Sclareol modulates the Treg intra-tumoral infiltrated cell and inhibits tumor growth in vivo

A regulatory or suppressor T cell is functionally defined as a T cell that inhibits an immune response by influencing the activity of another cell type. On the other hand, Th1 cells express IFN-γ and mediate cellular immunity.Sclareol exhibits growth inhibition and cytotoxic activity against a variety of human cancer cell lines. In the first set of experiments, Sclareol was isolated from the plant Salvia sclarea and our study assessed the immuno-therapeutic effectiveness of Sclareol by direct intra-tumoral injection. Secondly, several immunological parameters such as splenocytes proliferation, intra-tumor CD4⁺CD25⁺Foxp3⁺ Treg cells, IFN-γ and IL-4 secretion and tumor size were assessed to evaluate the anti-tumoral immune response. By all means, the findings confirmed that the activity of Sclareol could reduce the tumor growth in vivo against breast cancer.     

Constitutive expression of CIITA directs CD4 T cells to produce Th2 cytokines in the thymus

We generated mice expressing a human type III CIITA transgene (CIITA Tg) under control of the CD4 promoter to study the role of CIITA in CD4 T cell biology. The transgene is expressed in peripheral CD4 and CD8 T cells, as well as in thymocytes. When CD4 T cells were differentiated towards the Th2 lineage, both control and CIITA Tg Th2 cells expressed similar levels of Th2 cytokines. Th1 cells from control and CIITA Tg mice cells produced comparable levels of IFN-gamma. CIITA Tg Th1 cells also expressed IL-4, IL-5, and IL-13 in the absence of Stat6. There was an approximate 10-fold increase in the number of peripheral na?ve CD4 T cells and NK1.1- thymocytes producing IL-4 from CIITA Tg mice compared to control mice. Finally, Th1 cells from irradiated control mice reconstituted with CIITA Tg bone marrow displayed the same cytokine production profiles as Th1 cells from CIITA Tg mice. Together, our data demonstrate that CIITA expression pre-disposes CD4 T cells to produce Th2 type cytokines. Moreover, phenotypic similarities between Th1 cells expressing the CIITA transgene and CIITA deficient Th1 cells suggest that the role of CIITA in cytokine regulation is complex and may reflect both direct and indirect mechanisms of T cell development and differentiation.     

CD4+CD25+Foxp3hi细胞在夏氏疟原虫感染DBA/2小鼠作用研究

利用调节性T细胞消除的致死型夏氏疟原虫(Plasmodium chabaudi chabaudi AS,P.c chabaudi AS)感染鼠疟模型,探讨DBA/2小鼠对P.c chabaudi AS感染易感性的原因。DBA/2小鼠对P.c chabaudi AS易感,伴随原虫血症增加CD4+CD25+Foxp3+细胞数量明显增加,且以CD4+CD25+Foxp3hi增加更为明显。原虫血症达峰值时CD4+CD25+Foxp3hi细胞数量亦达到峰值。相比,Treg消除鼠的原虫出现时间和疟血症峰值时间均明显延迟,且在疟血症达峰值前(5～8 d)原虫血症水平明显低于对照组。与之相应,CD4+CD25+Foxp3hi细胞数量明显处于低水平。同时,Treg消除鼠生存期明显延长。由此提示,P.c chabaudi AS感染导致Foxp3表达增加,扩增的CD4+CD25+Foxp3hi细胞有利于疟原虫复制和逃避宿主免疫应答,进而影响疟疾感染的进程和最终结局。     

Constitutive Activation of MEK1 Promotes Treg Cell Instability in Vivo

The instability of regulatory T (Treg) cells is involved in the pathogenesis of autoimmune diseases and also highlights safety concerns with regard to clinical Treg cell therapy. Cell-intrinsic molecular events linked to this Treg cell instability in vivo cells, which leads to safety concerns regardingare still obscure. Here we developed a novel luciferase-based reporter system and performed an unbiased screening for kinases that potentially modulate Foxp3 function. We found that the active form of COT/Tpl2 specifically inhibits the DNA binding activity of Foxp3 through a MEK-ERK-dependent pathway. Moreover, Treg cell-specific expression of activated MEK1 led to dysregulation of Treg function and instability of Foxp3 expression in vivo. Our results support the hypothesis that outside inflammatory signals act through the COT/Tpl2-MEK-ERK signaling pathway to destabilize the Treg lineage.     

