphocyte–associated protein (BTLA), endothelial protein C receptor (PROCR), podoplanin (PDPN), programmed cell death 1 (PD-1), and T cell immunoglobulin mucin family containing molecule 3 (TIM-3), were determined by flow cytometric assay. ResultsThe moderate-to-severe plaque psoriasis patients had less circulating Tregs, which increased after infliximab treatment. They also had decreased TIGIT, LAG-3 but increased PDPN expression on peripheral CD4+ T cells. Infliximab enhanced TIGIT, LAG-3, CTLA-4 but reduced PROCR expression on circulating CD4+ T cells. Remarkably, both the frequency of circulating Tregs and the expression level of TIGIT on CD4+ T cells at baseline (pre-treatment) negatively correlated with the extent of PASI score reduction benefited from infliximab therapy. ConclusionAnti–TNF-α therapy increased the frequency of Tregs and TIGIT, LAG-3, CTLA-4 expression but reduced PROCR expression on circulating CD4+ T cells in psoriasis patients. The baseline proportion of Tregs and the expression level of TIGIT on circulating CD4+ T cells might serve as predictive markers for the degree of disease remission benefited from infliximab treatment.

Furin Expression in Patients With Psoriasis-A Patient Cohort Endangered to SARS-COV2?

Background: SARS-Cov2 has raised concerns among dermatologists regarding psoriasis and its respective treatments. Comorbidities, which induce the expression of the proprotease furin have been associated with severe course of COVID-19. Furin and angiotensin converting enzyme 2 (ACE2) play a major role in viral host cell entry of SARS-Cov2.Objective: To evaluate mRNA expression of Furin and ACE2 from blood cells in psoriasis patients, and whether systemic or topical treatment reduces expression levels.Methods: This observational translational study analyzed blood samples from patients from a clinical trial and samples retrieved from the biobank of the Psoriasis Registry Austria (PsoRA). Furin and ACE2 expression levels were analyzed prior to as well as 3 and 12–24 months after start of biologic treatment with either ustekinumab or secukinumab. Additionally, the study analyzed expression levels prior to, 6 days after start of dithranol treatment and 4–6 weeks after end of dithranol treatment.Results: Furin mRNA expression was significantly increased at baseline in the biologic (4.9 ± 2.6 fold, p < 0.0001) and in the dithranol group (2.7 ± 1.4 fold, p < 0.001) compared to controls. There was a trend for arthritis patients to express more furin than patients with psoriatic skin involvement only (5.26 ± 2.30 vs. 3.48 ± 2.27, p = 0.078). Analyzing furin mRNA expression after treatment initiation with secukinumab or ustekinumab revealed a normalization of levels after 3 and 12 to 24 months. Similar findings were obtained for patients treated with dithranol, with significantly decreased expression levels 6 days after start of dithranol treatment and also at follow-up, (4–6 weeks after dithranol treatment had been terminated). ACE2 expression levels did not differ from controls at any timepoint, regardless of biologic or topical treatment.Conclusion: Significantly overexpressed levels of furin were observed in untreated patients, and, thus, these patients may be at risk for infection and a severe course of COVID-19. However, the data indicate that successful therapeutic intervention in psoriasis, by systemic biologic or topical treatment, can efficiently reduce furin levels in blood cells, possibly limiting the risk of psoriasis patients for a severe COVID-19 course.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02752672.

