RESUMEN
Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types. In this study, we identified a gene on the chromosome 6p25.3 locus, encoding a lincRNA, that was up-regulated during early differentiation of human Tregs. The lincRNA regulated the expression of interleukin-2 receptor alpha (IL2RA), and we named it the lincRNA regulator of IL2RA (LIRIL2R). Through transcriptomics, epigenomics, and proteomics analysis of LIRIL2R-deficient Tregs, coupled with global profiling of LIRIL2R binding sites using chromatin isolation by RNA purification, followed by sequencing, we identified IL2RA as a target of LIRIL2R. This nuclear lincRNA binds upstream of the IL2RA locus and regulates its epigenetic landscape and transcription. CRISPR-mediated deletion of the LIRIL2R-bound region at the IL2RA locus resulted in reduced IL2RA expression. Notably, LIRIL2R deficiency led to reduced expression of Treg-signature genes (e.g., FOXP3, CTLA4, and PDCD1), upregulation of genes associated with effector T cells (e.g., SATB1 and GATA3), and loss of Treg-mediated suppression.
Asunto(s)
Factores de Transcripción Forkhead , Subunidad alfa del Receptor de Interleucina-2 , ARN Largo no Codificante , Linfocitos T Reguladores , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Epigénesis Genética , Regulación de la Expresión Génica , Diferenciación Celular/genéticaRESUMEN
Following viral infection, CD4+ T cell differentiation is tightly regulated by cytokines and TCR signals. Although most activated CD4+ T cells express IL-2Rα after lymphocytic choriomeningtis virus infection, by day 3 postinfection, only half of activated T cells maintain expression. IL-2Rα at this time point distinguishes precursors for terminally differentiated Th1 cells (IL-2Rαhi) from precursors for Tfh cells and memory T cells (IL-2Rαlo) and is linked to strong TCR signals. In this study, we test whether TCR-dependent IL-2 links the TCR to CD4+ T cell differentiation. We employ a mixture of anti-IL-2 Abs to neutralize IL-2 throughout the primary CD4+ T cell response to lymphocytic choriomeningitis virus infection in mice or only after the establishment of lineage-committed effector cells (day 3 postinfection). We report that IL-2 signals drive the formation of Th1 precursor cells in the early stages of the immune response and sustain Th1 responses during its later stages (after day 3). Effector-stage IL-2 also shapes the composition and function of resulting CD4+ memory T cells. Although IL-2 has been shown previously to drive Th1 differentiation by reducing the activity of the transcriptional repressor TCF-1, we found that sustained IL-2 signals were still required to drive optimal Th1 differentiation even in the absence of TCF-1. Therefore, we concluded that IL-2 plays a central role throughout the effector phase in regulating the balance between Th1 and Tfh effector and memory cells via mechanisms that are both dependent and independent of its role in modulating TCF-1 activity.
Asunto(s)
Interleucina-2 , Células TH1 , Animales , Ratones , Linfocitos T CD4-Positivos , Diferenciación Celular , Memoria Inmunológica , Subunidad alfa del Receptor de Interleucina-2 , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos TRESUMEN
Staphylococcal superantigens induce massive activation of T cells and inflammation, leading to toxic shock syndrome. Paradoxically, increasing evidence indicates that superantigens can also induce immunosuppression by promoting regulatory T cell (Treg) development. In this study, we demonstrate that stimulation strength plays a critical role in superantigen-mediated induction of immunosuppressive human CD4+CD25+FOXP3+ T cells. Suboptimal stimulation by a low dose (1 ng/ml) of staphylococcal enterotoxin C1 (SEC1) led to de novo generation of Treg-like CD4+CD25+FOXP3+ T cells with strong suppressive activity. In contrast, CD4+CD25+ T cells induced by optimal stimulation with high-dose SEC1 (1 µg/ml) were not immunosuppressive, despite high FOXP3 expression. Signal transduction pathway analysis revealed differential activation of the PI3K signaling pathway and expression of PTEN in optimal and suboptimal stimulation with SEC1. Additionally, we identified that FOXP3 isoforms in Treg-like cells from the suboptimal condition were located in the nucleus, whereas FOXP3 in nonsuppressive cells from the optimal condition localized in cytoplasm. Sequencing analysis of FOXP3 isoform transcripts identified five isoforms, including a FOXP3 isoform lacking partial exon 3. Overexpression of FOXP3 isoforms confirmed that both an exon 2-lacking isoform and a partial exon 3-lacking isoform confer suppressive activity. Furthermore, blockade of PI3K in optimal stimulation conditions led to induction of suppressive Treg-like cells with nuclear translocation of FOXP3, suggesting that PI3K signaling impairs induction of Tregs in a SEC1 dose-dependent manner. Taken together, these data demonstrate that the strength of activation signals determined by superantigen dose regulates subcellular localization of FOXP3 isoforms, which confers suppressive functionality.