Involvement of Sema4A in the progression of experimental autoimmune myocarditis

Dilated cardiomyopathy often results from autoimmunity triggered by microbial infections during myocarditis. However, it remains unclear how immunological disorders are implicated in pathogenesis of autoimmune myocarditis. Here, we demonstrated that Sema4A, a class IV semaphorin, plays key roles in experimental autoimmune myocarditis (EAM). Dendritic cells pulsed with myosin heavy chain-α peptides induced severe myocarditis in wild-type mice, but not in Sema4A-deficient mice. In adoptive transfer experiments, CD4⁺ T-cells from wild-type mice induced severe myocarditis, while CD4⁺ T-cells from Sema4A-deficient mice exhibited considerably attenuated myocarditis. Our results indicated that Sema4A is critically involved in EAM by regulating differentiation of T-cells.     

Taenia crassiceps infection abrogates experimental autoimmune encephalomyelitis

Helminth infections induce strong immunoregulation that can modulate subsequent pathogenic challenges. Taenia crassiceps causes a chronic infection that induces a Th2-biased response and modulates the host cellular immune response, including reduced lymphoproliferation in response to mitogens, impaired antigen presentation and the recruitment of suppressive alternatively activated macrophages (AAMФ). In this study, we aimed to evaluate the ability of T. crassiceps to reduce the severity of experimental autoimmune encephalomyelitis (EAE). Only 50% of T. crassiceps-infected mice displayed EAE symptoms, which were significantly less severe than uninfected mice. This effect was associated with both decreased MOG-specific splenocyte proliferation and IL-17 production and limited leukocyte infiltration into the spinal cord. Infection with T. crassiceps induced an anti-inflammatory cytokine microenvironment, including decreased TNF-α production and high MOG-specific production of IL-4 and IL-10. While the mRNA expression of TNF-α and iNOS was lower in the brain of T. crassiceps-infected mice with EAE, markers for AAMФ were highly expressed. Furthermore, in these mice, there was reduced entry of CD3⁺Foxp3⁻ cells into the brain. The T. crassiceps-induced immune regulation decreased EAE severity by dampening T cell activation, proliferation and migration to the CNS.     

The role of commensal bacteria in the regulation of sensitization to food allergens

The prevalence of life-threatening anaphylactic responses to food is rising at an alarming rate. The emerging role of the gut microbiota in regulating food allergen sensitization may help explain this trend. The mechanisms by which commensal bacteria influence sensitization to dietary antigens are only beginning to be explored. We have found that a population of mucosa-associated commensal anaerobes prevents food allergen sensitization by promoting an IL-22-dependent barrier protective immune response that limits the access of food allergens to the systemic circulation. This early response is followed by an adaptive immune response mediated in part by an expansion of Foxp3⁺ Tregs that fortifies the tolerogenic milieu needed to maintain non-responsiveness to food. Bacterial metabolites, such as short-chain fatty acids, may contribute to the process through their ability to promote Foxp3⁺ Treg differentiation. This work suggests that environmentally induced alterations of the gut microbiota offset the regulatory signals conferred by protective bacterial species to promote aberrant responses to food. Our research presents exciting new possibilities for preventing and treating food allergies based on interventions that modulate the composition of the gut microbiota.     