065 CDK7 inhibitor suppresses psoriasis inflammation via inhibiting glycolysis to modulate Th17/Treg balance

Psoriasis is a chronic inflammatory disease characterized by hyper-activated Th17 and suppressive Treg cells, but the mechanism of Th17/Treg cells imbalance is still unclear. Cyclin-dependent kinase 7(CDK7) which is known as a cell cycle regulator has been reported an anti-inflammatory effect in immuno-cells. Here we firstly found CD4+T cells of psoriasis patients expressed higher levels of CDK7 along with an increased glycolysis levels than those in healthy controls. The chemical inhibitor of CDK7 called THZ1 restricted glycolytic metabolism in CD4+T cells of psoriasis patients as well as typical glycolysis related genes. More importantly, THZ1 could suppress Th17 cell differentiation and promote Treg cell differentiation even under Th17 polarizing condition in vitro. Intraperitoneal injection of THZ1 in mice exhibited an alleviated epidermal hyperplasia and alleviated inflammation caused by imiquimod(IMQ) treatment. THZ1-treated IMQ mice had significantly lower ratio of Th17 cells and higher ratio of Treg cells from the splenocytes, in comparison with vehicle-treated IMQ mice. Furthermore, we identified IL-23 as an upstream regulator that stimulated CDK7 expression and glycolysis through p-AKT-Hif-1α signalling pathway. Taken together, our results showed that abnormal CDK7 expression induced by IL-23 in CD4+ T cells in psoriasis patients contributed to the enhanced glycolysis levels which lead to the imbalance of Th17/Treg cells. CDK7 inhibitor THZ1 may serve as an immuno-modulator for psoriasis therapy in the future.

Interleukin-33 alleviates psoriatic inflammation by suppressing the T helper type 17 immune response.

Psoriasis is a chronic inflammatory skin disease with unclear pathogenesis. Interleukin-33 (IL-33) is highly expressed in patients with psoriasis, but its role in psoriasis is unknown. The aim of this study was to investigate the possible role of IL-33 in the pathogenesis and treatment of psoriasis. IL-33 expression was determined using enzyme-linked immunosorbent assay, real-time fluorescent quantitative polymerase chain reaction and immunohistochemical staining. CD4+ T cells were sorted using magnetic beads and treated with or without IL-33. Imiquimod (IMQ) was used to induce psoriatic inflammation in mice. The frequency of immune cells was determined using flow cytometry. The cytokine level in mouse skin was measured using cytometric bead array. Our results showed that IL-33 was highly expressed in the lesional skin and serum of patients with moderate-to-severe plaque psoriasis. IL-33 inhibited the expression of IL-17 in CD4+ T cells of psoriasis patients. Subcutaneous injection of IL-33 alleviated the IMQ-induced psoriatic inflammation in mice, reduced tumor necrosis factor-α and IL-23 expression, and decreased the proportion of T helper type 17 (Th17) cells in the skin-draining lymph nodes in the mice. Our results suggest that IL-33 plays a protective role in the pathogenesis of psoriasis by suppressing Th17 cell differentiation and function. The potential therapeutic effect of IL-33 in treating psoriasis warrants further investigation.

Instantaneous depolarization of T cells via dopamine receptors, and inhibition of activated T cells of Psoriasis patients and inflamed human skin, by D1-like receptor agonist: Fenoldopam.

Activated T cells are pathological in variousautoimmune and inflammatory diseases including Psoriasis, and also in graft rejection and graft-versus-host-disease. In these pathological conditions, selective silencing of activated T cells through physiological receptors they express remains a clinical challenge. In our previous studies we found thatactivation ofdopamine receptors (DRs) in resting human T cells activates these cells, and induces by itself many beneficialT cell functions.In this study, we found that normal human T cells express all types of DRs, and that expression of D1R, D4R and D5R increases profoundly after T cell receptor (TCR) activation. Interestingly, DR agonists shift the membrane potential (Vm ) of both resting and activated human T cells, and inducesinstantaneousT cell depolarization within 15secondsonly.Thus, activation of DRs in T cells depolarize these immune cells, alike activation of DRs in neural cells. The skin of Psoriasis patients contains 20-fold more D1R+ T cells than healthy humanskin. In line with that, 25-fold more D1R+ T cells are present in Psoriasis humanized mouse model. Highly selective D1-like receptor agonists, primarily Fenoldopam(Corlopam) - aD1-like receptor agonist and a drug used in hypertension, induced the following suppressive effects on activated T cells of Psoriasis patients: reduced chemotactic migration towards the chemokine SDF-1/CXCL12; reduced dramatically the secretion of eight cytokines: tumor necrosis factor-α, interferon-γ, interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-8 and IL-10; and reduced three T cell activation proteins/markers: CD69, CD28 and IL-2. Next, we invented a novel topical/dermal Fenoldopam formulation, allowing it to be spreadon, and providing prolonged and regulated release in,diseased skin. Our novel topical/dermal Fenoldopam: reduced secretion of the eight cytokines by activated human T cells; reduced IL-1β and IL-6 secretion by human lipopolysaccharide-inflamed skin; eliminated preferentially >90% of live and large/proliferating human T cells. Together, our findings show for the first time that both resting and activatedT cells are depolarized instantaneously via DRs, and that targeting D1-like receptors in activated T cells and inflamed human skin by Fenoldopam, in Psoriasis, and potentially in other T cell-mediated diseases, could be therapeutic. Validation in vivo is required.