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Fosfatidilinositol 3-Quinasas , Superantígenos , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Linfocitos T CD4-Positivos , Linfocitos T Reguladores , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Enterotoxinas , Isoformas de Proteínas/metabolismo , Factores de Transcripción Forkhead/metabolismoRESUMEN
The Wiskott-Aldrich syndrome protein (WASp) regulates actin cytoskeletal dynamics and function of hematopoietic cells. Mutations in the WAS gene lead to two different syndromes; Wiskott-Aldrich syndrome (WAS) caused by loss-of-function mutations, and X-linked neutropenia (XLN) caused by gain-of-function mutations. We previously showed that WASp-deficient mice have a decreased number of regulatory T (Treg) cells in the thymus and the periphery. We here evaluated the impact of WASp mutations on Treg cells in the thymus of WAS and XLN mouse models. Using in vitro Treg differentiation assays, WAS CD4 single-positive thymocytes have decreased differentiation to Treg cells, despite normal early signaling upon IL-2 and TGF-ß stimulation. They failed to proliferate and express CD25 at high levels, leading to poor survival and a lower number of Foxp3+ Treg cells. Conversely, XLN CD4 single-positive thymocytes efficiently differentiate into Foxp3+ Treg cells following a high proliferative response to IL-2 and TGF-ß, associated with high CD25 expression when compared with WT cells. Altogether, these results show that specific mutations of WASp affect Treg cell development differently, demonstrating a critical role of WASp activity in supporting Treg cell development and expansion.
Asunto(s)
Diferenciación Celular , Proliferación Celular , Linfocitos T Reguladores , Timo , Proteína del Síndrome de Wiskott-Aldrich , Animales , Linfocitos T Reguladores/inmunología , Diferenciación Celular/inmunología , Proteína del Síndrome de Wiskott-Aldrich/genética , Proteína del Síndrome de Wiskott-Aldrich/metabolismo , Ratones , Timo/inmunología , Timo/citología , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Interleucina-2/metabolismo , Interleucina-2/inmunología , Mutación , Factor de Crecimiento Transformador beta/metabolismo , Síndrome de Wiskott-Aldrich/inmunología , Síndrome de Wiskott-Aldrich/genética , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/genética , Ratones Noqueados , Ratones Endogámicos C57BLRESUMEN
Recombinant human IL-2 has been used to treat inflammatory diseases and cancer; however, side effects like skin rashes limit the use of this therapeutic. To identify key molecules and cells inducing this side effect, we characterized IL-2-induced cutaneous immune reactions and investigated the relevance of CD25 (IL-2 receptor α) in the process. We injected IL-2 intradermally into WT mice and observed increases in immune cell subsets in the skin with preferential increases in frequencies of IL-4- and IL-13-producing group 2 innate lymphoid cells and IL-17-producing dermal γδ T cells. This overall led to a shift toward type 2/type 17 immune responses. In addition, using a novel topical genetic deletion approach, we reduced CD25 on skin, specifically on all cutaneous cells, and found that IL-2-dependent effects were reduced, hinting that CD25 - at least partly - induces this skin inflammation. Reduction of CD25 specifically on skin Tregs further augmented IL-2-induced immune cell infiltration, hinting that CD25 on skin Tregs is crucial to restrain IL-2-induced inflammation. Overall, our data support that innate lymphoid immune cells are key cells inducing side effects during IL-2 therapy and underline the significance of CD25 in this process.
