Treg Cells Research Articles

Decoding Behcet's Uveitis: an In-depth review of pathogenesis and therapeutic advances.

Behcet's disease (BD) is a rare but globally distributed vasculitis that primarily affects populations in the Mediterranean and Asian regions. Behcet's uveitis (BU) is a common manifestation of BD, occurring in over two-thirds of the patients. BU is characterized by bilateral, chronic, recurrent, non-granulomatous uveitis in association with complications such as retinal ischemia and atrophy, optic atrophy, macular ischemia, macular edema, and further neovascular complications (vitreous hemorrhage, neovascular glaucoma). Although the etiology and pathogenesis of BU remain unclear, numerous studies reveal that genetic factors (such as HLA-B51), dysregulated immune responses of both the innate and adaptive immune systems, infections (such as streptococcus), and environmental factors (such as GDP) are all involved in its development. Innate immunity, including hyperactivity of neutrophils and γδT cells and elevated NK1/NK2 ratios, has been shown to play an essential role in this disease. Adaptive immune system disturbance, including homeostatic perturbations, Th1, Th17 overaction, and Treg cell dysfunction, is thought to be involved in BU pathogenesis. Treatment of BU requires a tailored approach based on the location, severity of inflammation, and systemic manifestations. The therapy aims to achieve rapid inflammation suppression, preservation of vision, and prevention of recurrence. Systemic corticosteroids combined with other immunosuppressive agents have been widely used to treat BU, and beneficial effects are observed in most patients. Recently, biologics have been shown to be effective in treating refractory BU cases. Novel therapeutic targets for treating BU include the LCK gene, Th17/Treg balance, JAK pathway inhibition, and cytokines such as IL-17 and RORγt. This article summarizes the recent studies on BU, especially in terms of pathogenesis, diagnostic criteria and classification, auxiliary examination, and treatment options. A better understanding of the significance of microbiome composition, genetic basis, and persistent immune mechanisms, as well as advancements in identifying new biomarkers and implementing objective quantitative detection of BU, may greatly contribute to improving the adequate management of BU patients.

Conversion of dendritic cells into tolerogenic or inflammatory cells depends on the activation threshold and kinetics of the mTOR signaling pathway

BackgroundRestoring impaired peripheral immune tolerance is the primary challenge in treating autoimmune diseases. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs), a fraction of low molecular weight proteins, in inhibiting the progression of psoriatic arthritis, even in the presence of high levels of the proinflammatory cytokine TNFα in the bloodstream. When specifically targeting dendritic cells (DCs), SSPs transform them into tolerogenic cells, which efficiently induce the development of regulatory Foxp3+ Treg cells. In this study, we provide further insights into the mechanism of action of SSPs.ResultsWe found that SSPs stimulate the activation of the mTOR signaling pathway in dendritic cells, albeit in a different manner than the classical immunogenic stimulus LPS. While LPS-induced activation is rapid, strong, and sustained, the activity induced by SSPs is delayed, less intense, yet still significant. These distinct patterns of activation, as measured by phosphorylation of key components of the pathway are also observed in response to other immunogenic and tolerogenic stimuli such as GM-CSF + IL-4 or IL-10 and TGFβ. The disparity in mTOR activation between immunogenic and tolerogenic stimuli is quantitative rather than qualitative. In both cases, mTOR activation primarily occurs through the PI3K/Akt signaling axis and involves ERK and GSK3β kinases, with minimal involvement of AMPK or NF-kB pathways. Furthermore, in the case of SSPs, mTOR activation seems to involve adenosine receptors. Additionally, we observed that DCs treated with SSPs exhibit an energy metabolism with high plasticity, which is typical of tolerogenic cells rather than immunogenic cells.ConclusionHence, the decision whether dendritic cells enter an inflammatory or tolerogenic state seems to rely on varying activation thresholds and kinetics of the mTOR signaling pathway.

Current research insights into the role of CTLA-4 in hepatitis B virus (HBV) infection.

