Treg Cell Population Research Articles

Memory of Inflammation in Regulatory T Cells

Eukaryotic cells can "remember" transient encounters with a wide range of stimuli, inducing lasting states of altered responsiveness. Regulatory T (Treg) cells are a specialized lineage of suppressive CD4 Tcells that act as critical negative regulators of inflammation in various biological contexts. Treg cells exposed to inflammatory conditions acquire strongly enhanced suppressive function. Using inducible genetic tracing, we analyzed the long-term stability of activation-induced transcriptional, epigenomic, and functional changes in Treg cells. We found that the inflammation-experienced Treg cell population reversed many activation-induced changes and lost its enhanced suppressive function over time. The "memory-less" potentiation of Treg suppressor function may help avoid a state of generalized immunosuppression that could otherwise result from repeated activation.

Defective natural killer cell activity in a mouse model of eczema herpeticum

Patients with atopic dermatitis (AD) are susceptible to several viruses, including herpes simplex virus (HSV). Some patients experience 1 or more episodes of a severe skin infection caused by HSV termed eczema herpeticum (EH). There are numerous mouse models of AD, but no established model exists for EH. We sought to establish and characterize a mouse model of EH. We infected AD-like skin lesions with HSV1 to induce severe skin lesions in a dermatitis-prone mouse strain of NC/Nga. Gene expression was investigated by using a microarray and quantitative PCR; antibody titers were measured by means of ELISA; and natural killer (NK) cell, cytotoxic T-cell, regulatory T-cell, and follicular helper T-cell populations were evaluated by using flow cytometry. The role of NK cells in HSV1-induced development of severe skin lesions was examined by means of depletion and adoptive transfer. Inoculation of HSV1 induced severe erosive skin lesions in eczematous mice, which had an impaired skin barrier, but milder lesions in small numbers of normal mice. Eczematous mice exhibited lower NK cell activity but similar cytotoxic T-cell activity and humoral immune responses compared with normal mice. The role of NK cells in controlling HSV1-induced skin lesions was demonstrated by experiments depleting or transferring NK cells. A murine model of EH with an impaired skin barrier was established in this study. We demonstrated a critical role of defective NK activities in the development of HSV1-induced severe skin lesions in eczematous mice.

Epstein–Barr virus and regulatory T cells in Egyptian paediatric patients with acute B lymphoblastic leukaemia

ObjectiveAcute B lymphoblastic leukaemia (B-ALL) is the most common type of childhood malignancy worldwide but little is known of its origin. Recently, many studies showed both a high incidence of...

The balance between Foxp3 and Ror-γt expression in peripheral blood is altered by tocilizumab and abatacept in patients with rheumatoid arthritis.

BackgroundThe balance between Th17 cells and regulatory T (Treg) cells has been shown to play an important role in the development of rheumatoid arthritis (RA). Recent studies have shown that treatment with abatacept (ABT) or tocilizumab (TCZ) affects Th17 and Treg cell populations. Although not unanimously accepted, several reports have shown that Treg cells are decreased by ABT and increased by TCZ, and that Th17 cells are decreased by TCZ. To further investigate the effects of ABT and TCZ on the skewing of T cell populations, we analyzed the expression of master regulators genes of helper T cell lineages following ABT/TCZ treatment of RA patients.MethodsTen patients treated with ABT and 10 patients treated with TCZ were enrolled. Total RNA was extracted from peripheral blood cells at baseline, and after 12 and 24 weeks of therapy. The expression levels of T-bet, GATA3, Foxp3 and Ror-γt were semi-quantified using real-time PCR. The relative expression levels were expressed as the ratios of two genes (T-bet/GATA3, Foxp3/GATA3, Foxp3/T-bet, Foxp3/Ror-γt, Ror-γt/T-bet, Ror-γt/GATA3), and the changes in these ratios with treatment were determined.ResultsThe Foxp3/Ror-γt ratio was decreased after ABT therapy (0.67 ± 0.16 at 24 weeks, P = 0.0034) but was increased after TCZ therapy (2.00 ± 1.03 at 24 weeks, P = 0.0013). In addition, the Ror-γt/GATA3 ratio was decreased after TCZ therapy (0.78 ± 0.37 at 24 weeks, P = 0.0008). Except for these ratios, no significant skewing in the expression of these factors was detected. No significant relationship between clinical response to the treatment and change in the ratios of these factors was determined.ConclusionTreatment with TCZ or ABT differently affected the balance between Foxp3 and Ror-γt expression in the peripheral blood of patients with RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s12891-016-1137-1) contains supplementary material, which is available to authorized users.

