RÉSUMÉ
Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.
Sujet(s)
Interleukine-10 , Macrophages , Souris de lignée C57BL , Infarctus du myocarde , Lymphocytes T régulateurs , Animaux , Infarctus du myocarde/immunologie , Infarctus du myocarde/génétique , Infarctus du myocarde/anatomopathologie , Lymphocytes T régulateurs/immunologie , Macrophages/immunologie , Macrophages/métabolisme , Mâle , Souris , Interleukine-10/métabolisme , Interleukine-10/génétique , Phénotype , Myocarde/anatomopathologie , Myocarde/immunologie , Myocarde/métabolisme , Monocytes/immunologie , Monocytes/métabolisme , Myocytes cardiaques/métabolisme , Myocytes cardiaques/immunologie , Fibrose , Lymphocytes T CD8+/immunologie , Modèles animaux de maladie humaine , Souris knockoutRÉSUMÉ
OBJECTIVES: To measure regulatory T cell (Treg) levels in the peripheral blood of children with juvenile idiopathic arthritis (JIA) and analyse the association of this measure with disease activity, quality of life, adjustment of treatment, and hospitalisation. METHODS: We conducted a two-phase study (cross-sectional and prospective), including consecutive children with a JIA diagnosis according to ILAR criteria. Our independent variables were Tregs, Th1, Th2, and cytokines in peripheral blood, and our dependent variables in the cross-sectional phase were arthritis category, JIA activity, and patient-reported outcomes. To test associations, we used Spearman's correlation coefficient and the Mann-Whitney U test. In the prospective phase, we explored the probability of treatment adjustment and hospitalisation for JIA during follow-up according to Tregs levels at baseline, using Cox proportional regression. RESULTS: Our sample included 87 participants (median age 11 years, 63.2% girls). Tregs were not associated with most variables of interest. However, we found that higher Tregs concentration was associated with lower erythrocyte sedimentation rate (ESR) and better subjective disease status and course, while higher IL-10 and TGF-ß levels were associated with lower ESR, less pain, and better subjective disease status We found no association between Tregs and treatment adjustments or hospitalisation. CONCLUSIONS: Higher baseline Treg levels in the peripheral blood of children with JIA may be associated with reduced disease activity and better quality of life, though were not informative on the inflammatory progression on the follow-up.
Sujet(s)
Arthrite juvénile , Qualité de vie , Lymphocytes T régulateurs , Humains , Arthrite juvénile/sang , Arthrite juvénile/immunologie , Enfant , Femelle , Mâle , Lymphocytes T régulateurs/immunologie , Études transversales , Études prospectives , Adolescent , Sédimentation du sang , Hospitalisation/statistiques et données numériques , Indice de gravité de la maladie , Enfant d'âge préscolaireRÉSUMÉ
BACKGROUND: The interplay between regulatory T cells (Tregs) and neighboring cells, which is pivotal for anti-tumor immunity and closely linked to patient prognosis, remains to be fully elucidated. METHODS: Tissue microarrays of 261 operable NSCLC patients were stained by multiplex immunofluorescence (mIF) assay, and the interaction between Tregs and neighboring cells in the tumor microenvironment (TME) was evaluated. Employing various machine learning algorithms, we developed a spatial immune signature to predict the prognosis of NSCLC patients. Additionally, we explored the interplay between programmed death-1/programmed death ligand-1 (PD-1/PD-L1) interactions and their relationship with Tregs. RESULTS: Survival analysis indicated that the interplay between Tregs and neighboring cells in the invasive margin (IM) and tumor center was associated with recurrence in NSCLC patients. We integrated the intersection of the three algorithms to identify four crucial spatial immune features [P(CD8+Treg to CK) in IM, P(CD8+Treg to CD4) in IM, N(CD4+Treg to CK) in IM, N(CD4+Tcon to CK) in IM] and employed these characteristics to establish SIS, an independent prognosticator of recurrence in NSCLC patients [HR = 2.34, 95% CI (1.53, 3.58), P < 0.001]. Furthermore, analysis of cell interactions demonstrated that a higher number of Tregs contributed to higher PD-L1+ cells surrounded by PD-1+ cells (P < 0.001) with shorter distances (P = 0.004). CONCLUSION: We dissected the cell interplay network within the TME, uncovering the spatial architecture and intricate interactions between Tregs and neighboring cells, along with their impact on the prognosis of NSCLC patients.