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Inmunidad Innata , Interleucina-2 , Ratones , Humanos , Animales , Interleucina-2/efectos adversos , Interleucina-2/metabolismo , Linfocitos , Inflamación , Linfocitos T Reguladores , Subunidad alfa del Receptor de Interleucina-2/metabolismo , PielRESUMEN
The involvement of γδT cells, Th17 cells, and CD4+CD25+ regulatory T cells (Tregs) is crucial in the progression of pulmonary fibrosis (PF), particularly in maintaining immune tolerance and homeostasis. However, the dynamics of these cells in relation to PF progression, especially under pharmacological interventions, remains poorly understood. This study aims to unravel the interplay between the dynamic changes of these cells and the effect of pharmacological agents in a mouse model of PF induced by intratracheal instillation of bleomycin. We analyzed changes in lung histology, lung index, hydroxyproline levels, and the proportions of γδT cells, Th17 cells, and Tregs on the 3rd, 14th, and 28th days following treatment with Neferine, Isoliensinine, Pirfenidone, and Prednisolone. Our results demonstrate that these drugs can partially or dynamically reverse weight loss, decrease lung index and hydroxyproline levels, and ameliorate lung histopathological damage. Additionally, they significantly modulated the abnormal changes in γδT, Th17, and Treg cell proportions. Notably, on day 3, the proportion of γδT cells increased in the Neferine and Prednisolone groups but decreased in the Isoliensinine and Pirfenidone groups, while the proportion of Th17 cells decreased across all treated groups. On day 14, the Neferine group showed an increase in all three cell types, whereas the Pirfenidone group exhibited a decrease. In the Isoliensinine group, γδT and Th17 cells increased, and in the Prednisolone group, only Tregs increased. By day 28, an increase in Th17 cell proportion was observed in all treatment groups, with a decrease in γδT cells noted in the Neferine group. These shifts in cell proportions are consistent with the pathogenesis changes induced by these anti-PF drugs, suggesting a correlation between cellular dynamics and pharmacological interventions in PF progression. Our findings imply potential strategies for assessing the efficacy and timing of anti-PF treatments based on these cellular changes.
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Bleomicina , Fibrosis Pulmonar , Linfocitos T Reguladores , Células Th17 , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Células Th17/inmunología , Ratones , Piridonas/farmacología , Masculino , Prednisolona/farmacología , Progresión de la Enfermedad , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Pulmón/patología , Pulmón/inmunología , Pulmón/efectos de los fármacos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Isoquinolinas/farmacología , Bencilisoquinolinas/farmacologíaRESUMEN
Cytokines of the common-γ receptor chain (γc) family are crucial for T-cell differentiation and dysregulation of γc cytokine pathways is involved in the pathogenesis of autoimmune diseases. There is increasing evidence that the availability of the γc receptor (CD132) for the associated receptor chains has implications for T-cell functions. Here we studied the influence of differential γc expression on the expression of the IL-2Rα (CD25), the IL-7Rα (CD127) and the differentiation of activated naïve T cells. We fine-tuned the regulation of γc expression in human primary naïve T cells by lentiviral transduction using small hairpin (sh)RNAs and γc cDNA. Differential γc levels were then analysed for effects on T-cell phenotype and function after activation. Differential γc expression markedly affected IL-2Rα and IL-7Rα expression on activated naïve T cells. High γc expression (γc-high) induced significantly higher expression of IL-2Rα and re-expression of IL-7Rα after activation. Inhibition of γc caused lower IL-2Rα/IL-7Rα expression and impaired proliferation of activated naïve T cells. In contrast, γc-high T cells secreted significantly higher concentrations of effector cytokines (i.e., IFN-γ, IL-6) and showed higher cytokine-receptor induced STAT5 phosphorylation during initial stages as well as persistently higher pSTAT1 and pSTAT3 levels after activation. Finally, accelerated transition towards a CD45RO expressing effector/memory phenotype was seen especially for CD4+ γc-high naïve T cells. These results suggested that high expression of γc promotes expression of IL-2Rα and IL-7Rα on activated naïve T cells with significant effects on differentiation and effector cytokine expression.