Exploring the induction of preproinsulin-specific Foxp3(+) CD4(+) Treg cells that inhibit CD8(+) T cell-mediated autoimmune diabetes by DNA vaccination.

DNA vaccination is a promising strategy to induce effector T cells but also regulatory Foxp3+ CD25+ CD4+ Treg cells and inhibit autoimmune disorders such as type 1 diabetes. Little is known about the antigen requirements that facilitate priming of Treg cells but not autoreactive effector CD8+ T cells. We have shown that the injection of preproinsulin (ppins)-expressing pCI/ppins vector into PD-1- or PD-L1-deficient mice induced Kb/A12-21-monospecific CD8+ T cells and autoimmune diabetes. A pCI/ppinsΔA12-21 vector (lacking the critical Kb/A12-21 epitope) did not induce autoimmune diabetes but elicited a systemic Foxp3+ CD25+ Treg cell immunity that suppressed diabetes induction by a subsequent injection of the diabetogenic pCI/ppins. TGF-β expression was significantly enhanced in the Foxp3+ CD25+ Treg cell population of vaccinated/ppins-primed mice. Ablation of Treg cells in vaccinated/ppins-primed mice by anti-CD25 antibody treatment abolished the protective effect of the vaccine and enabled diabetes induction by pCI/ppins. Adoptive transfer of Treg cells from vaccinated/ppins-primed mice into PD-L1−/− hosts efficiently suppressed diabetes induction by pCI/ppins. We narrowed down the Treg-stimulating domain to a 15-residue ppins76–90 peptide. Vaccine-induced Treg cells thus play a crucial role in the control of de novo primed autoreactive effector CD8+ T cells in this diabetes model.

Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system

Type 2 phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) converts phosphatidylinositol-5-phosphate to phosphatidylinositol-4,5-bisphosphate. Mammals have three enzymes PI5P4Kα, PI5P4Kβ, and PI5P4Kγ, and these enzymes have been implicated in metabolic control, growth control, and a variety of stress responses. Here, we show that mice with germline deletion of type 2 phosphatidylinositol-5-phosphate 4-kinase gamma (Pip4k2c), the gene encoding PI5P4Kγ, appear normal in regard to growth and viability but have increased inflammation and T-cell activation as they age. Immune cell infiltrates increased in Pip4k2c(-/-) mouse tissues. Also, there was an increase in proinflammatory cytokines, including IFNγ, interleukin 12, and interleukin 2 in plasma of Pip4k2c(-/-) mice. Pip4k2c(-/-) mice had an increase in T-helper-cell populations and a decrease in regulatory T-cell populations with increased proliferation of T cells. Interestingly, mammalian target of rapamycin complex 1 (mTORC1) signaling was hyperactivated in several tissues from Pip4k2c(-/-) mice and treating Pip4k2c(-/-) mice with rapamycin reduced the inflammatory phenotype, resulting in a decrease in mTORC1 signaling in tissues and a decrease in proinflammatory cytokines in plasma. These results indicate that PI5P4Kγ plays a role in the regulation of the immune system via mTORC1 signaling.

Adaptive immune function in critical illness.

This review is being published to update the literature on the function of the adaptive immune system in critical illness, specifically sepsis and acute lung injury. We have focused on the role of T cells in these syndromes. The adaptive immune response becomes dysfunctional during sepsis and acute lung injury in very similar ways. Many of the abnormalities contribute to morbidity and mortality. Immunoparalysis captures the breadth of the dysfunction in that T-cell functions are broadly suppressed after the early proinflammatory stages of illness. Lymphocyte apoptosis, decreased antigen responsiveness, decreased and altered cytokine expression, upregulation of inhibitory molecules, and expansion of the suppressive regulatory T-cell population are mechanisms involved. Each of these abnormalities can be reversed with improvement in experimental outcomes. Immunoparalysis of the adaptive immune system occurs in sepsis and acute lung injury, and is critical to the outcome. Blocking the inhibited pathways and immunostimulant cytokines improved lymphocyte function and outcome. Many such blocking agents are already effective for other diseases and could be used for immunoparalysis. Unfortunately, there is no diagnostic marker yet. In order to provide the right therapy at the right time, advancements in immunomonitoring are necessary.