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Tumeurs du poumon , Récidive tumorale locale , Lymphocytes T régulateurs , Microenvironnement tumoral , Humains , Carcinome pulmonaire non à petites cellules/immunologie , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/mortalité , Lymphocytes T régulateurs/immunologie , Tumeurs du poumon/immunologie , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/mortalité , Microenvironnement tumoral/immunologie , Récidive tumorale locale/immunologie , Mâle , Femelle , Pronostic , Adulte d'âge moyen , Récepteur-1 de mort cellulaire programmée/métabolisme , Antigène CD274/métabolisme , Sujet âgé , Lymphocytes TIL/immunologie , Lymphocytes TIL/métabolismeRÉSUMÉ
We have previously reported that nanoparticles (NPs) loaded with IL-2 and TGF-ß and targeted to T cells induced polyclonal T regulatory cells (Tregs) that protected mice from graft-versus-host disease (GvHD). Here, we evaluated whether administration of these NPs during alloantigen immunization could prevent allograft rejection by converting immunogenic responses to tolerogenic ones. Using C57BL/6 mice and BALB/c mice as either donors or recipients of allogeneic splenocytes, we found that treatment with the tolerogenic NPs in both strains of mice resulted in a marked inhibition of mixed lymphocyte reaction (MLR) to donor cell alloantigen but not to third-party control mouse cells after transfer of the allogeneic cells. The decreased alloreactivity associated with a four- to fivefold increase in the number of CD4+ and CD8+ T regulatory cells (Tregs) and the acquisition of a tolerogenic phenotype by recipient dendritic cells (DCs) in NP-treated mice. As allogeneic cells persisted in NP-treated mice, these findings suggest that tolerogenic NPs can induce alloantigen-specific Tregs and tolerogenic DCs promoting tolerogenic responses to alloantigen. By inhibiting reactivity to allotransplant, this approach could help reduce the need for immune suppression for the maintenance of allografts.
Sujet(s)
Interleukine-2 , Isoantigènes , Souris de lignée BALB C , Souris de lignée C57BL , Nanoparticules , Lymphocytes T régulateurs , Facteur de croissance transformant bêta , Tolérance à la transplantation , Animaux , Isoantigènes/immunologie , Tolérance à la transplantation/immunologie , Souris , Facteur de croissance transformant bêta/immunologie , Lymphocytes T régulateurs/immunologie , Interleukine-2/immunologie , Cellules dendritiques/immunologie , Rejet du greffon/immunologie , Rejet du greffon/prévention et contrôle , Maladie du greffon contre l'hôte/immunologie , Maladie du greffon contre l'hôte/prévention et contrôle , FemelleRÉSUMÉ
Eosinophilic gastrointestinal disorders (EGIDs) are a group of conditions characterized by an abnormal accumulation of eosinophils in the gastrointestinal tract, leading to inflammation and tissue damage. Regulatory cells are a subset of immune cells that are crucial in maintaining the balance of the immune system and preventing the occurrence of autoimmune diseases. In EGIDs, regulatory cells are believed to play a key role in controlling the immune response and overseeing the growth and activation of eosinophils in the gastrointestinal tract. There is evidence indicating that regulatory T cells (Tregs) and regulatory eosinophils may play a role in suppressing the inflammatory response in EGIDs. Regulatory eosinophils are a subgroup of eosinophils that possess an anti-inflammatory role. Recent studies have shown that enhancing the number or effectiveness of regulatory eosinophils can reduce the severity of EGIDs. Regulatory eosinophils dampen inflammation through their regulatory mediators, such as galectin-10 and growth factor beta (TGF-ß), which promote Treg expansion and inhibit effector T cell function. Further research on regulatory cells in EGIDs may have significant implications for the advancement of novel therapies for these uncommon and intricate disorders. The aim of this review is to provide complete view of the immune responses connected to EGIDs, examine the regulatory cells that control these responses, and evaluate their potential as therapeutic targets for EGID treatment.