Chronic hepatitis B virus (HBV) infection is a significant global public health concern, and the clearance of HBV is closely linked to the activity of HBV-specific T cells, which is regulated by various co-suppressor molecules. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is among these co-suppressor molecules which induces T cell exhaustion by competitively inhibiting CD28 and dampening the function of HBV-specific T cells. CTLA-4 also plays a role in the regulation of T helper (Th) cell differentiation and influences cytokine release. In addition, CTLA-4 can impact glucose metabolism in hepatocellular carcinoma through its interaction with T regulatory (Treg) cells. This review aims to provide a comprehensive overview of the existing literature related to the role of CTLA-4 in HBV patients across different subsets of T cells. Additionally, we propose a discussion on the possible mechanisms through which CTLA-4 may contribute to HBV infection, as well as the development of HBV-induced cirrhosis and hepatocellular carcinoma.

Bioengineered Artificial Extracellular Vesicles Presenting PD-L1 and Gal-9 Ameliorate New-Onset Type 1 Diabetes.

An important factor in the development of Type 1 diabetes (T1D) is the deficiency of inhibitory immune checkpoint ligands, specifically programmed cell death ligand 1 (PD-L1) and Galectin-9 (Gal-9), in β-cells. Hence, modulation of the pancreas infiltrated T lymphocytes by exogenous PD-L1 or Gal-9 is an ideal approach for treating the new-onset T1D. Herein, we genetic engineered the macrophage cells to generate artificial extracellular vesicles (aEVs) overexpressing PD-L1 and Gal-9, which could restrict the islets autoreactive T lymphocytes and protect β-cells from destruction. Intriguingly, overexpressing Gal-9 spurred macrophage polarization to M2 phenotype with immune suppressive attribute. Alternatively, both of PD-L1 and Gal-9 presenting aEVs (PD-L1-Gal-9 aEVs) favorably adhere to T cells via the interaction of programmed cell death protein 1 (PD-1)/PD-L1 or T cell immunoglobulin mucin 3 (TIM-3)/Gal-9. Moreover, PD-L1-Gal-9 aEVs prominently promoted effector T cell apoptosis and splenic regulatory T cells (Treg) cells differentiation in vitro. Virtually, PD-L1-Gal-9 aEVs efficaciously reversed the new-onset hyperglycemia in the NOD mice, prevented T1D progress, and declined the proportion and activation of CD4+ and CD8+ T cells infiltrating the pancreas notably, which together contributed to preserving the residual β-cells survival and mitigating the hyperglycemia.

Prediction of prognosis and immunotherapy efficacy based on metabolic landscape in lung adenocarcinoma by bulk, single-cell RNA sequencing and Mendelian randomization analyses.

Immunotherapy has been a remarkable clinical advancement in cancer treatment, but only a few patients benefit from it. Metabolic reprogramming is tightly associated with immunotherapy efficacy and clinical outcomes. However, comprehensively analyzing their relationship is still lacking in lung adenocarcinoma (LUAD). Herein, we evaluated 84 metabolic pathways in TCGA-LUAD by ssGSEA. A matrix of metabolic pathway pairs was generated and a metabolic pathway-pair score (MPPS) model was established by univariable, LASSO, multivariable Cox regression analyses. The differences of metabolic reprogramming, tumor microenvironment (TME), tumor mutation burden and drug sensitivity in different MPPS groups were further explored. WGCNA and 117 machine learning algorithms were performed to identify MPPS-related genes. Single-cell RNA sequencing and in vitro experiments were used to explore the role of C1QTNF6 on TME. The results showed MPPS model accurately predicted prognosis and immunotherapy efficacy of LUAD patients regardless of sequencing platforms. High-MPPS group had worse prognosis, immunotherapy efficacy and lower immune cells infiltration, immune-related genes expression and cancer-immunity cycle scores than low-MPPS group. Seven MPPS-related genes were identified, of which C1QTNF6 was mainly expressed in fibroblasts. High C1QTNF6 expression in fibroblasts was associated with more infiltration of M2 macrophage, Treg cells and less infiltration of NK cells, memory CD8+ T cells. In vitro experiments validated silencing C1QTNF6 in fibroblasts could inhibit M2 macrophage polarization and migration. The study depicted the metabolic landscape of LUAD and constructed a MPPS model to accurately predict prognosis and immunotherapy efficacy. C1QTNF6 was a promising target to regulate M2 macrophage polarization and migration.