Asunto(s)
Diferenciación Celular , Activación de Linfocitos , Humanos , Diferenciación Celular/inmunología , Subunidad gamma Común de Receptores de Interleucina/genética , Subunidad gamma Común de Receptores de Interleucina/metabolismo , Receptores de Interleucina-7/metabolismo , Receptores de Interleucina-7/genética , Células Cultivadas , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transducción de Señal , Fosforilación , Factor de Transcripción STAT5/metabolismo , Regulación de la Expresión GénicaRESUMEN
CD25, also known as the interleukin-2 receptor α chain (IL-2Rα), is highly expressed on regulatory T cells (Tregs), but relatively lower on effector T cells (Teffs). This makes it a potential target for Treg depletion, which can be used in tumor immunotherapy. However, marketed anti-CD25 antibodies (Basiliximab and Daclizumab) were originally developed as immunosuppressive drugs to prevent graft rejection, because these antibodies can block IL-2 binding to CD25 on Teffs, which in turn destroys the function of Teffs. Recent studies have shown that non-IL-2-blocking anti-CD25 antibodies have displayed exciting antitumor effects. Here, we screened out a non-IL-2-blocking anti-CD25 monoclonal antibody (mAb) 7B7 by hybridoma technology, and confirmed its antitumor activity via depleting Tregs in a CD25 humanized mouse model. Subsequently, we verified that the humanized 7B7, named as h7B7-15S, has comparable activities to 7B7, and that its Treg depletion is further increased when combined with anti-CTLA-4, leading to enhanced remodeling of the tumor immune microenvironment. Moreover, our findings reveal that the Fab form of h7B7-15S has the ability to deplete Tregs, independent of the Fc region. Taken together, our studies expand the application of anti-CD25 in tumor immunotherapy and provide insight into the underlying mechanism.
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Anticuerpos Monoclonales , Neoplasias , Ratones , Animales , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Inmunosupresores , Linfocitos T Reguladores , Microambiente TumoralRESUMEN
A high percentage of patients with acute coronary syndrome develop heart failure due to the ischemic event. Regulatory T (Treg) cells are lymphocytes with suppressive capacity that control the immune response and include the conventional CD4+ CD25hi Foxp3+ cells and the CD4+ CD25var CD69+ LAP+ Foxp3- IL-10+ cells. No human follow-up studies focus on Treg cells' behavior after infarction and their possible relationship with ventricular function as a sign of postischemic cardiac remodeling. This study aimed to analyze, by flow cytometry, the circulating levels of CD69+ Treg cells and CD4+ CD25hi Foxp3+ cells, their IL-10+ production as well as their function in patients with acute myocardial infarction (AMI), and its possible relation with ventricular dysfunction. We found a significant difference in the percentage of CD4+ CD25hi Foxp3+ cells and IL-10+ MFI in patients with AMI at 72 hours compared with the healthy control group, and the levels of these cells were reduced 6 months post-AMI. Regarding the suppressive function of CD4+ CD25+ regulatory cells, they were dysfunctional at 3 and 6 months post-AMI. The frequency of CD69+ Treg cells was similar between patients with AMI at 72 hours postinfarction and the control groups. Moreover, the frequency of CD69+ Treg cells at 3 and 6 months postischemic event did not vary over time. Treg cells play a role in regulating inflammation after an AMI, and its function may be compromised in this pathology. This work is the first report to evaluate CD69+ Foxp3- Treg cells in AMI patients.