Sujet(s)
Entérite , Éosinophilie , Granulocytes éosinophiles , Gastrite , Lymphocytes T régulateurs , Humains , Lymphocytes T régulateurs/immunologie , Éosinophilie/immunologie , Entérite/immunologie , Granulocytes éosinophiles/immunologie , Gastrite/immunologie , AnimauxRÉSUMÉ
Liver cancer, which most commonly manifests as hepatocellular carcinoma (HCC), is the sixth most common cancer in the world. In HCC, the immune system plays a crucial role in the growth and proliferation of tumor cells. HCC achieve immune escape through the tumor microenvironment, which significantly promotes the development of this cancer. Here, this article introduces and summarizes the functions and effects of regulatory T cells (Tregs) in the tumor microenvironment, highlighting how Tregs inhibit and regulate the functions of immune and tumor cells, cytokines, ligands and receptors, etc, thereby promoting tumor immune escape. In addition, it discusses the mechanism of CAR-T therapy for HCC and elaborate on the relationship between CAR-T and Tregs.
Sujet(s)
Carcinome hépatocellulaire , Immunothérapie adoptive , Tumeurs du foie , Lymphocytes T régulateurs , Échappement de la tumeur à la surveillance immunitaire , Microenvironnement tumoral , Humains , Microenvironnement tumoral/immunologie , Carcinome hépatocellulaire/immunologie , Carcinome hépatocellulaire/thérapie , Carcinome hépatocellulaire/anatomopathologie , Lymphocytes T régulateurs/immunologie , Tumeurs du foie/immunologie , Tumeurs du foie/thérapie , Tumeurs du foie/anatomopathologie , Échappement de la tumeur à la surveillance immunitaire/immunologie , Immunothérapie adoptive/méthodes , Animaux , Récepteurs chimériques pour l'antigène/immunologie , Récepteurs chimériques pour l'antigène/génétiqueRÉSUMÉ
BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, which promotes a sustained inflammatory environment in the central nervous system. Regulatory T cells (Tregs) play an important role in the control of inflammation and might play a neuroprotective role. Indeed, a decrease in Treg number and function has been reported in PD. In this context, pramipexole, a dopaminergic receptor agonist used to treat PD symptoms, has been shown to increase peripheral levels of Treg cells and improve their suppressive function. The aim of this work was to determine the effect of pramipexole on immunoregulatory Treg cells and its possible neuroprotective effect on human dopaminergic neurons differentiated from human embryonic stem cells. METHODS: Treg cells were sorted from white blood cells of healthy human donors. Assays were performed with CD3/CD28-activated and non-activated Treg cells treated with pramipexole at concentrations of 2 or 200 ng/mL. These regulatory cells were co-cultured with in vitro-differentiated human dopaminergic neurons in a cytotoxicity assay with 6-hydroxydopamine (6-OHDA). The role of interleukin-10 (IL-10) was investigated by co-culturing activated IL-10-producing Treg cells with neurons. To further investigate the effect of treatment on Tregs, gene expression in pramipexole-treated, CD3/CD28-activated Treg cells was determined by Fluidigm analysis. RESULTS: Pramipexole-treated CD3/CD28-activated Treg cells showed significant protective effects on dopaminergic neurons when challenged with 6-OHDA. Pramipexole-treated activated Treg cells showed neuroprotective capacity through mechanisms involving IL-10 release and the activation of genes associated with regulation and neuroprotection. CONCLUSION: Anti-CD3/CD28-activated Treg cells protect dopaminergic neurons against 6-OHDA-induced damage. In addition, activated, IL-10-producing, pramipexole-treated Tregs also induced a neuroprotective effect, and the supernatants of these co-cultures promoted axonal growth. Pramipexole-treated, activated Tregs altered their gene expression in a concentration-dependent manner, and enhanced TGFß-related dopamine receptor regulation and immune-related pathways. These findings open new perspectives for the development of immunomodulatory therapies for the treatment of PD.