Differential expressions of endoplasmic reticulum stress-associated genes in aortic dissection and their correlation with immune cell infiltration

To explore differentially expressed endoplasmic reticulum stress-associated genes (ERSAGs) in aortic dissection (AD) and their correlations with immune cell infiltration to identify new therapeutic targets for AD. Two AD mRNA expression datasets (GSE190635 and GSE98770) were downloaded from GEO database for analysis of differentially expressed genes between the aorta of AD patients and normal aorta using R software. ERSAGs dataset was downloaded from GeneCards website, and GeneMANIA database was used to analyze the protein-protein interaction network of the differentially expressed ERSAGs and the proteins interacting with these genes. Based on GSE98770 dataset we analyzed the distributions of 22 immune cells within the aortic wall of AD patients using CIBERSORT package of R software. Surgical aortic wall specimens were obtained from 10 AD patients and 10 non-AD patients for detecting AGER mRNA expression using qRTPCR, and the upstream transcriptional factors, miRNAs, and chemicals targeting AGER were analyzed using the TRRUST database and NetworkAnalyst database. Bioinformatic analysis suggested significant differential expression of AGER in AD, which interacted with 20 proteins involved in pattern recognition receptor signaling pathway, positive regulation of DNA-binding transcription factor activity, myeloid leukocyte migration, leukocyte migration, and regulation of the I-κB kinase/NF-κB signaling. In AD, AGER expression level was positively correlated with Treg cell abundance (r=0.59, P < 0.05). The results of qRT-PCR demonstrated significantly lower expression of AGER mRNA in AD than in non-AD patients (1.00±0.30 vs 1.76±0.68, P < 0.05). ROC curve analysis showed that at the cut-off value of 1.335, AGER had an AUC of 0.86 (95% CI: 0.67-1.00, P= 0.0073) for predicting AD. Three transcriptional factors, 3 miRNAs, and 27 chemicals were predicted in the AGER regulatory network. AGER is lowly expressed in the aorta of AD patients and may influence the occurrence of AD through Treg cells.

Identification and Functional Analysis of a de novo IKZF3 Mutation in a Pediatric Patient with Combined Immunodeficiency.

AIOLOS, a vital member of the IKAROS protein family, plays a significant role in lymphocyte development and function through DNA binding and protein-protein interactions. Mutations in the IKZF3 gene, which encodes AIOLOS, lead to a rare combined immunodeficiency often linked with infections and malignancy. In this study, we evaluated a 1-year-4-month-old female patient presenting with recurrent infections, diarrhea, and failure to thrive. Laboratory investigations revealed decreased T lymphocyte and immunoglobulin levels. Through whole-exome and Sanger sequencing, we discovered a de novo mutation in IKZF3 (NM_012481; exon 5 c.571G > C, p.Gly191Arg), corresponding to the third DNA-binding zinc finger region of the encoded protein AIOLOS. Notably, the patient with the AIOLOS G191R mutation showed reduced recent thymic emigrants in naïve CD4+T cells compared to healthy counterparts of the same age, while maintaining normal levels of Th1, Th2, Th17, Treg, and Tfh cells. This mutation also resulted in decreased switched memory B cells and lower CD23 and IgM expression. In vitro studies revealed that AIOLOS G191R does not impact the expression of AIOLOS but compromises its stability, DNA binding and pericentromeric targeting. Furthermore, AIOLOS G191R demonstrated a dominant-negative effect over the wild-type protein. This case represents the first reported instance of a mutation in the third DNA-binding zinc finger region of AIOLOS highlighting its pivotal role in immune cell functionality.

