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Homeostatic chemokines mediate T cell migration to and through the skin. T cells (blue) that express CCR8 and/or CCR4 follow their respective ligand gradients, CCL1 (green dots), and/or CCL17/CCL22 (yellow dots) to enter the dermis, respectively. Epidermal positioning is mediated by CCL1/CCL8/CCL18 (green dots), which all bind to CCR8 on T cells. This second step of migration can also be mediated by CCL27 (pink) and its receptor CCR10. CCL20 (purple dots) is produced predominantly near the hair follicles, and serves to recruit and retain CCR6+ Tregs. T cells expressing CCR7 and CD62L follow CCL19/21 (turquoise) to exit the skin and enter the lymph node via afferent lymphatics. S1P1 mediates egress from the lymph node to the blood via an S1P gradient (red)
Source publication
Autoimmune skin diseases are complex processes in which autoreactive cells must navigate through the skin tissue to find their targets. Regulatory T cells in the skin help to mitigate autoimmune inflammation and may in fact be responsible for the patchy nature of these conditions. In this review, we will discuss chemokines that are important for gl...
Citations
... Importantly, our bioinformatic data implies a protumoral microenvironment in patients with pronounced PCDI. Previous studies revealed that chemokines such as CCL2, CCL4, CCL5, CLCX1, CLCX8 and CLCX10 are important for global recruitment of immune cells [28]. In our study, ELISA and qPCR results further illuminated that the knockdown of PRKDC augmented the concentration and expression of cytokines, encompassing CCL2, CCL4, CCL5, CLCX1, CLCX8, and CLCX10, in the cell microenvironment ( Figure 9C, 9D), lending weight to our bioinformatic findings. ...
Background:
Liver hepatocellular carcinoma (LIHC) ranks among the malignancies with the highest mortality rates, primarily due to chemoresistance culminating in treatment failure. Despite its impact, predictive models addressing disease progression, tumor microenvironment, and drug sensitivity remain elusive for LIHC patients. Recognizing the significant influence of various programmed cell death (PCD) modes on tumor evolution, this study investigates PCD genes to elucidate their implications on the prognosis and immune landscape of LIHC.
Methods:
To develop the classification and model, we employed a total of 17 genes associated with PCD patterns. To collect data, we acquired gene expression profiles, somatic mutation information, copy number variation data, and corresponding clinical data from the TCGA database, specifically from LIHC patients. Moreover, we obtained spatial transcriptome data and additional bulk datasets from the Gene Expression Omnibus (GEO) database to conduct further analysis. Various experiments were conducted to validate the role of the PCD gene PRKDC in proliferation, migration, invasion, EMT, cell cycle, therapeutic sensitivity, and antitumor immunity.
Results:
A novel LIHC classification based on these genes divided patients into two clusters, C1 and C2. The C2 cluster exhibited characteristics indicative of poor prognosis and an immune-activated microenvironment. This group showed greater response potential to immune checkpoint inhibitors, displaying higher levels of certain immune signatures and receptors. A programmed cell death index (PCDI) was constructed using 17 selected PCD genes. This index could effectively predict patient prognosis, with higher PCDI indicating poorer survival rates and a more pro-tumor microenvironment. Immune landscapes revealed varying interactions with PCDI, suggesting therapeutic targets and insights into treatment resistance. Moreover, experiments results suggested that PRKDC can augment the invasive nature and growth of malignant cells and it can serve as a potential target for therapy, offering hope for ameliorating the prognosis of LIHC patients.
Conclusions:
The study uncovers the insights of programmed cell death in the prognosis and potential therapeutic interventions. And we found that PRKDC can serve as a target for enhancing the efficacy of antitumor immunity while sensitizing chemotherapy and targeted therapy in liver hepatocellular carcinoma.
... The CCL6-CCR6 interaction regulates the migration of macrophages, neutrophils, astrocytes, and microglia in various inflammatory disorders 35 . Similar to CCL27, the IL-16-CD4 axis is related to increased sensitization, resulting in skin inflammation, and is involved in CD4+ T cell expansion 36 . ...