Sujet(s)
Benzothiazoles , Neurones dopaminergiques , Oxidopamine , Pramipexole , Lymphocytes T régulateurs , Humains , Pramipexole/pharmacologie , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/métabolisme , Oxidopamine/toxicité , Benzothiazoles/pharmacologie , Techniques de coculture , Interleukine-10/métabolisme , Cellules cultivées , Neuroprotecteurs/pharmacologie , Agonistes de la dopamine/pharmacologieRÉSUMÉ
Anti-CTLA-4 antibodies faced challenges due to frequent adverse events and limited efficacy, which spurred the exploration of next-generation CTLA-4 therapeutics to balance regulatory T cells (Tregs) depletion and CD8 T cells activation. CCR8, identified primarily on tumor-infiltrating Tregs, has become a target of interest due to the anti-tumor effects demonstrated by CCR8 antibody-mediated Tregs depletion. Single-cell RNA sequencing analysis reveals that CCR8-positive Tregs constitute a small subset, with concurrent expression of CCR8 and CTLA-4. Consequently, we proposed a novel bispecific antibody targeting CCR8 and CTLA-4 that had the potential to enhance T cell activation while selectively depleting intratumor Tregs. The candidate molecule 2MW4691 was developed in a tetravalent symmetric format, maintaining a strong binding affinity for CCR8 while exhibiting relatively weaker CTLA-4 binding. This selective binding ability allowed 2MW4691 to target and deplete tumor-infiltrating Tregs with higher specificity. In vitro assays verified the antibody's capacity for antibody-dependent cellular cytotoxicity (ADCC) to Tregs with high level of CTLA-4 expression, but not CD8 T cells with relatively low level of CTLA-4 on cell surface. Also, 2MW4691 inhibited the CTLA-4 pathway and enhanced T cell activation. The in vivo therapeutic efficacy of 2MW4691 was further demonstrated using hCCR8 or hCTLA-4 humanized mouse models and hCCR8/hCTLA-4 double knock-in mouse models. In cynomolgus monkeys, 2MW4691 was well-tolerated, exhibited the anticipated pharmacokinetic profile, and had a minimal impact on the peripheral T cell population. The promising preclinical results supported the further evaluation of 2MW4691 as a next-generation Treg-based therapeutics in clinical trials.
Sujet(s)
Anticorps bispécifiques , Lymphocytes T CD8+ , Antigène CTLA-4 , Lymphocytes T régulateurs , Animaux , Souris , Anticorps bispécifiques/pharmacologie , Anticorps bispécifiques/immunologie , Anticorps bispécifiques/usage thérapeutique , Humains , Antigène CTLA-4/antagonistes et inhibiteurs , Antigène CTLA-4/immunologie , Lymphocytes T régulateurs/immunologie , Lymphocytes T CD8+/immunologie , Récepteurs CCR8/immunologie , Tumeurs/immunologie , Tumeurs/traitement médicamenteux , Tumeurs/thérapie , Transduction du signal/effets des médicaments et des substances chimiques , Femelle , Tests d'activité antitumorale sur modèle de xénogreffe , Macaca fascicularisRÉSUMÉ
Various organ allografts differ in their propensity to be spontaneously accepted without any immunosuppressive treatment. Understanding the mechanisms behind these differences can aid in managing alloimmune responses in general. C57BL/6 mice naturally accept DBA/2J kidney allografts, forming tertiary lymphoid organs containing regulatory T cells (rTLOs), crucial for graft acceptance. In this issue of the JCI, Yokose and colleagues revealed that rTLOs promote conversion of cytotoxic alloreactive CD8+ T cells into exhausted/regulatory ones, through an IFN-γ-mediated mechanism. Their study provides insights into tolerance development that could help promote the acceptance of grafts at higher risk of rejection.