Triptolide promotes differentiation of human monocytes into immunosuppressive MDSCs

BackgroundMyeloid-derived suppressor cells (MDSCs) negatively modulate immune activity. Prior investigations have shown much promise in using MDSCs-assisted immunotherapy for organ transplantation patients. Additionally, owing to its immunosuppressive activity, MDSCs can also be used to manage immune-associated disorders. MethodsGranulocyte-macrophage colony-stimulating factor (GM-CSF) was employed to stimulate myeloid progenitor cell differentiation. Triptolide (PG490) was introduced toward the later phases of in vitro MDSCs induction. Lastly, real-time PCR (RT-PCR) and flow cytometry were used to assess transcript expression and cell phenotype, and a mouse skin transplantation model was established to evaluate the MDSCs-mediated immune suppression in vivo. ResultsCo-stimulation with PG490 and GM-CSF potently induced myeloid-derived monocytes to form MDSCs, with remarkable immune-suppressive activity. The underlying mechanism involved downregulation of T cell proliferation, activation, enhancement of inflammatory cytokine release, as well as T cell conversion to Treg cells. PG490 strongly enhanced iNOS expression in MDSCs, and iNOS inhibition successfully reversed the immune-suppression. The PG490- and GM-CSF-induced MDSCs substantially extended survival duration of murine skin grafts, thereby validating their strong immune-suppressive activity in vivo. ConclusionsHerein, we presented a new approach involving MDSCs-based immunosuppression in vitro. PG490 and GM-CSF co-treatment strongly induced immuno-suppressive activity in MDSCs both in vitro and in vivo. Our findings highlight the promise of applying MDSCs-based therapy in clinical organ transplantation treatment.

The combination of Butyricicoccus pullicaecorum and 3-hydroxyanthranilic acid prevents postmenopausal osteoporosis by modulating gut microbiota and Th17/Treg

BackgroundPostmenopausal osteoporosis (PMO) is a chronic condition characterized by decreased bone strength. This study aims to investigate the effects and mechanisms of the combination of Butyricicoccus pullicaecorum (Bp) and 3-hydroxyanthranilic acid (3-HAA) on PMO.MethodsThe effects of Bp and 3-HAA on PMO were evaluated in ovariectomized (OVX) rats by assessing stereological parameters, femur microstructure, and autophagy levels. The T helper (Th) 17/Regulatory T (Treg) cells of rats were detected using flow cytometric analysis. Furthermore, the impact of Bp and 3-HAA on the gut microbiota of rats was assessed using 16S rRNA gene sequencing. The correlation between the gut microbiota of rats and Th17/Treg immune factors, as well as femoral stereo parameters, was separately assessed using Spearman rank correlation analysis.ResultsBp and 3-HAA treatments protected OVX rats by promoting osteogenesis and inhibiting autophagy. Compared to the Sham group, OVX rats showed an increase in Th17 cells and a decrease in Treg cells. Bp and 3-HAA reversed these changes. Enterorhabdus and Pseudomonas were significantly enriched in OVX rats. Bp and 3-HAA regulated the gut microbiota of OVX rats, enriching pathways related to nutrient metabolism and immune function. There was a correlation between the gut microbiota and the Th17/Treg, as well as femoral stereo parameters. The concurrent administration of Bp and 3-HAA medication facilitated the enrichment of gut microbiota associated with the improvement of PMO.ConclusionThe combination therapy of Bp and 3-HAA can prevent PMO by modulating the gut microbiota and restoring Th17/Treg immune homeostasis.

The role of regulatory T-cells in the development of endometriosis.