The importance of neuroinflammation during the ischemic stroke has been extensively studied. The role of CD4+CD25+ regulatory T (Treg) cells during the recovery phase have shown infarct size reduction and functional improvement, possibly through the mitigation of inflammatory immune responses. We aimed to investigate the molecular factors involved in microglia-Treg cell communication that result in Treg trafficking. First, we observed the migration patterns of CD8+ (cytotoxic) T cells and Treg cells and then searched for chemokines released by activated microglia in an oxygen–glucose deprivation (OGD) model. The transwell migration assay showed increased migration into OGD media for both cell types, in agreement with the increase in chemokines involved in immune cell trafficking from the mouse chemokine profiling array. MSCV retrovirus was transduced to overexpress CCR4 in Treg cells. CCR4-overexpressed Treg cells were injected into the mouse transient middle cerebral artery occlusion (tMCAO) model to evaluate the therapeutic potential via the tetrazolium chloride (TTC) assay and behavioral tests. A general improvement in the prognosis of animals after tMCAO was observed. Our results suggest the increased mobility of CCR4-overexpressed Treg cells in response to microglia-derived chemokines in vitro and the therapeutic potential of Treg cells with increased mobility in cellular therapy.
... The secretion of multiple cytokines by these T cells can result in melanocyte destruction, either through direct mechanisms or by activating autoreactive T cells in vitiligo [8][9][10]. Furthermore, chemo-attractant cytokines play a pivotal role in recruiting leukocytes to inflammatory sites, amplifying the inflammatory reaction, and inducing melanocyte death [11]. Serum cytokine levels can be mea- ...
... The current literature strongly supported the pivotal role of Th1 cytokines in the pathogenesis of vitiligo [11]. In this study, a significant increase in the levels of signature cytokines IFN-γ and IL-2 secreted by Th1 cells was observed among patients with active vitiligo. ...
... In this study, a significant increase in the levels of signature cytokines IFN-γ and IL-2 secreted by Th1 cells was observed among patients with active vitiligo. IFN-γ plays a pivotal role as a cytokine in the pathogenesis of vitiligo, exerting direct cytotoxic effects on melanocytes or driving CD8 + T cells to attack them, ultimately resulting in melanocyte destruction and subsequent skin depigmentation [11]. Previous investigations have indicated a significant elevation in the proportion of circulating skin-homing cells that produce IFN-γ among patients with vitiligo [5]. ...
Introduction
Vitiligo is an immune-related skin disease. Cytokines regulate immune response and inflammation and are involved in the pathogenesis of vitiligo.
Aim
To assess the serum levels of pro-inflammatory cytokines pre- and post- systemic glucocorticoid treatment in patients with active vitiligo.
Material and methods
We measured serum cytokine levels using the enzyme-linked immunosorbent assay in 31 patients with active vitiligo before and after treatment. All patients received systemic glucocorticoid (compound betamethasone injection) in combination with topical halometasone cream and tacrolimus ointment for 3 months. Twenty healthy controls were also examined. The cytokines measured included TNF-α, IL-1β, IL-6, IFN-γ, IL-2, IL-17, IL-10, IL-8, and CXCL10.
Results
The serum levels of TNF-α, IL-1β, IL-6, IFN-γ, IL-2, IL-17, IL-8, and CXCL10 were significantly higher, and levels of IL-10 were lower in vitiligo patients compared to controls. Additionally, serum IFN-γ (r = 0.378; p = 0.036), IL-17 (r = 0.426; p = 0.017), and CXCL10 (r = 0.514; p = 0.003) showed a positive correlation with affected body surface area in vitiligo patients. After 3 months of systemic glucocorticoid treatment, the levels of IL-1β, IFN-γ, IL-2, IL-17, and CXCL10 in responders were significantly decreased and nearly restored to normal levels. The IL-10 level was also increased in response to treatment. In contrast, the non-responder group had persistently high IL-6, IL-17, IL-8, and CXCL10 levels, and negligible changes in TNF-α, IL-1β, IFN-γ, IL-2, and IL-10.