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Antígenos CD , Factores de Transcripción Forkhead , Interleucina-10 , Infarto del Miocardio , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Infarto del Miocardio/inmunología , Masculino , Femenino , Persona de Mediana Edad , Interleucina-10/sangre , Anciano , Factores de Transcripción Forkhead/metabolismo , Lectinas Tipo C/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/inmunología , Citometría de FlujoRESUMEN
Sepsis is characterized by a dysfunctional host response to infection culminating in life-threatening organ failure that requires complex patient management and rapid intervention. Timely diagnosis of the underlying cause of sepsis is crucial, and identifying those at risk of complications and death is imperative for triaging treatment and resource allocation. Here, we explored the potential of explainable machine learning models to predict mortality and causative pathogen in sepsis patients. By using a modelling pipeline employing multiple feature selection algorithms, we demonstrate the feasibility of identifying integrative patterns from clinical parameters, plasma biomarkers, and extensive phenotyping of blood immune cells. While no single variable had sufficient predictive power, models that combined five and more features showed a macro area under the curve (AUC) of 0.85 to predict 90-day mortality after sepsis diagnosis, and a macro AUC of 0.86 to discriminate between Gram-positive and Gram-negative bacterial infections. Parameters associated with the cellular immune response contributed the most to models predictive of 90-day mortality, most notably, the proportion of T cells among PBMCs, together with expression of CXCR3 by CD4+ T cells and CD25 by mucosal-associated invariant T (MAIT) cells. Frequencies of Vδ2+ γδ T cells had the most profound impact on the prediction of Gram-negative infections, alongside other T-cell-related variables and total neutrophil count. Overall, our findings highlight the added value of measuring the proportion and activation patterns of conventional and unconventional T cells in the blood of sepsis patients in combination with other immunological, biochemical, and clinical parameters.
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Sepsis , Humanos , Sepsis/inmunología , Sepsis/microbiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Biomarcadores/sangre , Receptores CXCR3/metabolismo , Aprendizaje Automático , Subunidad alfa del Receptor de Interleucina-2/sangre , Subunidad alfa del Receptor de Interleucina-2/inmunología , Inmunidad Celular , Linfocitos T CD4-Positivos/inmunología , Linfocitos T/inmunología , Pronóstico , Infecciones por Bacterias Gramnegativas/inmunologíaRESUMEN
BACKGROUND: Developmental delay (DD) occurs when children fail to reach developmental milestones in comparison to peers of the same age range. However, there are no valuable biomarkers for the early diagnosis of DD. Since there is no specific marker for screening the disease, we evaluated plasma NSE, TNF-α and sIL2-Rα as potential markers for this purpose. METHODS: In this cross-sectional randomized case-control study, a total of 174 DD patients and 49 matched elderly controls aged between 2 months and 60 months were recruited. A sensitive enzyme-linked immunosorbent assay and an immunoradiometric assay were used to evaluate the levels of plasma IL-1, IL-6, IL-8, IL-10, sIL2-Rα, TNF-α, and NSE. Statistical analyses using t test, χ2, ANOVA, ROC curves and binary logistic regression models were performed. RESULTS: In comparison to the control group, the DD group had greater levels of NSE, TNF-α, and sIL2-Rα(p < 0.05). In the binary logistic regression analysis of DD, NSE had an odds ratio (OR) of 1.783 (95 % CI 1.297 to 2.451, p = 0.000), indicating that NSE was an independent risk factor for DD. The plasma TNF-α level was positively correlated with plasma NSE and sIL2-Rα levels in the DD group (r = 0.366 and 0.433, respectively), and the DQ score and plasma sIL2-Rα level in the DD group were positively correlated. The ROC curve revealed that the respective areas under the NSE, TNF-α, and sIL2-Rα ROC curves were 0.9797, 0.9365, and 0.8533, respectively. Moreover, a significant increase in AUC was observed using combined ROC curve analysis. CONCLUSIONS: Children with DD have significantly altered plasma concentrations of sIL2-Rα, NSE, and TNF-α. NSE, TNF-α and sIL2-Rα can be used as DD blood biomarkers. This information may be helpful in early diagnosis and intervention.
