Cell Differentiation In Thymus Research Articles

Prediction of acute myeloid leukemia prognosis based on autophagy features and characterization of its immune microenvironment.

Autophagy promotes the survival of acute myeloid leukemia (AML) cells by removing damaged organelles and proteins and protecting them from stress-induced apoptosis. Although many studies have identified candidate autophagy genes associated with AML prognosis, there are still great challenges in predicting the survival prognosis of AML patients. Therefore, it is necessary to identify more novel autophagy gene markers to improve the prognosis of AML by utilizing information at the molecular level. In this study, the Random Forest, SVM and XGBoost algorithms were utilized to identify autophagy genes linked to prognosis, respectively. Subsequently, six autophagy genes (TSC2, CALCOCO2, BAG3, UBQLN4, ULK1 and DAPK1) that were significantly associated with patients' overall survival (OS) were identified using Lasso-Cox regression analysis. A prediction model incorporating these autophagy genes was then developed. In addition, the immunological microenvironment analysis of autophagy genes was performed in this study. The experimental results showed that the predictive model had good predictive ability. After adjusting for clinicopathologic parameters, this feature proved an independent prognostic predictor and was validated in an external AML sample set. Analysis of differentially expressed genes in patients in the high-risk and low-risk groups showed that these genes were enriched in immune-related pathways such as humoral immune response, T cell differentiation in thymus and lymphocyte differentiation. Then immune infiltration analysis of autophagy genes in patients showed that the cellular abundance of T cells CD4+ memory activated, NK cells activated and T cells CD4+ in the high-risk group was significantly lower than that in the low-risk group. This study systematically analyzed autophagy-related genes (ARGs) and developed prognostic predictors related to OS for patients with AML, thus more accurately assessing the prognosis of AML patients. This not only helps to improve the prognostic assessment and therapeutic outcome of patients, but may also provide new help for future research and clinical applications.

P53 prevents maturation of T cell development to the immature CD4 −CD8 + stage in Bcl11b−/− mice

Signaling pathways such as the pre-TCR and Wnt pathways regulate α/β T cell differentiation in thymus. Mice lacking an essential component of the pre-TCR exhibit arrest at the (CD4 −CD8 −) (CD44 −CD25 +) stage (DN3) of thymocyte development, and introduction of p53 deficiency into those mice abrogates this arrest, resulting in transition to the (CD4 +CD8 +) double-positive (DP) stage. This paper examines the effect of inactivation of p53 on thymocyte development in Bcl11b −/− mice that exhibit arrest at the DN3 or (CD4 −CD8 +) immature single-positive (ISP) stage. No DP thymocytes were detected in thymocytes of adoptive transfer experiments in scid mice that were derived from p53 −/− Bcl11b −/− precursors but ISP thymocytes increased in the proportion and in the cell number approximately three times higher than those from Bcl11b −/− precursors. Consistently, the level of apoptosis decreased to the level of wild-type precursors. These results suggest that inactivation of p53 is sufficient for DN3 thymocytes to differentiate into the ISP, but not to DP, stage of thymocyte development in Bcl11b −/− mice. This provides evidence for a novel p53-mediated checkpoint that regulates the transition from the DN3 to ISP stage of thymocyte development.

Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus.

T cell differentiation in the thymus depends on sequential interactions between lymphoid progenitors and stromal cells in discrete regions of the cortex. Here we show that CXCL12/CXCR4 signaling is absolutely required for proper localization of early progenitors into the cortex and thus for successful steady state differentiation. All early progenitors in the thymus express CXCR4, and its ligand (CXCL12) is expressed only by stromal cells in the cortex, where early progenitors are found. Early progenitors migrate in response to CXCL12 in vitro, while thymus-specific deletion of CXCR4 in vivo results in failed cortical localization and developmental arrest. These findings indicate a crucial and nonredundant role for CXCR4 in facilitating localization of early lymphoid progenitors to tissue regions of the thymus, where lineage commitment and proliferation are controlled.