IL-21 Induces an Imbalance of Th17/Treg Cells in Moderate-to-Severe Plaque Psoriasis Patients

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease, with over-activated interleukin (IL)-17-producing CD4+ T cells (Th17) and repressed regulatory T (Treg) cells. IL-21 is a Th17-related cytokine and plays an important role in the pathogenesis of psoriasis. However, the mechanism by which IL-21 affects the pathogenic progress of psoriasis remains poorly understood.Methods: IL-21 and IL-21 receptor (IL-21R) expression in normal and psoriatic lesional skin were determined by immumohistochemical staining, immunofluorescence staining, and western blotting. The levels of IL-21, IL-17A, and IL-22 in the culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). The level of IL-10 in the culture supernatants was measured by cytometric bead array (CBA). The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). CD4+ T cells were isolated from the peripheral blood mononuclear cells (PBMCs) from the psoriasis patients and healthy individuals and then treated with or without IL-21 for 3 days. The proportions of Th17 and Treg cells were determined by flow cytometric analysis.Results: IL-21 and IL-21R were highly expressed in the lesional skin and peripheral blood of psoriasis patients. IL-21 promoted CD4+ T cells proliferation and Th17 cells differentiation and inhibiting Treg cells differentiation by upregulating RORγt expression and downregulating Foxp3 expression, with increased expression and secretion of IL-17A and IL-22. The proportion of Treg cells was negatively correlated with that of Th17 cells in psoriasis patients.Conclusion: Our results suggest that IL-21 may promote psoriatic inflammation by inducing imbalance in Th17 and Treg cell populations.

322 Dysregulation of Akt-FOXO1 pathway leads to Dysfunction of Regulatory T Cells in Psoriasis Patients

322 Dysregulation of Akt-FOXO1 pathway leads to Dysfunction of Regulatory T Cells in Psoriasis Patients

Blood to skin recirculation of CD4+ memory T cells associates with cutaneous and systemic manifestations of psoriatic disease

Blood to skin recirculation could play a role in the pathogenesis of psoriasis. To investigate this possibility we dissected the phenotype of circulating T cells in psoriasis patients, calculated the correlation the clinical parameters of the disease and performed a parallel bioinformatics analysis of gene expression data in psoriatic skin.We found that circulating CCR6+ CD4+ TEM and TEFF cells significantly correlated with systemic inflammation. Conversely, the percentage of CXCR3+ CD4+ TEM cells negatively correlated with the severity of the cutaneous disease.Importantly CLA+ CD4+ TCM cells expressing CCR6+ or CCR4+CXCR3+ negatively correlated with psoriasis severity suggesting recruitment to the skin compartment. This assumption was reinforced by gene expression data showing marked increase of CCR7 and CLA-encoding gene SELPLG expression in psoriatic skin and strong association of their expression. The data enlightens a role for CD4+ T cells trafficking between blood and skin in cutaneous and systemic manifestations of psoriasis.