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Fosfopiruvato Hidratasa , Factor de Necrosis Tumoral alfa , Anciano , Niño , Humanos , Lactante , Curva ROC , Estudios de Casos y Controles , Estudios Transversales , Subunidad alfa del Receptor de Interleucina-2 , BiomarcadoresRESUMEN
Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis, and their dysfunction is implicated in the pathogenesis of various autoimmune disorders, including dry eye disease (DED). Treg dysfunction in DED allows T-helper cell 17 (Th17) mediated chronic inflammation at the ocular surface. In this study, the factors causing Treg dysfunction in DED were investigated. We observed reduced expression of Treg functional markers - FoxP3, CD25, and CTLA-4 in the cells isolated from DED mice (DED Tregs). Additionally, DED Tregs showed increased expression levels of receptors for pro-inflammatory cytokine receptors, namely IL-6R, IL-17RA, and IL-23R. An increased expression level of pro-inflammatory cytokine receptors was observed on exposing Tregs isolated from naïve mice (NTregs) to IL-6 or IL-17, but not IL-23, with a concomitant downregulation of FoxP3, CD25, and CTLA-4 in these cells. Furthermore, among these cytokines, IL-6 induced the most pronounced loss of Treg mediated suppression of Th17 proliferation and IL-10 secretion. In vitro and in vivo blockade of IL-6 effectively restored function in DED Tregs, leading to enhanced suppressive function against proliferating Th17 cells and ameliorating disease severity. In conclusion, this study provides insights into mechanisms of Treg dysregulation in DED, specifically delineating the effect of Th17-associated cytokines, with IL-6 emerging as the critical factor inducing Treg dysfunctionality. These findings highlight the potential for developing novel therapeutic interventions for DED through restoration of immunosuppressive function of Tregs.
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Modelos Animales de Enfermedad , Síndromes de Ojo Seco , Factores de Transcripción Forkhead , Interleucina-6 , Ratones Endogámicos C57BL , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Síndromes de Ojo Seco/metabolismo , Síndromes de Ojo Seco/inmunología , Ratones , Interleucina-6/metabolismo , Factores de Transcripción Forkhead/metabolismo , Células Th17/inmunología , Antígeno CTLA-4/metabolismo , Femenino , Citometría de Flujo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Desecación , Células CultivadasRESUMEN
Aberrant neuronal excitability in the anterior cingulate cortex (ACC) is implicated in cognitive and affective pain processing. Such excitability may be amplified by activated circulating immune cells, including T lymphocytes, that interact with the central nervous system. Here, we conducted a study of individuals with chronic pain using magnetic resonance spectroscopy (MRS) to investigate the clinical evidence for the interaction between peripheral immune activation and prefrontal excitatory-inhibitory imbalance. In thirty individuals with chronic musculoskeletal pain, we assessed markers of peripheral immune activation, including soluble interleukin-2 receptor alpha chain (sCD25) levels, as well as brain metabolites, including Glx (glutamate + glutamine) to GABA+ (γ-aminobutyric acid + macromolecules/homocarnosine) ratio in the ACC. We found that the circulating level of sCD25 was associated with prefrontal Glx/GABA+. Greater prefrontal Glx/GABA+ was associated with higher pain catastrophizing, evaluative pain ratings, and anxiodepressive symptoms. Further, the interaction effect of sCD25 and prefrontal Glx/GABA+ on pain catastrophizing was significant, indicating the joint association of these two markers with pain catastrophizing. Our results provide the first evidence suggesting that peripheral T cellular activation, as reflected by elevated circulating sCD25 levels, may be linked to prefrontal excitatory-inhibitory imbalance in individuals with chronic pain. The interaction between these two systems may play a role as a potential mechanism underlying pain catastrophizing. Further prospective and treatment studies are needed to elucidate the specific role of the immune and brain interaction in pain catastrophizing.
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Dolor Crónico , Subunidad alfa del Receptor de Interleucina-2 , Corteza Prefrontal , Humanos , Masculino , Femenino , Dolor Crónico/metabolismo , Corteza Prefrontal/metabolismo , Adulto , Persona de Mediana Edad , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-2/sangre , Giro del Cíngulo/metabolismo , Ácido Glutámico/metabolismo , Ácido Glutámico/sangre , Espectroscopía de Protones por Resonancia Magnética , Glutamina/metabolismo , Glutamina/sangre , Ácido gamma-Aminobutírico/metabolismo , Catastrofización/metabolismoRESUMEN
The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the clinical treatment for tumor. However, the low response rate of ICIs remains the major obstacle for curing patients and effective approaches for patients with primary or secondary resistance to ICIs remain lacking. In this study, immune stimulating agent unmethylated CG-enriched (CpG) oligodeoxynucleotide (ODN) was locally injected into the tumor to trigger a robust immune response to eradicate cancer cells, while anti-CD25 antibody was applied to remove immunosuppressive regulatory T cells, which further enhanced the host immune activity to attack tumor systematically. The combination of CpG and anti-CD25 antibody obtained notable regression in mouse melanoma model. Furthermore, rechallenge of tumor cells in the xenograft model has resulted in smaller tumor volume, which demonstrated that the combinational treatment enhanced the activity of memory T cells. Remarkably, this combinational therapy presented significant efficacy on multiple types of tumors as well and was able to prevent relapse of tumor partially. Taken together, our combinational immunotherapy provides a new avenue to enhance the clinical outcomes of patients who are insensitive or resistant to ICIs treatments.