Conclusions
Our study indicated that the levels of inflammatory cytokines were significantly ameliorated in the glucocorticoid responder group. Altered cell-mediated immunity may contribute to the resistance in vitiligo. The cytokines such as TNF-α, IL-1β, IFN-γ and IL-2 could serve as therapeutic targets for managing glucocorticoid-resistant vitiligo.
... This infiltration in and around the HF has been coined a "swarm of bees" and primarily consists of T cells but also NK cells, eosinophils, plasmacytoid dendritic cells (pDCs), mast cells, and macrophages (51,52). Because immune cells transit into skin via the vascular system, there may be a role for S1P and C-X-C motif chemokine receptor 3A (CXCR3A) signaling in mediating the cellular infiltrate (53)(54)(55). The persistence of CD8 + T cells around the lower anagen HF may contribute to prolonged hair loss in chronic and/or severe AA by promoting the HF to enter the telogen phase and preventing the empty or "kenogen" HF from reentering the anagen phase (52); further, the presence of CD8 + T cells may indicate that specific chemokines drive AA pathogenesis. ...
Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8⁺ T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration–approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell–mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell–signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell–signaling pathways is also provided in this review.
... These chemotactic cytokines are shown to play a very important role in mice with vitiligo. Whereas CXCL9 plays the role of a "recruit" signal, especially in the dermis, CXCL10 acts as a tethering signal that increases T cell activity and controls their movement [9]. This process enables immune cell homing and leukocyte transendothelial migration toward endothelium adhesion molecules of peripheral inflammatory cells [10]. ...
Citation: Kassab, A.; Khalij, Y.; Ayed, Y.; Dar-Odeh, N.; Kokandi, A.A.; Denguezli, M.; Youssef, M. Serum Inflammatory and Oxidative Stress Markers in Patients with Vitiligo. J. Clin. Med. 2023, 12, 5861. https://
... Vitiligo, an autoimmune skin disease affecting 0.5% to 2% of the global population, is characterized by the progressive destruction of melanocytes by autoreactive CD8 + T cells [1][2][3][4][5][6][7][8][9][10][11]. ...
Punch grafting procedures, where small pieces of normal skin are transplanted into stable vitiligo patches, results in repigmentation in only half of patients treated, yet the factors that determine whether a patient responds to treatment or not are still unknown. Reflectance confocal microscopy (RCM) is adept at visualizing melanocyte migration and epidermal changes over large areas while multiphoton microscopy (MPM) can capture metabolic changes in keratinocytes. With the overall goal of identifying optical biomarkers for early treatment response, we followed 12 vitiligo lesions undergoing punch grafting. Dendritic melanocytes adjacent to the graft site were observed before clinical evidence of repigmentation in treatment responsive patients but not in treatment non-responsive patients, suggesting that the early visualization of melanocytes is indicative of a therapeutic response. Keratinocyte metabolic changes in vitiligo skin adjacent to the graft site also correlated with treatment response, indicating that a keratinocyte microenvironment that more closely resembles normal skin is more hospitable for migrating melanocytes. Taken together, these studies suggest that successful melanocyte transplantation requires both the introduction of new melanocytes and modulation of the local tissue microenvironment.
... The activation and fine-tuning migration of autoreactive CD8 + T cells to melanocytes are necessary and sufficient for the progression, exacerbation, and relapse of vitiligo [49]. JAKs are essential enzymes in this process by mediating type I/II cytokines signaling such as IL-2, IL-15, IFN-γ, etc. [50]. ...