Cross-primed CD8+ cytotoxic T cells induce severe Helicobacter-associated gastritis in the absence of CD4+ T cells

BACKGROUND: Although previous studies have reported important roles of CD4(+) type 1-helper T cells and regulatory T cells in Helicobacter-associated gastritis, the significance of CD8(+) cytotoxic T cells remains unknown. To study the roles of CD8(+) T cells, we examined the immune response in the gastric mucosa of Helicobacter felis-infected major histocompatibility complex (MHC) class II-deficient (II(-/-)) mice, which lack CD4(+) T cells. MATERIALS AND METHODS: Stomachs from H. felis-infected wild-type and infected MHC II(-/-) mice were examined histologically and immunohistochemically. Gastric acidity and serum levels of anti-H. felis antibodies were measured. The expression of pro-inflammatory and anti-inflammatory cytokine, Fas-ligand, perforin, and Foxp3 genes in the gastric mucosa was investigated. RESULTS: H. felis-infected MHC II(-/-) mice developed severe gastritis, accompanied by marked infiltration of CD8(+) cells. At 1 and 2 months after inoculation, mucosal inflammation and atrophy were more severe in MHC II(-/-) mice, although gastritis had reached similar advanced stages at 3 months after inoculation. There was little infiltration of CD4(+) cells, and no Foxp3-positive cells were detected in the gastric mucosa of the infected MHC II(-/-) mice. The expression of the interleukin-1beta and Fas-ligand genes was up regulated, but that of Foxp3 was down regulated in the infected MHC II(-/-) mice. Serum levels of anti-H. felis antibodies were lower in the infected MHC II(-/-) mice, despite severe gastritis. CONCLUSIONS: The present study suggests that cross-primed CD8(+) cytotoxic T cells can induce severe H.-associated gastritis in the absence of CD4(+) helper T cells and that Foxp3-positive cells may have an important role in the control of gastric inflammation.     

Do CD4+ Foxp3+ Treg cells correlate with transplant outcomes: a systematic review on recipients of solid organ transplantation

Regulatory T cells (Tregs) are considered to be critical for the induction of transplant tolerance. Tregs counts were measured in blood, biopsy and urine sample after transplantation in many studies. Although not unanimous, some studies have suggested that Tregs is associated with better outcome and can also serve as an immune marker to predict the individual risk of rejection and identify tolerant patients. In this study, we systematically reviewed the correlation between Tregs and transplant outcomes, identifying if Tregs can predict transplant rejection and tolerance. A total of 22 articles were included and assessed, the results showed that Tregs in recipients are helpful to maintain a stable graft function, reduce acute/chronic rejection rate. And the Tregs in graft and urine, rather than in PBL, may have a better diagnostic value for transplant outcomes. However, since the low quality of included studies, results may be influenced by bias. More high quality studies with bigger sample size are still needed in future.     

白介素-33在疾病中的作用

白介素-33(IL-33)是近年来新发现的IL-1家族的新成员,通过结合其受体ST2诱导Th2型细胞因子的产生。IL-33既可以调节Th2型免疫反应、刺激肥大细胞产生前炎性因子,又可以作为核因子调控基因转录。IL-33在血管性疾病、变态反应性疾病、自身免疫性疾病和炎症性疾病中均发挥重要作用。对IL-33功能及机制的研究将有助于进一步了解这些疾病的致病机制,为疾病治疗提供新的策略。     

Splenectomy changes the pattern of cytokine production in beta-thalassemic patients

A major cause of morbidity and mortality in beta-thalassemic patients is infections, assumed to be the result of immunological changes. To determine the possible defect, we investigated the cytokine productions by blood cells of beta-thalassemic patients using in-vivo and in-vitro methods. Heparinized blood samples collected aseptically from 22 beta-thalassemic children aged 10-12yrs (half of them were splenectomized). Samples from 10 healthy children served as control group. Part of samples was used for evaluation of plasma IL-2, IL-10 and TGF-beta1. Other part were stimulated with a mixture of LPS and PHA (1 and 10 microg/ml final concentration), for different time period (4, 24, 48 and 72h). Results showed circulating TGF-beta1 of splenectomized patients was significantly higher (p<0.01) than the control group. In-vitro results showed IL-2 production of patients' groups were significantly (p<0.01) lower than corresponding value obtained for the control group. In addition, IL-10 production by splenectomized group were less than other two group (p<0.01), while their TGF-beta1 were higher (p<0.001) at all time points treated. In conclusion, multi-transfusions could be responsible for a change in the subset of circulating lymphocytes that could contribute to a state of partial immune deficiency in beta-thalassemic patients, which is more prominence among the splenectomized patient.     