Decreased PD-1 positive blood follicular helper T cells in patients with psoriasis

Follicular helper T (Tfh) cells are recently characterized subset of helper T cells, which are initially found in the germinal centers of B cell follicles. The major role of Tfh cells is helping B cell activation and antibody production during humoral immunity. Recently, blood Tfh cells were shown to be associated with autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigoid and psoriasis. There is only one study which investigated Tfh cells in psoriasis patients. Therefore, in this study, we evaluated and analyzed blood Tfh cells in Korean patients with psoriasis. A total of 28 psoriasis patients and 16 healthy controls were enrolled. The frequency and absolute number of CXCR5(+)PD-1(+) Tfh cells were decreased in patients with psoriasis compared to healthy controls. CD4(+)CXCR5(+) T cells and CXCR5(+)ICOS(+) Tfh cells did not show differences. The frequency and absolute number of CXCR5(+)PD-1(+) Tfh cells in psoriasis patients negatively correlated with erythrocyte sedimentation rate and positively correlated with disease duration. The absolute number of CXCR5(+)ICOS(+) Tfh cells also showed positive correlation with disease duration. However, the subpopulations of Tfh cells did not correlate with Psoriasis Area and Severity Index. Serum interleukin-21 level was significantly increased in psoriasis patients compared to healthy controls, however, its level did not correlate with clinical and experimental parameters of psoriasis patients. These findings suggest the decreased function of Tfh cells in psoriasis, which could result in attenuated B cell immune responses in the pathogenesis of psoriasis. However, further investigations are necessary to confirm the function of Tfh cells in psoriasis vulgaris.

A role for CCR5+CD4 T cells in cutaneous psoriasis and for CD103+ CCR4+ CD8 Teff cells in the associated systemic inflammation

Recent results have identified critical components of the T cell response involved in the initiation and amplification phases of psoriasis. However the link between T cell responses arising in the skin and the systemic inflammation associated with severe psoriasis is largely unknown. We hypothesized that specific subsets of memory T cells recirculating from the skin could play a role. We therefore dissected the circulating memory T cell compartment in patients by analyzing the TCM, TEM and Teff phenotype, the pattern of CCR4 and CCR5 chemokine receptor expression and the expression of the tissue homing molecule CD103. For each subset we calculated the correlation with the Psoriasis Area and Severity Index (PASI) and with the extent of systemic inflammation measured as serum level of the prototypic short pentraxin, C reactive protein (CRP). Validation was performed by comparison with gene expression data in psoriatic plaques. We found that circulating CD103+CCR4+CCR5+ and CCR4+CCR6- CD8+ Teff cells, were highly correlated with CRP levels as well as with the validated index PASI, reflecting a link between skin involvement and systemic inflammation in patients with severe psoriasis. In addition we observed a contraction of circulating CCR5+ T cells in psoriasis patients, with a highly significant inverse correlation between CCR5+CD4 T cells and the PASI score. Increased expression of CCR5 and CCL5 genes in psoriatic skin lesions was consistent with an accumulation of CCR5+ cells in psoriatic plaques indicating a role for CCR5/CCL5 axis in disease pathogenesis.

Activated Circulating T Follicular Helper Cells Are Associated with Disease Severity in Patients with Psoriasis.

Circulating T follicular helper (cTfh) cells are known to be involved in numerous immune-mediated diseases, but their pathological role in psoriasis is less fully investigated. Herein, we aimed to identify whether cTfh cells contributed to the pathogenesis of psoriasis. The frequency and function of cTfh cells were compared between patients with psoriasis vulgaris and healthy controls, and the infiltration of Tfh cells was detected between lesional and nonlesional skin tissues of psoriasis patients. Moreover, the dynamic change of cTfh cells before and after acitretin treatment was evaluated. Our results showed both increased frequency and activation (indicated by higher expression of ICOS, PD-1, HLA-DR, and Ki-67 and increased production of IL-21, IL-17, and IFN-γ) of cTfh cells in psoriasis patients. Compared with nonlesional skin tissues of psoriasis patients, the number of infiltrated Tfh cells was significantly increased in psoriasis lesions. In addition, positive correlations between the percentage of cTfh, functional markers on cTfh cells in peripheral blood and disease severity were noted. Furthermore, the frequency of cTfh cells and the levels of cytokines secreted by cTfh cells were all significantly decreased after 1-month treatment.