Background
The activation of CD8⁺ T cells and their trafficking to the skin through JAK-STAT signaling play a central role in the development of vitiligo. Thus, targeting this key disease pathway with innovative drugs is an effective strategy for treating vitiligo. Natural products isolated from medicinal herbs are a useful source of novel therapeutics. Demethylzeylasteral (T-96), extracted from Tripterygium wilfordii Hook F, possesses immunosuppressive and anti-inflammatory properties.
Methods
The efficacy of T-96 was tested in our mouse model of vitiligo, and the numbers of CD8⁺ T cells infiltration and melanocytes remaining in the epidermis were quantified using whole-mount tail staining. Immune regulation of T-96 in CD8⁺ T cells was evaluated using flow cytometry. Pull-down assay, mass spectrum analysis, molecular docking, knockdown and overexpression approaches were utilized to identify the target proteins of T-96 in CD8⁺ T cells and keratinocytes.
Results
Here, we found that T-96 reduced CD8⁺ T cell infiltration in the epidermis using whole-mount tail staining and alleviated the extent of depigmentation to a comparable degree of tofacitinib (Tofa) in our vitiligo mouse model. In vitro, T-96 decreased the proliferation, CD69 membrane expression, and IFN-γ, granzyme B, (GzmB), and perforin (PRF) levels in CD8⁺ T cells isolated from patients with vitiligo. Pull-down assays combined with mass spectrum analysis and molecular docking showed that T-96 interacted with JAK3 in CD8⁺ T cell lysates. Furthermore, T-96 reduced JAK3 and STAT5 phosphorylation following IL-2 treatment. T-96 could not further reduce IFN-γ, GzmB and PRF expression following JAK3 knockdown or inhibit increased immune effectors expression upon JAK3 overexpression. Additionally, T-96 interacted with JAK2 in IFN-γ-stimulated keratinocytes, inhibiting the activation of JAK2, decreasing the total and phosphorylated protein levels of STAT1, and reducing the production and secretion of CXCL9 and CXCL10. T-96 did not significantly inhibit STAT1 and CXCL9/10 expression following JAK2 knockdown, nor did it suppress upregulated STAT1-CXCL9/10 signaling upon JAK2 overexpression. Finally, T-96 reduced the membrane expression of CXCR3, and the culture supernatants pretreated with T-96 under IFN-γ stressed keratinocytes markedly blocked the migration of CXCR3⁺CD8⁺ T cells, similarly to Tofa in vitro.
Conclusion
Our findings demonstrated that T-96 might have positive therapeutic responses to vitiligo by pharmacologically inhibiting the effector functions and skin trafficking of CD8⁺ T cells through JAK-STAT signaling.
... Correlation analysis between TANK expression and infiltration of protumor immune cells in the TCGA cohort revealed that gliomas with high TANK expression contained more immunosuppressive cells, except for CD56dim NK cells (P < 0.05, Figure 4B In the high-TANK group, most MHC molecules were overexpressed, indicating an enhanced ability to present and process antigens. In addition, the levels of CXCL9, CXCL10, and CCR3, which increase the recruitment of CD8+ T cells into the microenvironment of glioma, were increased in gliomas with high TANK expression (46,47). Chemokines and paired receptors, including CCL2 and CCR2, were upregulated in TANKexpressing gliomas ( Figure 4F). ...
Background
Glioma, the most prevalent malignant intracranial tumor, poses a significant threat to patients due to its high morbidity and mortality rates, but its prognostic indicators remain inaccurate. Although TRAF-associated NF-kB activator (TANK) interacts and cross-regulates with cytokines and microenvironmental immune cells, it is unclear whether TANK plays a role in the immunologically heterogeneous gliomas.
Methods
TANK mRNA expression patterns in public databases were analyzed, and qPCR and IHC were performed in an in-house cohort to confirm the clinical significance of TANK. Then, we systematically evaluated the relationship between TANK expression and immune characteristics in the glioma microenvironment. Additionally, we evaluated the ability of TANK to predict treatment response in glioma. TANK-associated risk scores were developed by LASSO-Cox regression and machine learning, and their prognostic ability was tested.