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Oligodesoxirribonucleótidos , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Oligodesoxirribonucleótidos/uso terapéutico , Oligodesoxirribonucleótidos/farmacología , Ratones , Ratones Endogámicos C57BL , Femenino , Humanos , Línea Celular Tumoral , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Subunidad alfa del Receptor de Interleucina-2/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/terapia , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Vacunación , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéuticoRESUMEN
Profound immune dysregulation and impaired response to the SARS-CoV-2 vaccine put patients with chronic lymphocytic leukemia (CLL) at risk of severe COVID-19. We compared humoral memory and T-cell responses after booster dose vaccination or breakthrough infection. (Green) Quantitative determination of anti-Spike specific antibodies. Booster doses increased seroconversion rate and antibody titers in all patient categories, ultimately generating humoral responses similar to those observed in the postinfection cohort. In detail, humoral response with overscale median antibody titers arose in >80% of patients in watch and wait, off-therapy in remission, or under treatment with venetoclax single-agent. Anti-CD20 antibodies and active treatment with BTK inhibitors (BTKi) represent limiting factors of humoral response, still memory mounted in ~40% of cases following booster doses or infection. (Blue) Evaluation of SARS-CoV-2-specific T-cell responses. Number of T-cell functional activation markers documented in each patient. The vast majority of patients, including those seronegative, developed T-cell responses, qualitatively similar between treatment groups or between vaccination alone and infection cases. These data highlight the efficacy of booster doses in eliciting T-cell immunity independently of treatment status and support the use of additional vaccination boosters to stimulate humoral immunity in patients on active CLL-directed treatments.
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COVID-19 , Leucemia Linfocítica Crónica de Células B , Humanos , SARS-CoV-2 , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Vacunas contra la COVID-19 , Anticuerpos , Subunidad alfa del Receptor de Interleucina-2 , Inmunidad Celular , Anticuerpos Antivirales , VacunaciónRESUMEN
Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.
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Linfocitos T CD8-positivos , Infecciones por Citomegalovirus , Factores de Transcripción Forkhead , Subunidad alfa del Receptor de Interleucina-2 , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/prevención & control , Femenino , Masculino , Linfocitos T CD8-positivos/inmunología , Persona de Mediana Edad , Factores de Transcripción Forkhead/metabolismo , Adulto , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Anciano , Complejo CD3/metabolismo , Citomegalovirus/inmunología , Factores de Riesgo , Receptores de Trasplantes , Supervivencia de Injerto/inmunologíaRESUMEN
Mycosis fungoides (MF) has been widely reported to mimick a considerable number of different dermatoses, including scarring alopecia, bullous dermatoses or cysts, and comedones. In atypical presentations, histopathology is essential for the diagnosis. We present two cases of MF with clinical urticarial lesions and a striking blood involvement that responded to mogamulizumab treatment. Histopathologically, both cases had classic MF features and shared a peculiar immunophenotype, with positivity for CD25 and FOXP3. Differential diagnoses included urticarial lymphomatoid drug reactions and other lymphomas, like T-cell prolymphocytic leukemia, atypical Sézary syndrome, or adult T-cell lymphocytic leukemia. A low suspicion threshold is necessary for the diagnosis of atypical presentations of MF.