Sujet(s)
Lymphocytes T CD8+ , Interféron gamma , Transplantation rénale , Lymphocytes T régulateurs , Animaux , Souris , Lymphocytes T régulateurs/immunologie , Lymphocytes T CD8+/immunologie , Interféron gamma/immunologie , Interféron gamma/génétique , Interféron gamma/métabolisme , Tolérance à la transplantation/immunologie , Humains , Souris de lignée C57BL , Rejet du greffon/immunologie , Souris de lignée DBA , Rein/immunologie , Rein/métabolisme , AllogreffesRÉSUMÉ
BACKGROUND: In mammals, amino acid metabolism has evolved to control immune responses. Tryptophan (Trp) is the rarest essential amino acid found in food and its metabolism has evolved to be a primary regulatory node in the control of immune responses. Celiac disease (CeD) is a developed immunological condition caused by gluten intolerance and is linked to chronic small intestine enteropathy in genetically predisposed individuals. Dendritic cells (DCs), serving as the bridge between innate and adaptive immunities, can influence immunological responses in CeD through phenotypic alterations. OBJECTIVE: This review aims to highlight the connection between Trp metabolism and tolerogenic DCs, and the significance of this interaction in the pathogenesis of CeD. RESULTS: It is been recognized that various DC subtypes contribute to the pathogenesis of CeD. Tolerogenic DCs, in particular, are instrumental in inducing immune tolerance, leading to T-reg differentiation that helps maintain intestinal immune tolerance against inflammatory responses in CeD patients and those with other autoimmune disorders. T-regs, a subset of T-cells, play a crucial role in maintaining intestinal immunological homeostasis by regulating the activities of other immune cells. Notably, Trp metabolism, essential for T-reg function, facilitates T-reg differentiation through microbiota-mediated degradation and the kynurenine pathway. CONCLUSION: Therefore, alterations in Trp metabolism could potentially influence the immune response in CeD, affecting both the development of the disease and the persistence of symptoms despite adherence to a gluten-free diet.
Sujet(s)
Maladie coeliaque , Cellules dendritiques , Tolérance immunitaire , Tryptophane , Humains , Cellules dendritiques/immunologie , Cellules dendritiques/métabolisme , Tryptophane/métabolisme , Maladie coeliaque/immunologie , Maladie coeliaque/métabolisme , Animaux , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolismeRÉSUMÉ
We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells.
Sujet(s)
Oxyde de diméthyl-diazène , Tumeurs colorectales , Sulfate dextran , Facteurs de transcription Forkhead , Acide glycyrrhizique , Rate , Lymphocytes T régulateurs , Animaux , Acide glycyrrhizique/pharmacologie , Facteurs de transcription Forkhead/métabolisme , Rate/métabolisme , Rate/anatomopathologie , Tumeurs colorectales/anatomopathologie , Tumeurs colorectales/métabolisme , Tumeurs colorectales/induit chimiquement , Tumeurs colorectales/traitement médicamenteux , Souris , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Souris de lignée ICR , Mâle , Immunohistochimie , Protéine HMGB1/métabolismeRÉSUMÉ
EGFR mutations are critical oncogenic drivers in lung adenocarcinoma (LUAD). However, the mechanisms by which they impact the tumor microenvironment (TME) and tumor immunity are unclear. Furthermore, the reasons underlying the poor response of EGFR-mutant (EGFR-MU) LUADs to immunotherapy with PD-1/PD-L1 inhibitors are unknown. Utilizing single-cell RNA (sc-RNA) and bulk RNA sequencing datasets, we conducted high-dimensional weighted gene coexpression network analysis to identify key genes and immune-related pathways contributing to the immunosuppressive TME. EGFR-MU cancer cells downregulated MHC class I genes to evade CD8+ cytotoxic T cells, expressed substantial levels of MHC class II molecules, and engaged with CD4+ regulatory T cells (Tregs). EGFR-MU tumors may recruit Tregs primarily through the CCL17/CCL22/CCR4 axis, leading to a Treg-enriched TME. High levels of MHC class II-positive cancer-associated fibroblasts and tumor endothelial cells were found within EGFR-MU tumors. Owing to the absence of costimulatory factors, they may inhibit rather than activate the tumor antigen-specific CD4+ T-cell response, contributing further to immune suppression. Multiplex immunohistochemistry analyses in a LUAD cohort confirmed increased expression of MHC class II molecules in cancer cells and fibroblasts in EGFR-MU tumors. Our research elucidates the highly immunosuppressive TME in EGFR-MU LUAD and suggests potential targets for effective immunotherapy.