Results
TANK was specifically overexpressed in glioma and enriched in the malignant phenotype, and its overexpression was related to poor prognosis. The presence of a tumor microenvironment that is immunosuppressive was evident by the negative correlations between TANK expression and immunomodulators, steps in the cancer immunity cycle, and immune checkpoints. Notably, treatment for cancer may be more effective when immunotherapy is combined with anti-TANK therapy. Prognosis could be accurately predicted by the TANK-related risk score.
Conclusions
High expression of TANK is associated with the malignant phenotype of glioma, as it shapes an immunosuppressive tumor microenvironment. Additionally, TANK can be used as a predictive biomarker for responses to various treatments and prognosis.
... In our patient having underlying psoriasis with a decrease in the regulatory T-cells, when cytokine imbalance occurs toward Th1 pathway after secukinumab administration, IFN-γ secreted by CD8+ resident memory T cells may play an important role in the pathogenesis of vitiligo 9,10 as can be seen from our immunohistochemical results. Also, CXCL9 and CXCL10 can facilitate CD8+ T cells-IFN-γinduced destruction of melanocytes, especially in active vitiligo rather than in stable vitiligo 11 . In the other viewpoint that TNF-α and IL-17 contribute to the reduction of melanogenesis in psoriasis lesions 12 , our case in which secukinumab treatment made the demarcation of vitiligo clear may be related to this mechanism. ...
Vitiligo has been considered an unexplained paradoxical phenomenon during biologics use. Herein, we report an adult case of progression of pre-existing vitiligo during secukinumab treatment for psoriasis, and we also examined the immunohistochemical changes in relation to biologics use. He was being administered monthly secukinumab of 300 mg dose for 2 years, and all psoriatic lesions were cleared, but pre-existing hypopigmented lesions became more distinct and larger than before unlike when using adalimumab. A skin biopsy of the hypopigmented lesion showed loss of epidermal melanocytes and absence of gp100 immune activities, and he was finally diagnosed with progression of pre-existing vitiligo. Immunohistochemical staining of vitiligo lesion showed decrease in interleukin-17 and tumor necrosis factor-α and increase in CD8+ T cells, interferon-γ, and CXCL10 after the use of secukinumab. In this study, we suggest that biologics-induced cytokine imbalance play a critical role in vitiligo progression in patients with chronic inflammatory diseases, including psoriasis.
... The progression of vitiligo is driven by IFN-γ-producing autoreactive CD8 T cells which leads to the Th1-specific destruction of melanocytes. The IFN-γ-chemokine signalling axis is responsible for autoreactive CD8 T cell recruitment and localisation as well as their effector function in the inflamed site through a positive feedback loop [181]. The role of MCs in vitiligo pathogenesis might be both positive and negative [182]. ...
The skin is exposed to environmental challenges and contains skin-resident immune cells, including mast cells (MCs) and CD8 T cells that act as sentinels for pathogens and environmental antigens. Human skin MCs and their mediators participate in the maintenance of tissue homeostasis and regulate the recruitment and activity of immune cells involved in the pathogenesis of skin diseases. The cutaneous CD8 T cell compartment is comprised of long-persisting resident memory T cells (TRM) and migratory or recirculating cells; both populations provide durable site immune surveillance. Several lines of evidence indicate that MC-derived products, such as CCL5 and TNF-α, modulate the migration and function of CD8 T cells. Conversely, activated CD8 T cells induce the upregulation of MC costimulatory molecules. Moreover, the close apposition of MCs and CD8 T cells has been recently identified in the skin of several dermatoses, such as alopecia areata. This review outlines the current knowledge about bidirectional interactions between human MCs and CD8 T cells, analyses the alteration of their communication in the context of three common skin disorders in which these cells have been found altered in number or function—psoriasis, atopic dermatitis, and vitiligo—and discusses the current unanswered questions.