Asunto(s)
Inmunofenotipificación , Micosis Fungoide , Neoplasias Cutáneas , Humanos , Micosis Fungoide/patología , Micosis Fungoide/diagnóstico , Neoplasias Cutáneas/patología , Masculino , Inmunofenotipificación/métodos , Diagnóstico Diferencial , Persona de Mediana Edad , Femenino , Urticaria/patología , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Anciano , Factores de Transcripción ForkheadRESUMEN
Regulatory T cells (Tregs) are a subset of T cells participating in a variety of diseases including mycoplasmal pneumonia, contagious ecthyma, and so on. The role of Tregs in goat contagious ecthyma is not completely understood due to the lack of species-specific antibodies. Here, we developed a combination of CD4 and CD25 fluorescence monoclonal antibodies (mAb) to recognize goat Tregs and assessed its utility in flow cytometry, immunofluorescence staining. Using immunofluorescence staining, we found that the frequency of Treg cells was positively correlated with the viral load during orf virus infection. These antibodies could serve as important tools to monitor Tregs during orf virus infection in goats. KEY POINTS: ⢠A combination of fluorescent mAbs (C11 and D12) was prepared for the detection of goat Tregs. ⢠C11 and D12 are effective in flow cytometry, immunofluorescence staining, and C11 has excellent species specificity. ⢠The frequency of Treg cells was positively correlated with the viral load during orf virus infection.
Asunto(s)
Anticuerpos Monoclonales , Citometría de Flujo , Cabras , Linfocitos T Reguladores , Carga Viral , Animales , Linfocitos T Reguladores/inmunología , Anticuerpos Monoclonales/inmunología , Ectima Contagioso/diagnóstico , Ectima Contagioso/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Virus del Orf/inmunología , Técnica del Anticuerpo Fluorescente/métodos , Antígenos CD4/inmunología , Enfermedades de las Cabras/inmunología , Enfermedades de las Cabras/virología , Enfermedades de las Cabras/diagnósticoRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) constitutes a rare, potentially life-threatening hyperinflammatory immune dysregulation syndrome that can present with a variety of clinical signs and symptoms, including fever, hepatosplenomegaly, and abnormal laboratory and immunological findings such as cytopenias, hyperferritinemia, hypofibrinogenemia, hypertriglyceridemia, elevated blood levels of soluble CD25 (interleukin (IL)-2 receptor α-chain), or diminished natural killer (NK)-cell cytotoxicity (reviewed in detail in Chapter 11 of this book). While HLH can be triggered by an inciting event (e.g., infections), certain monogenic causes have been associated with a significantly elevated risk of development of HLH, or recurrence of HLH in patients who have recovered from their disease episode. These monogenic predisposition syndromes are variably referred to as "familial" (FHL) or "primary" HLH (henceforth referred to as "pHLH") and are the focus of this chapter. Conversely, secondary HLH (sHLH) often occurs in the absence of monogenic etiologies that are commonly associated with pHLH and can be triggered by infections, malignancies, or rheumatological diseases; these triggers and the genetics associated with sHLH are discussed in more detail in other chapters in this book.
Asunto(s)
Linfohistiocitosis Hemofagocítica , Animales , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/inmunología , Recurrencia , Factores de Riesgo , Predisposición Genética a la Enfermedad , Subunidad alfa del Receptor de Interleucina-2/inmunología , Células T Asesinas Naturales/inmunología , Citotoxicidad InmunológicaRESUMEN
While eosinophilic esophagitis (EOE) is defined by histologic presence of eosinophils, a few studies have established the presence of mast cells in EOE and even shown their correlation with symptom persistence despite resolution of eosinophils. Expression of aberrant mast cell markers CD25 and CD2 have not been studied in EOE. This study quantifies the number of hotspot cells per high power field expressing CKIT/CD117, tryptase, CD25, CD2 and CD3 by immunohistochemical stains in endoscopic esophageal biopsies of the following three cohorts: (1) established and histologically confirmed EOE, (2) suspected EOE with biopsies negative for eosinophils, and (3) no history of or suspicion for EOE with histologically unremarkable biopsies. In this study, mast cells were highlighted by CKIT and tryptase in EOE, and not seen in other clinically mimicking cases. There were also significantly higher densities of CD25 and pan-T-cell marker staining in EOE cases. These findings suggest an inflammatory cellular milieu in EOE, beyond just eosinophils, that can be demonstrated by immunohistochemistry, and that invite further study into the role that these cells may play in EOE.