Dysregulated T-cell homeostasis and decreased CD30+ Treg proliferating in aplastic anemia
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ABSTRACT:
SUBMITTER: Sun N
PROVIDER: S-EPMC11337026 | biostudies-literature | 2024 Aug
REPOSITORIES: biostudies-literature
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Project description:Fanconi Anemia (FA) is a rare and complex inherited blood disorder associated with bone marrow failure and malignancies. Many alterations in FA physiology appear linked to red-ox unbalance including alterations in the morphology and structure of nuclei, intermediate filaments and mitochondria, defective respiration, reduced ATP production and altered ATP/AMP ratio. These defects are consistently associated with impaired oxygen metabolism indeed treatment with antioxidants N-acetylcysteine (NAC) and resveratrol (RV) does rescue FA physiology. Due to the importance of the intracellular calcium signaling and its key function in the control of intracellular functions we were interested to study calcium homeostasis in FA. We found that FANCA cells display a dramatically low intracellular calcium concentration ([Ca(2+)]i) in resting conditions. This condition affects cellular responses to stress. The flux of Ca(2+) mobilized by H2O2 from internal stores is significantly lower in FANCA cells in comparison to controls. The low basal [Ca(2+)]i in FANCA appears to be an actively maintained process controlled by a finely tuned interplay between different intracellular Ca(2+) stores. The defects associated with the altered Ca(2+) homeostasis appear consistently overlapping those related to the unbalanced oxidative metabolism in FA cells underlining a contiguity between oxidative stress and calcium homeostasis.
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Project description:Acquired aplastic anemia is an idiopathic paradigm of human bone marrow failure syndrome, which involves active destruction of hematopoietic stem cells and progenitors by cytotoxic T cells in the bone marrow. Aberrant expression of microRNAs in T cells has been shown to lead to development of certain autoimmune diseases. In the present study, we performed a microarray analysis of miRNA expression in bone marrow CD3+ T cells from patients with aplastic anemia and healthy controls. Overexpression of miR34a and underexpression of its target gene diacylglycerol kinase (DGK) ζ in bone marrow mononuclear cells were validated in 41 patients and associated with the severity of aplastic anemia. Further, the level of miR34a was higher in naïve T cells from patients than from controls. The role of miR34a and DGKζ in aplastic anemia was investigated in a murine model of immune-mediated bone marrow failure using miR34a-/- mice. After T-cell receptor stimulation in vitro, lymph node T cells from miR34a-/- mice demonstrated reduced activation and proliferation accompanied with a less profound down-regulation of DGKζ expression and decreased ERK phosphorylation compared to those from wild-type C57BL6 control mice. Infusion of 5 × 106 miR34a-/- lymph node T cells into sublethally irradiated CB6F1 recipients led to increased Lin-Sca1+CD117+ cells and less vigorous expansion of CD8+ T cells than injection of same number of wild-type lymph node cells. Our study demonstrates that the miR34a/DGKζ dysregulation enhances T-cell activation in aplastic anemia and targeting miR34a may represent a novel molecular therapeutic approach for patients with aplastic anemia.
| S-EPMC5351619 | biostudies-literature
Project description:Regulatory T cells (Tregs) are often enriched in tumors, where their immunosuppressive function has a key role in tumor persistence and progression. In colorectal cancer (CRC), however, Tregs are frequently associated with an improved clinical outcome. Tumor-infiltrating Tregs have been shown to exhibit a distinct signature comprising the co-stimulatory molecules (OX40, 4-1BB), cytokine receptors (IL1R2, IL21R, CCR8, CD30), and co-inhibitory molecules (PD-L1, TIGIT). Here, we showed by flow cytometry that circulating CD45RO+ Tregs from patients with CRC (n = 25) have elevated CD30 and OX40 expression compared to healthy subjects (n = 14). We identified co-expression of CD30 and OX40 on circulating CD45RO+ Tregs using single-cell images captured by the DEPArray™ system. The frequency of CD30+OX40+CD45RO+ Tregs was significantly higher in CRC patients than in healthy subjects (P < 0.001). Importantly, receiver operating characteristic analysis confirmed that this CD30+OX40+ Treg subset could strongly discriminate between CRC patients and healthy subjects with the highest accuracy of 92.3%, an AUC of 0.92, a sensitivity of 88%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 82.35%, and a trade-off value of 3.44%, compared to other Treg subsets. Consistently, multiplex-IHC/IF of tumor-infiltrating Tregs revealed a significant association between high densities of CD30+OX40+ Tregs and improved overall survival; no such association was found for other subsets. These data suggest a potential role for CD30+OX40+ Tregs as a diagnostic or prognostic biomarker in CRC.