Sujet(s)
Récepteurs ErbB , Analyse de profil d'expression de gènes , Tumeurs du poumon , Mutation , Microenvironnement tumoral , Humains , Récepteurs ErbB/génétique , Récepteurs ErbB/métabolisme , Tumeurs du poumon/génétique , Tumeurs du poumon/immunologie , Tumeurs du poumon/anatomopathologie , Microenvironnement tumoral/immunologie , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Régulation de l'expression des gènes tumoraux , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/immunologie , Adénocarcinome pulmonaire/anatomopathologie , Transcriptome , Analyse sur cellule uniqueRÉSUMÉ
The modulation of cellular phenotypes within adipose tissue provides a potential means for therapeutic intervention for diabetes. Endogenous interleukin-10 (IL-10) protects against diet-induced insulin resistance. We examined the effects and mechanisms of action of IL-10-treated adipose-derived stromal cells on diabetes-induced insulin resistance and liver gluconeogenesis. We harvested stromal vascular fractions (SVFs) from the adipose tissue of diabetic (Leprdb/db) mice and treated them with IL-10 in vitro. SVFs treated with 10 or 100 ng of IL-10 were injected into the inguinal adipose tissue of Leprdb/db mice. IL-10 treatment suppressed the mRNA expression of IL-6, IL-33, CCL2, TNF-α, and IL-1ß. Additionally, it suppressed the protein expression of IL-6, pmTOR, pJNK, and pNF-κB but enhanced Foxp3 mRNA expression in SVFs from diabetic mice. Meanwhile, IL-10 treatment repressed CCL2 and PDGFRα expression in adipose tissue macrophages (ATMs) and IL-6 expression in non-ATMs but increased the Foxp3 and IL-10 mRNA expression of ATMs from diabetic mice. Injection of IL-10-treated SVFs decreased the IL-6, IL-33, CCL2, IL-1ß, and CCL2 but enhanced the Foxp3 and IL-10 mRNA expression of adipose tissue from Leprdb/db mice. Furthermore, injection of IL-10-treated SVFs increased CD4+ regulatory T cells (Tregs) in SVFs and adipose IL-10 levels and suppressed plasma adiponectin levels and DPP4 activity in diabetic mice. Injection of IL-10-treated SVFs decreased hepatic G6PC and PCK1 mRNA expression and increased Akt activation, STAT3 phosphorylation in the liver, and glucose tolerance in diabetic mice. Our data suggest that IL-10 treatment decreases inflammation in adipose SVFs of diabetic mice. Injection of IL-10-treated SVFs into the adipose tissue decreased diabetes-induced gluconeogenesis gene expression, DPP4 activity, and insulin resistance by enhancing Treg cells in diabetic mice. These data suggest that IL-10-treated adipose stromal vascular cells could be a promising therapeutic strategy for diabetes mellitus.
Sujet(s)
Tissu adipeux , Néoglucogenèse , Insulinorésistance , Interleukine-10 , Foie , Cellules stromales , Lymphocytes T régulateurs , Animaux , Interleukine-10/métabolisme , Souris , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Néoglucogenèse/effets des médicaments et des substances chimiques , Tissu adipeux/métabolisme , Tissu adipeux/cytologie , Cellules stromales/métabolisme , Cellules stromales/effets des médicaments et des substances chimiques , Foie/métabolisme , Mâle , Diabète expérimental/métabolisme , Diabète expérimental/thérapie , Souris de lignée C57BLRÉSUMÉ
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a urinary disorder that affects youthful to middle-aged men most frequently. It has been revealed that Th17/Treg imbalance is a crucial factor in the pathophysiological mechanisms behind this disease. However, this imbalance's mechanisms are unknown. In the experimental autoimmune prostatitis (EAP) mouse model, the NLRP3 inflammasome was turned on, IL-1ß levels went up. Moreover, there exists a discernible positive association between the upsurge in IL-1ß and the perturbation of Th17/Treg equilibrium. Additionally, we have revealed that IL-1ß plays a vital role in promoting the differentiation of Naïve CD4+ T cells into the Th17 cells and enhances the conversion of Treg cells into Th17 cells. Further studies revealed that IL-1ß promotes STAT3 phosphorylation, which is what causes Treg cells to become Th17 cells. All data strongly suggest that the NLRP3 inflammatory influence Th17 cell development and the conversion of Treg cells into Th17 cells through IL-1ß, disrupting the Th17/Treg balance and exacerbating EAP inflammation. In this article, we provide new theories for the pathogenesis of CP/CPPS and propose new prevention and therapy methods.