Dynamic changes of circulating Th1 and Th17 cells in psoriasis patients:a report of 3 cases treated by Chinese herbal medicine

Dynamic changes of circulating Th1 and Th17 cells in psoriasis patients:a report of 3 cases treated by Chinese herbal medicine

Frequency and clonality of peripheral γδ T cells in psoriasis patients receiving anti-tumour necrosis factor-α therapy.

Hepatosplenic γδ T cell lymphoma (HSTCL) has been observed in patients with Crohn's disease (CD) who received anti-tumour necrosis factor (TNF)-α agents and thiopurines, but only one case was reported in a psoriasis patient worldwide. This difference could be due to differences in either the nature of the inflammatory diseases or in the use of immunomodulators. We investigated the impact of anti-TNF-α agents on the level and repertoire of γδ T cells in peripheral blood from psoriasis patients. Forty-five men and 10 women who were treated with anti-TNF-α agents for psoriasis were monitored for a median 11 months for the level and clonality of γδ T cells via flow cytometry and polymerase chain reaction (PCR) analysis of T cell receptor gamma (TCR-γ) gene rearrangements. Seventeen men had a repeated analysis within 48 h of the infliximab infusion to reveal a possible expansion of γδ T cells, as observed previously in CD patients. Ten psoriasis patients who were never exposed to biologicals and 20 healthy individuals served as controls. In the majority of psoriasis patients, the level and clonal pattern of γδ T cells was remarkably stable during infliximab treatment. A single male patient repeatedly experienced a significant increase in the level of γδ T cells after infliximab infusions. A monoclonal γδ T cell repertoire in a polyclonal background tended to be more frequent in anti-TNF-α-treated patients than naive patients, suggesting that anti-TNF-α therapy may promote the clonal selection of γδ T cells in psoriasis patients.

DNA methylation analysis of CD4+ T cells in patients with psoriasis

Psoriasis is a chronic inflammatory skin disease that is characterized by aberrant cross-talk between keratinocytes and immune cells such as CD4+ T cells, resulting in keratinocyte hyperproliferation in the epidermis. DNA methylation, one of several epigenetic mechanisms, plays an important role in gene expression without changing the DNA sequence. Several studies have suggested the involvement of epigenetic regulation in skin lesions from patients with psoriasis. In this study, we investigated the genome-wide DNA methylation status of CD4+ T cells in patients with psoriasis compared with healthy subjects using methylated DNA immunoprecipitation sequencing (MeDIP-Seq). The results of MeDIP-Seq showed that the global methylation values of CD4+ T cells are higher in patients with psoriasis than in healthy controls, particularly in the promoter regions. Among the most hypermethylated genes in the promoter regions, we selected the genes whose expression is significantly reduced in the CD4+ T cells of psoriasis patients. Studies using the methylation inhibitor 5-azacytidine in vitro methylation assays have shown that the differential expression levels were associated with the methylation status of each gene. Bisulfite sequencing of the transcription start region of phosphatidic acid phosphatase type 2 domain containing 3 (PPAPDC3), one of the selected genes, showed hypermethylation in the CD4+ T cells of psoriasis patients. These results suggested that the methylation status, which is identified by MeDIP-Seq of the genes, was correlated with the mRNA expression level of the genes. Collectively, the DNA methylation status in CD4+ T cells might be associated with the pathogenesis of psoriasis.