| S-EPMC8289785 | biostudies-literature
Project description:Severe aplastic anemia (SAA) is an autoimmune disease characterized by immune-mediated destruction of hematopoietic stem and progenitor cells. Autoreactive CD8+ T cells have been reported as the effector cells; however, the mechanisms regulating their cell activation in SAA remain largely unknown. Here, we performed proteomics and metabolomics analyses of plasma and bone marrow supernatant, together with transcriptional analysis of CD8+ T cells from SAA patients and healthy donors, to find key pathways that are involved in pathogenic CD8+ T-cell activation. We identified 21 differential proteins and 50 differential metabolites in SAA patients that were mainly involved in energy metabolism, complement and coagulation cascades, and HIF-1α signaling pathways. Interestingly, we found that these pathways are also enriched in T cells from SAA patients by analyzing available single-cell RNA sequencing data. Moreover, CD8+ T cells from SAA patients contain a highly activated CD38+ subset, which was increased in the bone marrow of SAA patients and a murine model of SAA. This subset presented enriched genes associated with the glycolysis or gluconeogenesis pathway, HIF-1α signaling pathway, and complement associated pathways, all of which were of importance in T-cell activation. In conclusion, our study reveals new pathways that may regulate CD8+ T-cell activation in SAA patients and provides potential therapeutic targets for SAA treatment.
| S-EPMC8764265 | biostudies-literature
Project description:Immune-mediated hematopoietic destruction is a key factor in idiopathic severe aplastic anemia (SAA). With great immunomodulatory functions, mesenchymal stem cells (MSCs) are important for bone marrow niche. While the underlying etiology of immunologic changes in SAA bone marrow remains unknown, dysfunctional MSCs are implicated as a major cause. To provide evidence for their defects in immunomodulation, alterations of SAA MSCs in regulating T cell differentiation were determined. During differentiation from CD4+ T cells into T helper 17 (Th17) cells under polarization conditions, impaired inhibition on IL-17 and IL-1β production was noted when cocultured with SAA MSCs compared to control MSCs (P < 0.05). After stimulation of Th17 activation, the percentage of IL-17-secreting cells was significantly increased in the SAA group (9.1 ± 1.5% vs 6.6 ± 0.4%, P < 0.01). Under regulatory T (Treg) polarization, a higher percentage of CD4+CD25+FoxP3+ Treg cells was detected when cocultured with SAA MSCs compared to control MSCs (8.1 ± 0.5% vs 5.8 ± 0.8%, P < 0.01). Inconsistently, transforming growth factor-β (TGF-β) concentrations in the culture supernatant were decreased and IL-1β concentrations were elevated in the SAA group. Our data indicated impaired inhibition of SAA MSCs on Th17 activation and aberrant regulation of SAA MSCs on Treg differentiation. Increased IL-17 and IL-1β levels with decreased TGF-β levels in the supernatant suggested the potential of SAA MSCs for triggering a hyperinflammatory environment. Dysfunctional MSCs could contribute to the lack of immunoprotection in the bone marrow, which may be associated with SAA.
| S-EPMC9925683 | biostudies-literature
Project description:Idiopathic aplastic anemia (AA) has 2 key characteristics: an autoimmune response against hematopoietic stem/progenitor cells and regulatory T-cells (Tregs) deficiency. We have previously demonstrated reduction in a specific subpopulation of Treg in AA, which predicts response to immunosuppression. The aims of the present study were to define mechanisms of Treg subpopulation imbalance and identify potential for therapeutic intervention. We have identified 2 mechanisms that lead to skewed Treg composition in AA: first, FasL-mediated apoptosis on ligand interaction; and, second, relative interleukin-2 (IL-2) deprivation. We have shown that IL-2 augmentation can overcome these mechanisms. Interestingly, when high concentrations of IL-2 were used for in vitro Treg expansion cultures, AA Tregs were able to expand. The expanded populations expressed a high level of p-BCL-2, which makes them resistant to apoptosis. Using a xenograft mouse model, the function and stability of expanded AA Tregs were tested. We have shown that these Tregs were able to suppress the macroscopic clinical features and tissue manifestations of T-cell-mediated graft-versus-host disease. These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions. Supplementation of ex vivo expansion cultures of Tregs with high concentrations of IL-2 or delivery of IL-2 directly to patients could improve clinical outcomes in addition to standard immunosuppressive therapy.