Sujet(s)
Maladies auto-immunes , Modèles animaux de maladie humaine , Interleukine-1 bêta , Protéine-3 de la famille des NLR contenant un domaine pyrine , Prostatite , Lymphocytes T régulateurs , Cellules Th17 , Animaux , Mâle , Prostatite/immunologie , Prostatite/métabolisme , Prostatite/anatomopathologie , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Interleukine-1 bêta/métabolisme , Cellules Th17/immunologie , Cellules Th17/métabolisme , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Souris , Maladies auto-immunes/immunologie , Maladies auto-immunes/métabolisme , Facteur de transcription STAT-3/métabolisme , Inflammasomes/métabolisme , Différenciation cellulaire , Souris de lignée C57BLRÉSUMÉ
Regulatory T cells (Tregs), characterized by the expression of Forkhead Box P3 (FOXP3), constitute a distinct subset of T cells crucial for immune regulation. Tregs can exert direct and indirect control over immune homeostasis by releasing inhibitory factors or differentiating into Th-like Treg (Th-Treg), thereby actively contributing to the prevention and treatment of autoimmune diseases. The epigenetic regulation of FOXP3, encompassing DNA methylation, histone modifications, and post-translational modifications, governs the development and optimal suppressive function of Tregs. In addition, Tregs can also possess the ability to maintain homeostasis in diverse microenvironments through non-suppressive mechanisms. In this review, we primarily focus on elucidating the epigenetic regulation of Tregs as well as their multifaceted roles within diverse physiological contexts while looking forward to potential strategies involving augmentation or suppression of Tregs activity for disease management, particularly in light of the ongoing global COVID-19 pandemic.
Sujet(s)
COVID-19 , Épigenèse génétique , Facteurs de transcription Forkhead , Homéostasie , Lymphocytes T régulateurs , Humains , Lymphocytes T régulateurs/immunologie , Facteurs de transcription Forkhead/métabolisme , Facteurs de transcription Forkhead/génétique , COVID-19/immunologie , Méthylation de l'ADN , SARS-CoV-2/immunologie , SARS-CoV-2/physiologieRÉSUMÉ
BACKGROUND: Oncolytic viruses (OVs) are an attractive way to increase immune infiltration into an otherwise cold tumor. While OVs are engineered to selectively infect tumor cells, there is evidence that they can infect other non-malignant cells in the tumor. We sought to determine if oncolytic vaccinia virus (VV) can infect lymphocytes in the tumor and, if so, how this was linked to therapeutic efficacy. METHODS: To investigate infection of lymphocytes by VV, we used a GFP reporting VV in a murine head and neck squamous cell carcinoma tumor model. We also performed in vitro infection studies to determine the mechanism and consequences of VV lymphocyte infection by VV. RESULTS: Our findings show that VV carries the capacity to infect proportions of immune cells, most notably T cells, after intratumoral treatment. Notably, this infection is preferential to terminally differentiated T cells that tend to reside in hypoxia. Infection of T cells leads to both virus production by the T cells as well as the eventual death of these cells. Using a mouse model which overexpressed the antiapoptotic protein Bcl2 in all T cells, we found that reducing T cell death following VV infection in MEER tumors reduced the number of complete regressions and reduced survival time compared with littermate control mice. CONCLUSIONS: These findings suggest that OVs are capable of infecting more than just malignant cells after treatment, and that this infection may be an important part of the OV mechanism. We found that exhausted CD8+ T cells and regulatory CD4+ T cells were preferentially infected at early timepoints after treatment and subsequently died. When cell death in T cells was mitigated, mice responded poorly to VV treatment, suggesting that the deletion of these populations is critical to the therapeutic response to VV.
Sujet(s)
Thérapie virale de cancers , Virus oncolytiques , Virus de la vaccine , Animaux , Virus de la vaccine/génétique , Souris , Thérapie virale de cancers/méthodes , Virus oncolytiques/immunologie , Humains , Lymphocytes TIL/immunologie , Lymphocytes TIL/métabolisme , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Lignée cellulaire tumorale , Femelle , Modèles animaux de maladie humaineRÉSUMÉ
Regulatory T cells (Treg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25+Foxp3- and CD25-Foxp3lo precursors. However, the mechanisms regulating the recently identified Foxp3lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α1ß2 (LTα1ß2) heterocomplex is upregulated during Treg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of Treg from Foxp3lo precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTα1ß2-lymphotoxin ß receptor-mediated interactions with mTEC limit Treg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic Treg development that fine-tunes the Foxp3lo Treg precursor pathway by limiting IL-4 availability.