Reduction of CD18 Promotes Expansion of Inflammatory γδ T Cells Collaborating with CD4+ T Cells in Chronic Murine Psoriasiform Dermatitis

IL-17 is a critical factor in the pathogenesis of psoriasis and other inflammatory diseases. The impact of γδ T cells, accounting for an important source of IL-17 in acute murine IL-23- and imiquimod-induced skin inflammation, in human psoriasis is still unclear. Using the polygenic CD18(hypo) PL/J psoriasis mouse model spontaneously developing chronic psoriasiform dermatitis due to reduced CD18/β2 integrin expression to 2-16% of wild-type levels, we investigated in this study the influence of adhesion molecule expression on generation of inflammatory γδ T cells and analyzed the occurrence of IL-17-producing γδ and CD4(+) T cells at different disease stages. Severity of CD18(hypo) PL/J psoriasiform dermatitis correlated with a loss of skin-resident Vγ5(+) T cells and concurrent skin infiltration with IL-17(+), IL-22(+), and TNF-α(+) γδTCR(low) cells preceded by increases in Vγ4(+) T cells in local lymph nodes. In vitro, reduced CD18 levels promoted expansion of inflammatory memory-type γδ T cells in response to IL-7. Similar to IL-17 or IL-23/p19 depletion, injection of diseased CD18(hypo) PL/J mice with anti-γδTCR Abs significantly reduced skin inflammation and largely eliminated pathological γδ and CD4(+) T cells. Moreover, CD18(hypo) γδ T cells induced allogeneic CD4(+) T cell responses more potently than CD18(wt) counterparts and, upon adoptive transfer, triggered psoriasiform dermatitis in susceptible hosts. These results demonstrate a novel function of reduced CD18 levels in generation of pathological γδ T cells that was confirmed by detection of increases in CD18(low) γδ T cells in psoriasis patients and may also have implications for other inflammatory diseases.

IL-17A�producing CD8+ T cells in psoriasis: correlation with psoriasis severity and relationship with MAIT cell lineage

Event Abstract Back to Event IL-17A–producing CD8+ T cells in psoriasis: correlation with psoriasis severity and relationship with MAIT cell lineage Marcel B. Teunissen1*, Nataliya G. Yeremenko2, Dominique L. Baeten2, Saskia Chielie1, Phyllis I. Spuls1, Menno A. De Rie1 and Pieter C. Res1 1 Academic Medical Center, Dermatology, Netherlands 2 Academic medical Center, Clinical Immunology and Rheumatology, Netherlands Our observation that IL-17A–producing CD8+ T cells are overrepresented in psoriatic lesions is in line with the general consensus that T cells and IL-17A are critically involved in psoriasis. Here we provide further proof that CD8+ T cells are involved in the pathogenesis and analyzed T cells derived from peripheral blood and lesional dermis and epidermis by flow cytometry. The frequency of IL-17A–producing CD8+ T cells in blood correlated with psoriasis severity. Such correlation was not found for IL-22–producing CD8+ and CD4+ T cells. Of note, a remarkable higher frequency of skin-homing molecule CLA was found in IL-17A and/or IL-22 producing CD8+ blood T cells of psoriasis patients. However, this feature was also observed in healthy individuals. IL-17A–producing CD8+ T cells in blood have been described to belong to the mucosa-associated invariant T (MAIT) cell lineage, expressing the invariant T cell receptor Vα7.2-Jα33 chain, CD161 (high) and IL-18Rα. We unequivocally show the presence of MAIT cells in psoriatic as well as healthy skin. IL-17A–producing CD8+ MAIT cells were only present in psoriatic lesional skin, suggesting contribution to psoriasis development. IL-17A was also expressed by a considerable proportion of CD8+ T cells without MAIT cell characteristics, likely containing MHC class I-restricted psoriasis-associated autoreactive T cells. In conclusion, we provide supporting evidence that implicates conventional CD8+ T cells in the pathogenesis of psoriasis and describe the presence of innate MAIT cells in psoriatic lesions as an additional source of IL-17, a feature that was not appreciated before. Keywords: Psoriasis, IL-17A, MAIT cell, CD8+ T cell, T cell receptor Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Teunissen MB, Yeremenko NG, Baeten DL, Chielie S, Spuls PI, De Rie MA and Res PC (2013). IL-17A–producing CD8+ T cells in psoriasis: correlation with psoriasis severity and relationship with MAIT cell lineage. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00786 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 18 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Marcel B Teunissen, Academic Medical Center, Dermatology, Amsterdam, 1105 AZ, Netherlands, m.b.teunissen@amsterdamumc.nl Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Marcel B Teunissen Nataliya G Yeremenko Dominique L Baeten Saskia Chielie Phyllis I Spuls Menno A De Rie Pieter C Res Google Marcel B Teunissen Nataliya G Yeremenko Dominique L Baeten Saskia Chielie Phyllis I Spuls Menno A De Rie Pieter C Res Google Scholar Marcel B Teunissen Nataliya G Yeremenko Dominique L Baeten Saskia Chielie Phyllis I Spuls Menno A De Rie Pieter C Res PubMed Marcel B Teunissen Nataliya G Yeremenko Dominique L Baeten Saskia Chielie Phyllis I Spuls Menno A De Rie Pieter C Res Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Ustekinumab Improves Psoriasis without Altering T Cell Cytokine Production, Differentiation, and T Cell Receptor Repertoire Diversity