| S-EPMC7532000 | biostudies-literature
Project description:BackgroundAngelica sinensis polysaccharide (ASP) is an effective medicine for aplastic anemia (AA). The present study aims to investigate whether mitochondrial apoptosis in aplastic anemia could be corrected by ASP by adjusting an abnormal level of regulatory T cell (Treg)/ IL-17 secreting CD4 T cell (Th17) ratio.MethodsBALB/c mice were treated with 5.0 Gy Co60 γ -radiation. Then 2 × 106 lymph node cells from DBA/2 donor mice were transplanted within 4 h after radiation. The mice in the various groups were fed saline or ASP for 2 weeks. For the in vitro experiment, bone marrow nucleated cells (BMNCs) and Treg cells were sorted from the mice on the 2nd day of modeling, and then cultured with or without ASP.ResultsThe mice treated with the medium dose of ASP for 14 days showed increased white blood cell (WBC), red blood cell (RBC), platelet (PLT), BMNC counts and Lin-Sca-1 + c-Kit+ (LSK) populations viability compared with the mice in the AA group mice. The data showed that ASP decreased damage to the mitochondrial outer membrane, improved the stabilization of the mitochondrial membrane, and corrected the abnormal levels of ROS and mitochondrial-associated apoptosis proteins, including the Bcl-2/Bax ratio and caspase-3 and caspase-9 expression, in BMNCs which were sorted from the bone marrow cells of AA mice. The changes to the p-P38/P38 and Treg/Th17 ratios induced by AA were also reversed by the medium dose of ASP. The same ASP effect including the Bcl-2/Bax and p-P38/P38 ratio, caspase-3 and caspase-9 expression of BMNCs were observed in vivo. The viability of Treg cells were increased by treatment of ASP in vivo.ConclusionsASP might prevent mitochondrial apoptosis to restore the function of hematopoietic stem cells by suppressing abnormal T-cell immunity in AA.
| S-EPMC7309996 | biostudies-literature
Project description:TGF-? signaling in T cells is critical for peripheral T-cell tolerance by regulating effector CD4(+) T helper (Th) cell differentiation. However, it is still controversial to what extent TGF-? signaling in Foxp3(+) regulatory T (Treg) cells contributes to immune homeostasis. Here we showed that abrogation of TGF-? signaling in thymic T cells led to rapid type 1 diabetes (T1D) development in NOD mice transgenic for the BDC2.5 T-cell receptor. Disease development in these mice was associated with increased peripheral Th1 cells, whereas Th17 cells and Foxp3(+) Treg cells were reduced. Blocking of IFN-? signaling alone completely suppressed diabetes development in these mice, indicating a critical role of Th1 cells in this model. Furthermore, deletion of TGF-? signaling in peripheral effector CD4(+) T cells, but not Treg cells, also resulted in rapid T1D development, suggesting that conventional CD4(+) T cells are the main targets of TGF-? to suppress T1D. TGF-? signaling was dispensable for Treg cell function, development, and maintenance, but excessive IFN-? production due to the absence of TGF-? signaling in naive CD4(+) T cells indirectly caused dysregulated Treg cell homeostasis. We further showed that T cell-derived TGF-?1 was critical for suppression of Th1 cell differentiation and T1D development. These results indicate that autocrine/paracrine TGF-? signaling in diabetogenic CD4(+) T cells, but not Treg cells, is essential for controlling T1D development.
| S-EPMC3637710 | biostudies-literature
Project description: Not available
| S-EPMC6978321 | biostudies-literature
Project description:Hepatitis-associated aplastic anemia (HAA) is a variant of acquired aplastic anemia (AA) in which immune-mediated bone marrow failure (BMF) develops following an acute episode of seronegative hepatitis. Dyskeratosis congenita (DC) is an inherited BMF syndrome characterized by the presence of short telomeres, mucocutaneous abnormalities, and cancer predisposition. While both conditions may cause BMF and hepatic impairment, therapeutic approaches are distinct, making it imperative to establish the correct diagnosis. In clinical practice, lymphocyte telomere lengths (TL) are used as a first-line screen to rule out inherited telomeropathies before initiating treatment for AA. To evaluate the reliability of TL in the HAA population, we performed a retrospective analysis of TL in 10 consecutively enrolled HAA patients compared to 19 patients with idiopathic AA (IAA). HAA patients had significantly shorter telomeres than IAA patients (P = 0.009), including four patients with TL at or below the 1st percentile for age-matched controls. HAA patients had no clinical features of DC and did not carry disease-causing mutations in known genes associated with inherited telomere disorders. Instead, short TLs were significantly correlated with severe lymphopenia and skewed lymphocyte subsets, features characteristic of HAA. Our results indicate the importance of caution in the interpretation of TL measurements in HAA, because, in this patient population, short telomeres have limited specificity.
| S-EPMC4724330 | biostudies-literature