Endometriosis is a benign disease of the female reproductive tract, characterized by the process of chronic inflammation and alterations in immune response. It is estimated to affect 2-19% of women in the general population and is commonly associated with symptoms of chronic pelvic pain and infertility. Regulatory T cells (Treg) are a subpopulation of T lymphocytes that are potent suppressors of inflammatory immune response, essential in preventing destructive immunity in all tissues. In endometriosis, several studies have investigated the possible role of Treg cells in the development of the disease. Most studies to date are heterogeneous in methodology and are based on a small number of cases, which means that it is impossible to define their exact role at present. Based on current knowledge, it seems that disturbed Treg homeostasis, leading to increased systemic and local inflammation within ectopic and eutopic endometrium, is present in women who eventually develop endometriosis. It is also evident that different subsets of human Treg cells have different roles in suppressing the immune response. Recent studies in patients with endometriosis have investigated naive/resting FOXP3lowCD45RA+ Treg cells, which upon T cell receptor stimulation, differentiate into activated/effector FOXP3highCD45RA- Treg cells, characterized by a strong immunosuppressive activity. In addition, critical factors controlling expression of Treg/effector genes, including reactive oxygen species and heme-responsive master transcription factor BACH2, were found to be upregulated in endometriotic lesions. As shown recently for cancer microenvironments, microbial inflammation may also contribute to the local composition of FOXP3+ subpopulations in endometriotic lesions. Furthermore, cytokines, such as IL-7, which control the homeostasis of Treg subsets through the tyrosine phosphorylation STAT5 signalling pathway, have also been shown to be dysregulated. To better understand the role of Treg in the development of endometriosis, future studies should use clear definitions of Tregs along with specific characterization of the non-Treg (FOXP3lowCD45RA-) fraction, which itself is a mixture of follicular Tregs and cells producing inflammatory cytokines.

T cell activation and deficits in T regulatory cells are associated with major depressive disorder and severity of depression

Major depressive disorder (MDD) is associated with T cell activation, but no studies have examined the combined effects of T cell activation and deficits in T regulatory (Treg) cells on the severity of acute phase MDD. Using flow cytometry, we determined the percentage and median fluorescence intensity of CD69, CD71, CD40L, and HLADR-bearing CD3+, CD4+, and CD8+ cells, and cannabinoid type 1 receptor (CB1), CD152 and GARP (glycoprotein A repetitions predominant)-bearing CD25+ FoxP3 T regulatory (Treg) cells in 30 MDD patients and 20 healthy controls in unstimulated and stimulated (anti-CD3/CD28) conditions. Based on cytokine levels, we assessed M1 macrophage, T helper (Th)-1 cell, immune-inflammatory response system (IRS), T cell growth, and neurotoxicity immune profiles. We found that the immune profiles (including IRS and neurotoxicity) were significantly predicted by decreased numbers of CD152 or GARP-bearing CD25+ FoxP3 cells or CD152 and GARP expression in combination with increases in activated T cells (especially CD8+ CD40L+ percentage and expression). MDD patients showed significantly increased numbers of CD3+ CD71+, CD3+ CD40L+, CD4+ CD71+, CD4+ CD40L+, CD4+ HLADR+, and CD8+ HLADR+ T cells, increased CD3+ CD71+, CD4+ CD71+ and CD4+ HLADR+ expression, and lowered CD25+ FoxP3 expression and CD25+ FoxP+ CB1+ numbers as compared with controls. The Hamilton Depression Rating Scale score was strongly predicted (between 30 and 40% of its variance) by a lower number of CB1 or GARP-bearing Treg cells and one or more activated T cell subtypes (especially CD8+ CD40L+). In conclusion, increased T helper and cytotoxic cell activation along with decreased Treg homeostatic defenses are important parts of MDD that lead to enhanced immune responses and, as a result, neuroimmunotoxicity.

Synergistic antitumor activity by dual blockade of CCR1 and CXCR2 expressed on myeloid cells within the tumor microenvironment