Ustekinumab is a fully human IgG1κ monoclonal antibody targeting interleukin (IL)-12/23 p40 subunit. The role of IL-12/23-mediated pathway in the mechanism of various inflammatory disorders especially psoriasis has been well recognized. Recently the long-term efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis has been evaluated in phase 2/3 clinical trials, and the results showed no significant risk for serious adverse effects, infections, or malignancies. Ustekinumab inhibits the function of the IL-12/23 p40 subunit, and therefore it is believed that inhibition of IL-12 p40 pathway decreases IFN-γ production. The major concern for the use of ustekinumab is the possibility of increased immunosuppression due to low IFN-γ production. However, the effects of ustekinumab on CD4+ T cell function have not been fully investigated so far. In this study, we explored changes in cytokine production by memory CD4+ T cells as well as in the differentiation of naïve T cells to helper T cell (Th) 1, Th2, or Th17 cells in psoriasis patients treated with ustekinumab. The effect of the treatment on T cell receptor repertoire diversity was also evaluated. The results showed that ustekinumab improves clinical manifestation in patients with psoriasis without affecting cytokine production in memory T cells, T cell maturation, or T cell receptor repertoire diversity. Although the number of patients is limited, the present study suggests that T cell immune response remains unaffected in psoriasis patients treated with ustekinumab.

Identification of a Novel Proinflammatory Human Skin-Homing Vγ9Vδ2 T Cell Subset with a Potential Role in Psoriasis

γδ T cells mediate rapid tissue responses in murine skin and participate in cutaneous immune regulation including protection against cancer. The role of human γδ cells in cutaneous homeostasis and pathology is characterized poorly. In this study, we show in vivo evidence that human blood contains a distinct subset of proinflammatory cutaneous lymphocyte Ag and CCR6-positive Vγ9Vδ2 T cells, which is rapidly recruited into perturbed human skin. Vγ9Vδ2 T cells produced an array of proinflammatory mediators including IL-17A and activated keratinocytes in a TNF-α- and IFN-γ-dependent manner. Examination of the common inflammatory skin disease psoriasis revealed a striking reduction of circulating Vγ9Vδ2 T cells in psoriasis patients compared with healthy controls and atopic dermatitis patients. Decreased numbers of circulating Vγ9Vδ2 T cells normalized after successful treatment with psoriasis-targeted therapy. Taken together with the increased presence of Vγ9Vδ2 T cells in psoriatic skin, these data indicate redistribution of Vγ9Vδ2 T cells from the blood to the skin compartment in psoriasis. In summary, we report a novel human proinflammatory γδ T cell involved in skin immune surveillance with immediate response characteristics and with potential clinical relevance in inflammatory skin disease.