Sujet(s)
Facteurs de transcription Forkhead , Interleukine-4 , Récepteur à la lymphotoxine-bêta , Lymphotoxine alpha , Transduction du signal , Lymphocytes T régulateurs , Animaux , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/métabolisme , Facteurs de transcription Forkhead/métabolisme , Facteurs de transcription Forkhead/génétique , Interleukine-4/métabolisme , Souris , Lymphotoxine alpha/métabolisme , Lymphotoxine alpha/génétique , Récepteur à la lymphotoxine-bêta/métabolisme , Récepteur à la lymphotoxine-bêta/génétique , Thymus (glande)/immunologie , Thymus (glande)/cytologie , Thymus (glande)/métabolisme , Cellules épithéliales/métabolisme , Souris de lignée C57BL , Différenciation cellulaire , Souris transgéniques , Interleukine-2/métabolisme , Prolifération cellulaire , Hétérotrimère de lymphotoxines alpha1 bêta2/métabolisme , Hétérotrimère de lymphotoxines alpha1 bêta2/génétiqueRÉSUMÉ
Rheumatoid arthritis (RA) is an autoimmune disease characterized by a polyarticular synovitis. In recent years, elderly onset rheumatoid arthritis (EORA) has been increasing. Treg cells in RA have been reported to be dysfunctional, but the relationship between aging and their functional changes is unclear. Here, we found that Treg cells from EORA patients had increased percentages, but decreased activity compared to those from younger onset RA (YORA) patients. In experiments using arthritis model mice, decreased suppressive function and oxygen consumption rate (OCR) were observed in Treg cells only from old arthritic mice. Furthermore, type I interferon (IFN) signaling was upregulated in Treg cells from old GIA mice, and IFN-ß decreased the suppressive function of Treg cells. Our findings demonstrate that increased type I IFN signaling in old Treg cells is induced only in the arthritic environment and relates to decreased suppressive function of Treg cells, gets involved in EORA.
Sujet(s)
Vieillissement , Polyarthrite rhumatoïde , Lymphocytes T régulateurs , Lymphocytes T régulateurs/immunologie , Animaux , Polyarthrite rhumatoïde/immunologie , Humains , Sujet âgé , Souris , Mâle , Adulte d'âge moyen , Vieillissement/immunologie , Femelle , Transduction du signal , Adulte , Arthrite expérimentale/immunologie , Interféron de type I/immunologie , Interféron de type I/métabolisme , Consommation d'oxygène , Interféron bêta/immunologieRÉSUMÉ
Objective: This article aims to investigate the changes of T helper 17 (Th17) cells, regulatory T (Treg) cells and their associated cytokines in patients with systemic lupus erythematosus (SLE). Methods: Multiple databases were investigated to identify articles that explored Th17 cells, Treg cells and relevant cytokines in SLE patients. A random effects model was used for calculating pooled standardized mean differences. Stata version 15.0 was utilized to conduct the meta-analysis. Results: The levels of Th17 cells, IL-17, IL-6, IL-21 and IL-10 were higher in SLE patients than in healthy controls (HCs), but the TGF-ß levels were lower. The percentage of Treg cells was lower than HCs in SLE individuals older than 33. Among studies that had 93% or lower females, the percentage of Th17 cells was greater in patients than in HCs. However, the percentage of Treg cells was lower when the proportion of females was less than 90%. Patients with lupus nephritis or active SLE had an increased proportion of Th17 cells and a decreased proportion of Treg cells. Conclusions: The increased level of Th17 cells and related cytokines could be the main reason for the elevated Th17/Treg ratio in SLE. The percentages of Th17 and Treg cells were associated with gender, age, disease activity and kidney function. Furthermore, the reduced proportions of Treg cells may primarily result in a rise in the Th17/Treg ratio in older or active SLE patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023454937.