BackgroundChemokine signaling within the tumor microenvironment can promote tumor progression. Although CCR1 and CXCR2 on myeloid cells could be involved in tumor progression, it remains elusive what effect would be observed if both of those are blocked.MethodsWe employed two syngeneic colorectal cancer mouse models: a transplanted tumor model and a liver metastasis model. We generated double-knockout mice for CCR1 and CXCR2, and performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type, Ccr1−/−, Cxcr2−/− or Ccr1−/−Cxcr2−/− mice.ResultsMyeloid cells that express MMP2, MMP9 and VEGF were accumulated around both types of tumors through CCR1- and CXCR2-mediated pathways. Mice reconstituted with Ccr1−/−Cxcr2−/− BM exhibited the strongest suppression of tumor growth and liver metastasis compared with other three groups. Depletion of CCR1+CXCR2+ myeloid cells led to a higher frequency of CD8+ T cells, whereas the numbers of Ly6G+ neutrophils, FOXP3+ Treg cells and CD31+ endothelial cells were significantly decreased. Furthermore, treatment with a neutralizing anti-CCR1 mAb to mice reconstituted with Cxcr2−/− BM significantly suppressed tumor growth and liver metastasis.ConclusionDual blockade of CCR1 and CXCR2 pathways in myeloid cells could be an effective therapy against colorectal cancer.

Majie Cataplasm Alleviates Asthma by Regulating Th1/Th2/Treg/Th17 Balance

Introduction: T cells play a critical role in inflammatory diseases. The aim of the present study was to investigate the effects of Majie cataplasm (MJC) on asthma and to propose a possible mechanism involved in this process. Methods: Airway inflammation, infiltration of inflammatory cells, levels of interleukin (IL)-4, IL-10, IL-17, and interferon (IFN)-γ, levels of Th2, Treg, Th17, and Th1 cells, and the expressions of IL-4, IL-10, IL-17, IFN-γ, GATA binding protein 3 (GATA-3), Foxp3, RAR-related orphan receptor gamma (RORγt), and T-bet were detected. Result: MJC treatment reduced lung airway resistance and inflammatory infiltration in lung tissues. MJC treatment also reduced the numbers of eosinophils and neutrophils in the blood and bronchoalveolar lavage fluid (BALF). The levels of IL-4 and IL-17 in the blood, BALF, and lungs were suppressed by MJC, and IFN-γ and IL-10 were increased. Furthermore, MJC suppressed the percentage of Th2 and Th17 and increased the percentage of Th1 and Treg in spleen cells. In addition, MJC can inhibit asthma by increasing expressions of IFN-γ, IL-10, T-bet, and Foxp3, as well as decreasing expressions of IL-4, IL-17, GATA-3, and RORγt. Conclusion: MJC may improve airway hyperresponsiveness and inflammation by regulating Th1/Th2/Treg/Th17 balance in ovalbumin-induced rats. And MJC may be a new source of anti-asthma drugs.

Complanatuside A ameliorates 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice by regulating the Th17/Treg balance via the JAK2/STAT3 signaling pathway.

Immunity imbalance of T helper 17 (Th17)/regulatory T (Treg) cells is involved in the pathogenesis of Crohn's disease (CD). Complanatuside A (CA), a flavonol glycoside, exerts anti-inflammatory activities and our study aimed to identify its effect on TNBS-induced colitis and the possible mechanisms. We found that CA alleviated the symptoms of colitis in TNBS mice, as demonstrated by prevented weight loss and colon length shortening, as well as decreased disease activity index scores, inflammatory scores, and levels of proinflammatory factors. Flow cytometry analysis showed that CA markedly reduced the percentage of Th17 cells while increasing the percentage of Treg cells in TNBS mice. Under Th17 cell polarizing conditions, CA inhibited the differentiation of Th17 cells while the Treg cell differentiation was elevated under Treg cell polarizing conditions. Furthermore, it was observed that JAK2 interacted with CA through six hydrogen bonds via molecular docking. The phosphorylation of JAK2/STAT3 was reduced by CA, which might be correlated with the protective effect of CA on colitis. In conclusion, CA reduced the imbalance of Th17/Treg cells by inhibiting the JAK2/STAT3 signaling pathway in TNBS-induced colitis, which may provide novel strategies for CD treatment.