Tolerance of mice to lipopolysaccharide is correlated with inhibition of caspase-3-mediated apoptosis in mouse liver cells

Bacterial endotoxin lipopolysaccharide (LPS) often results in multiple organ failure.However,pre-exposure of mice to a sublethal dose of LPS renders the animal tolerant to a lethal dose of LPS.Thisstudy was designed to determine whether pre-exposure of a small dose of LPS was able to suppressapoptosis in mice when challenged with LPS in combination with D-galactosamine,and to investigate theexpression changes of the apoptosis-associated molecules.The results showed that a characteristic apoptoticDNA fragmentation existed in mouse livers of the LPS-naive group,but not in control groups;and the miceof the LPS-naive group were all dead after 2 d.However,in the LPS-tolerance groups,both the lethal rateand apoptotic DNA fragmentation were suppressed after the mice were challenged with LPS/D-galactosamine,and the protection against the lethality and apoptotic reaction could be maintained for up to 7 d.In thisperiod, significantly lower levels of caspase-3 and its mRNA appeared in LPS-tolerant groups compared tothose of the LPS-naive group (P<0.05),and the caspase-3 activities gradually recovered as the observationwas prolonged.Our findings suggest that LPS tolerance could suppress apoptosis in mouse liver cells,andthe expression and activity of caspase-3 could be down-regulated.     

The life, death, and replacement of oligodendrocytes in the adult CNS

Oligodendrocytes (OLs) are mature glial cells that myelinate axons in the brain and spinal cord. As such, they are integral to functional and efficient neuronal signaling. The embryonic lineage and postnatal development of OLs have been well-studied and many features of the process have been described, including the origin, migration, proliferation, and differentiation of precursor cells. Less clear is the extent to which OLs and damaged/dysfunctional myelin are replaced following injury to the adult CNS. OLs and their precursors are very vulnerable to conditions common to CNS injury and disease sites, such as inflammation, oxidative stress, and elevated glutamate levels leading to excitotoxicity. Thus, these cells become dysfunctional or die in multiple pathologies, including Alzheimer's disease, spinal cord injury, Parkinson's disease, ischemia, and hypoxia. However, studies of certain conditions to date have detected spontaneous OL replacement. This review will summarize current information on adult OL progenitors, mechanisms that contribute to OL death, the consequences of their loss and the pathological conditions in which spontaneous oligodendrogenesis from endogenous precursors has been observed in the adult CNS.     

SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells

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Constitutive presence of cytochrome c in the cytosol of a chemoresistant leukemic cell line

The release of holocytochrome c (cyt c) from mitochondria into the cytosol is reportedly a landmark of the execution phase of apoptosis. As shown here, the P-glycoprotein- (P-gp) expressing K562/ADR cell line (but not the parental K562 cell line) exhibits both cytosolic and mitochondrial cyt c in the absence of any signs of apoptosis. K562/ADR cells were found to be relatively resistant to a variety of different inducers of apoptosis, and blocking the P-gp did not reverse this resistance. The release of cyt c in non-apoptotic K562/ADR cells was not accompanied by that of any other mitochondrial apoptogenic protein, such as AIF or Smac/DIABLO, and was inhibited by Bcl-2 over expression. In addition, using a cell-free system, we show that mitochondria isolated from K562/ADR cells spontaneously released cyt c. These data suggest that cyt c release may be compatible with the preservation of mitochondrial integrity and function, as well as cell proliferation.