Vitamin E enhances T cell differentiation through increased epithelial cell function in rat thymus

This study was designed to elucidate the mechanism on increased T cell differentiation in thymus following vitamin E supplementation and discussed on the changes of epithelial cell (TEC) and macrophage functions in thymus following vitamin E supplementation. Thymic epithelial cells isolated by panning method from thymocytes of rats fed the high vitamin E (500 IU α-tocopherol nicotinate/kg) diet for 7 weeks increased the proportion of CD4+CD8- T cells in thymocytes. In addition, when thymic epithelial cell line IT45-R1 was pretreated with vitamin E for 24 h and then incubated with immature T cells for 48 h, they also enhanced the proportion of CD4+CD8-T cells in thymocytes. On the contrary, the supernatant of IT45-R1 treated in vitro with vitamin E for 24 h did not have any effect on the proportions of T cell subsets in thymocytes. Furthermore, in vitro treatment with vitamin E significantly enhanced the binding capacity of TEC to immature T cells. The expression of adhesion molecule, ICAM-1, on the membrane of TEC was also greatly increased by high vitamin E diet. However, in vitro incubation with macrophages isolated from rats fed the regular or high vitamin E diet did not induce a significant difference in the changes of T cell subsets in immature T cells. These results suggest that vitamin E enhances T cell differentiation through the increase of not macrophage but TEC function in thymus, which is associated with the increased binding capacity of TEC to immature T cells via increased expression of ICAM-1.

Vitamin E supplementation induces an early recovery of cellular immunity decreased following X-ray irradiation

We have previously reported that vitamin E has an ability to enhance T cell differentiation in rat thymus. The aim of this study is to investigate whether T cell differentiation enhanced by vitamin E supplementation is effective in decreasing cellular immunity after X-ray irradiation in rats. Male Fisher rats, 4-weeks old, were fed control (50 mg vitamin E/kg diet) or high vitamin E diet (585 mg vitamin E/kg diet) for 4 weeks and then irradiated X-ray. On 2, 5 and 9 days after X-ray irradiation, rats were killed under anesthesia and their cellular immune functions were assayed. Vitamin E supplementation did not result in decreased thymic weights or change in the numbers of thymocytes and peripheral blood lymphocytes (PBL) following X-ray irradiation. In addition, proliferation of PBL with T cell mitogens, phytohemagglutinin (PHA) and concanavalin A (ConA), also decreased in both control and high vitamin E groups following X-ray irradiation. On the contrary, proliferation of bone marrow cells (BMC) was maintained much the same as pretreatment of X-ray irradiation in high vitamin E group even after X-ray irradiation compared to a significant decrease in the control group. The proliferation of thymocytes with PHA or ConA also showed an early recovery in high vitamin E, which was associated with not the production of interleukin 2 (IL2), T cell growth factors, but early recovery in the proportion of CD4 +CD8 + T cells in thymocyte. These results suggest that vitamin E supplementation accelerates the recovery of the X-ray irradiation-induced decrease in cellular immunity. The signs of accelerated recovery were enhanced T cell differentiation in thymus and the maintenance of bone marrow cell (BMC) proliferation during X-ray irradiation.

Vitamin E is an important factor in T cell differentiation in thymus of F344 rats.

The effect of vitamin E (dl-alpha-tocopheryl acetate) on T cell differentiation in thymus of F344 rats was examined in this study. The rats were divided into three groups: vitamin E-free, regular and high vitamin E groups and fed a diet containing various levels of vitamin E (0, 50, and 585 mg/kg diet) for 7 weeks. The number of thymocytes was significantly lower in the vitamin E-free group relative to the regular group. Although the proportions of both CD4+CD8- and CD4-CD8+ T cells in thymocytes were significantly greater in the high vitamin E group, the proportion of CD4+CD8- T cells inversely decreased in vitamin E-free group compared to that of the regular group. The ratio of CD4+CD8-/CD4-CD8+ T cells increased in the high vitamin E group (p < 0.01) and significantly decreased in the vitamin E-free group (p < 0.001) compared to that of the regular group. Although the marked changes of T cell subsets were not seen in peripheral blood lymphocytes (PBL), the ratio of CD4+CD8-/CD4-CD8+ T cells was significantly lower in the vitamin E-free group and significantly greater in the high vitamin E group compared to that of the regular group. Production of interleukin (IL) 2 by thymocytes following the stimulation with Con A for 48 h increased about threefold in the high vitamin E group compared to the regular group. Conversely, thymocytes from rats fed the vitamin E-free diet showed a significant decrease of IL2 production compared to that of the regular group. Prostaglandin E2 (PGE2) production from thymocytes was significantly lower in the high vitamin E group compared to that of the regular group, whereas thymocytes of rats fed the vitamin E-free diet showed a significant increase of PGE2 production compared to that of rats fed the regular diet. Furthermore, in vitro addition of indomethacin provided a restoration of IL2 production from thymocytes of rats fed the vitamin E-free diet to the level of rats fed the regular diet. These results suggest that vitamin E plays an important role in T cell differentiation in thymus, which may be related to the action of vitamin E as antioxidant.