Density of tumor-infiltrating NK and Treg cells is associated with 5 years progression-free and overall survival in resected lung adenocarcinoma

Surgical resection of pulmonary adenocarcinoma is considered to be curative but progression-free survival (PFS) has remained highly variable. Antitumor immune response may be important, however, the prognostic significance of tumor-infiltrating natural killer (NK) and regulatory T (Treg) lymphocytes is uncertain. Resected pulmonary adenocarcinoma tissues (n = 115) were studied by immunohistochemical detection of NKp46 and FoxP3 positivity to identify NK and Treg cells, respectively. Association of cell densities with clinicopathological features and progression-free survival (PFS) as well as overall survival (OS) were analyzed with a follow-up time of 60 months. Both types of immune cells were accumulated predominantly in tumor stroma. NK cell density showed association with female gender, non-smoking and KRAS wild-type status. According to Kaplan-Meier analysis, PFS and OS proved to be longer in patients with high NK or Treg cell densities (p = 0.0293 and p = 0.0375 for PFS, p = 0.0310 and p = 0.0448 for OS, respectively). Evaluating the prognostic effect of the combination of NK and Treg cell density values revealed that PFS and OS were significantly longer in NKhigh/Treghigh cases compared to the other groups combined (p = 0.0223 and p = 0.0325, respectively). Multivariate Cox regression analysis indicated that high NK cell density was independent predictor of longer PFS while high NK and high Treg cell densities both proved significant predictors of longer OS. The NKhigh/Treghigh combination also proved to be an independent prognostic factor for both PFS and OS. In conclusion, NK and Treg cells can be components of the innate and adaptive immune response at action against progression of pulmonary adenocarcinoma.

The effect of PDK1 in maintaining immune cell development and function

3-phosphoinositide-dependent protein kinase 1 (PDK1) exhibits a substantial influence on immune cell development by establishing a vital connection between PI3K and downstream mTOR signaling cascades. However, it remains unclear whether PDK1 signaling affects the homeostasis and functionality of immune cells. To explore the impact of PDK1 on different immune cells within immune organs, transgenic mouse strains with lymphocyte-specific PDK1 knockout (PDK1fl/fl CD2-Cre) were generated. Unlike wild-type (WT) mice, lymphocyte-specific PDK1 knockout (KO) mice exhibited thymic atrophy, elevated percentages of CD8+ T cells and neutrophils, and reduced proportions of γδ T cells, B cells, and NK cells in the spleen. Functional analysis revealed elevated release of IFN-γ and IL-17A by T cells in PDK1 KO mice, contrasting with diminished levels observed in γδ T cells and Treg cells. Furthermore, the activation, cytotoxicity, and migratory potential of γδ T cells in PDK1 KO mice are heightened, indicating a potential association with the regulation of the mTOR signaling pathway. To conclude, the findings of this research demonstrated that specific knockout of PDK1 in lymphocytes hindered T cell development in the thymus and exhibited a substantial influence on immune cell homeostasis in the spleen and lymph nodes.

Regulation of Treg cells by cytokine signaling and co-stimulatory molecules.

CD4+CD25+Foxp3+ regulatory T cells (Tregs), a vital component of the immune system, are responsible for maintaining immune homeostasis and preventing excessive immune responses. This review explores the signaling pathways of the cytokines that regulate Treg cells, including transforming growth factor beta (TGF-β), interleukin (IL)-2, IL-10, and IL-35, which foster the differentiation and enhance the immunosuppressive capabilities of Tregs. It also examines how, conversely, signals mediated by IL-6 and tumor necrosis factor -alpha (TNF-α) can undermine Treg suppressive functions or even drive their reprogramming into effector T cells. The B7 family comprises indispensable co-stimulators for T cell activation. Among its members, this review focuses on the capacity of CTLA-4 and PD-1 to regulate the differentiation, function, and survival of Tregs. As Tregs play an essential role in maintaining immune homeostasis, their dysfunction contributes to the pathogenesis of autoimmune diseases. This review delves into the potential of employing Treg-based immunotherapy for the treatment of autoimmune diseases, transplant rejection, and cancer. By shedding light on these topics, this article aims to enhance our understanding of the regulation of Tregs by cytokines and their therapeutic potential for various pathological conditions.

The role of microRNA-142a in Toxoplasma gondii infection-induced downregulation of Foxp3: implications for adverse pregnancy outcomes

BackgroundToxoplasma gondii (T. gondii) is capable of infecting nearly all warm-blooded animals and approximately 30% of the global population. Though most infections are subclinical in immunocompetent individuals, congenital contraction can lead to severe consequences such as spontaneous abortion, stillbirth, and a range of cranio-cerebral and/or ocular abnormalities. Previous studies reported that T. gondii-infected pregnancy mice unveiled a deficit in both the amount and suppressive functions of regulatory T (Treg) cells, accompanied with reduced levels of forkhead box p3 (Foxp3). Recently, accumulative studies have demonstrated that microRNAs (miRNAs) are, to some extent, relevant to T. gondii infection. However, the link between alterations in miRNAs and downregulation of Foxp3 triggered by T. gondii has been only sporadically studied.MethodsQuantitative reverse transcription polymerase chain reaction (RT-qPCR), protein blotting and immunofluorescence were employed to evaluate the impact of T. gondii infection and antigens on miRNA transcription and Foxp3 expression. Dual-luciferase reporter gene assays were performed to examine the fluorescence activity in EL4 cells, which were transfected with recombinant plasmids containing full-length/truncated/mutant microRNA-142a-3p (miR-142a) promoter sequence or wild type/mutant of Foxp3 3’ untranslated region (3’ UTR).ResultsWe found a pronounced increase in miR-142a transcription, concurrent with a decrease in Foxp3 expression in T. gondii-infected mouse placental tissue. Similarly, comparable findings have been experimentally confirmed through the treatment of EL4 cells with T. gondii antigens (TgAg) in vitro. Simultaneously, miR-142a mimics attenuated Foxp3 expression, whereas its inhibitors markedly augmented Foxp3 expression. miR-142a promoter activity was elevated upon the stimulation of T. gondii antigens, which mitigated co-transfection of mutant miR-142a promoter lacking P53 target sites. miR-142a mimics deceased the fluorescence activity of Foxp3 3’ untranslated region (3’ UTR), but it did not affect the fluorescence activity upon the co-transfection of mutant Foxp3 3’ UTR lacking miR-142a target site.ConclusionIn both in vivo and in vitro studies, a negative correlation was discovered between Foxp3 expression and miR-142a transcription. TgAg enhanced miR-142a promoter activity to facilitate miR-142a transcription through a P53-dependent mechanism. Furthermore, miR-142a directly targeted Foxp3 3’ UTR, resulting in the downregulation of Foxp3 expression. Therefore, harnessing miR-142a may be a possible therapeutic approach for adverse pregnancy caused by immune imbalances, particularly those induced by T. gondii infection.

Planning for success with an allogeneic Treg cell sourcing strategy

Planning for success with an allogeneic Treg cell sourcing strategy

Thymic gene expression analysis reveals a potential link between HIF-1A and Th17/Treg imbalance in thymoma associated myasthenia gravis

Myasthenia gravis (MG) is an immune-mediated disease frequently associated with thymic changes. Increased T helper 17 (Th17) cell activity and dysfunctional regulatory T (Treg) cells have been demonstrated in subgroups of MG. On the other hand, hypoxia-inducible factor 1 (HIF-1) has been shown to regulate the Th17/Treg balance by inducing Th17 differentiation while attenuating Treg development. To identify the underlying mechanisms of different thymic pathologies in MG development, we evaluated thymic samples from thymoma-associated myasthenia gravis (TAMG), MG with hyperplasia (TFH-MG) and thymoma without MG (TOMA) patients. Differential gene expression analysis revealed that TAMG and TFH-MG cells are associated with different functional pathways. A higher RORC/FOXP3 ratio provided evidence for Th17/Treg imbalance in TAMG potentially related to increased HIF1A. The hypoxic microenvironment in thymoma may be a driver of TAMG by increasing HIF1A. These findings may lead to new therapeutic approaches targeting HIF1A in the development of TAMG.