A dynamic relationship between mucosal T helper type 17 and regulatory T-cell populations in nasopharynx evolves with age and associates with the clearance of pneumococcal carriage in humans

Pneumococcal carriage is common in young children, which may account for the high incidence of disease in this age group. Host factors determining the clearance of carriage in humans remain unclear. We aimed to study the relationships between T helper type 17 (Th17) and Foxp3+ regulatory T (Treg) cells in nasopharynx-associated lymphoid tissue (NALT) and carriage in children and adults. Frequencies of Th17 and Treg cells in NALT were analysed by flow cytometry in association with age and pneumococcal carriage status. Cytokine responses following pneumococcal stimulation were analysed by cytometric beads array. The frequencies of Th17 and Treg cells in NALT were inversely correlated (R –0.60). Whereas Treg cell frequency decreased with age (R –0.63), both Th17 and the Th17: Treg ratio increased with age (R 0.62 and R 0.64, respectively). Also, the Th17: Treg ratio was higher in carriage-negative than in carriage-positive children (p <0.01). Pneumococcal stimulation of tonsillar cells increased both Th17 and Treg cell numbers, but the Th17: Treg ratio and pattern of cytokine responses differed between carriage-negative and carriage-positive children. The former showed markedly higher Th17: Treg and interleukin-17A: interleukin-10 ratios than in the latter (p <0.01). Pneumococcal stimulation also induces Th17, although the capacity of this Th17 differentiation from naive T cells of young children was low, but increased with age. We demonstrated a dynamic relationship between Th17 and Treg cells in human nasopharynx that evolves with age. The balance between Th17 and Treg cells in NALT appears to be a major host factor closely associated with the clearance of Streptococcus pneumoniae from the nasopharynx.

Rosiglitazone-mediated dendritic cells ameliorate collagen-induced arthritis in mice

Rosiglitazone is a selective ligand for peroxisome proliferator-activated receptor-gamma (PPAR-γ), which serves diverse biological functions. A number of autoimmune disease models have been used to examine the anti-inflammatory and immunosuppressive effects of tolerogenic dendritic cells (tDCs). The aim of the present study was to investigate whether rosiglitazone-mediated DC (Rosi-DC) therapy suppressed arthritis in a collagen-induced arthritis (CIA) mouse model.Rosi-DCs were generated by treating immature DCs with TNF-α, type II collagen, and rosiglitazone. CIA mice then received subcutaneously (s.c.) two injections of Rosi-DCs. The severity of arthritis was then assessed histopathologically. The phenotypes of the DC and regulatory T (Treg) cell populations in CIA mice were determined by flow cytometry and the effect of Rosi-DCs on the secretion of autoimmunity-inducing cytokines was examined by ELISA.Rosi-DCs expressed lower levels of DC-related surface markers than mature DCs. Histopathological examination revealed that the degree of inflammation in the paws of Rosi-DC-treated mice was much lower than that in the paws of PBS-treated CIA mice.Taken together, these results clearly show that rosiglitazone-mediated DCs ameliorate CIA, most likely via the induction of antigen-specific Treg cells.

FVIII tolerance induction in hemophilia A mice utilizing low dose IL2 treatment

Abstract Hemophilia A patients lack or possess low levels of functional FVIII protein, which results in an inability for the blood to clot when injury occurs. The current treatment for hemophilia A patients is FVIII protein replacement, but this treatment is expensive and often results in anti-FVIII immune responses, neutralizing the clotting effect. Regulatory T (Treg) cells help balance T effector (Teff) cells through their suppressive function during an immune response and keep autoimmunity in check. Treg cells possess a high affinity epitope of the IL2 receptor. With a low dose of IL2, the Treg population outcompetes the Teff cells, leading to an increase in activation and number. The increased suppressive activity may induce tolerance in hemophilia A mice treated with FVIII. Hemophilia A mice were hydrodynamically injected with IL2 and FVIII plasmids. Cell staining data showed a marked increase in Treg cell population and activation. In addition, the Treg/Teff ratio was significantly increased in the first 3 weeks and maintained at increased levels over several weeks afterwards. On Day 28-post FVIII injection, control mice had started to develop inhibitors associated with significant decrease of FVIII expression, while mice treated with IL2 showed no inhibitors with persistent FVIII expression. The treated mice are monitored to determine the potential long term tolerance induced by low dose IL2. Combined gene transfer of FVIII and IL2 plasmids can produce therapeutic FVIII and simultaneously prevent inhibitory antibody formation, thus providing a potentially effective treatment of hemophilia A.

441. IL2 Plasmid Treated Hemophilia A Mice Show an Increase in Regulatory T Cell Population and Initial Tolerance to FVIII

Hemophilia A is an inherited X chromosomal linked recessive disease. Hemophilia A patients lack or possess low levels of functional FVIII protein, which results in an inability for the blood to clot when injury occurs. This inability to clot can result in major blood loss and potential death. The current treatment for patients with hemophilia A is FVIII protein replacement, but this treatment is expensive and often results in anti-FVIII immune responses, neutralizing the clotting effect. In order to overcome this potential immune response patients undergo a high dose regimen of FVIII to induce tolerance. However, a third of patients still develop an immune response.Regulatory T (Treg) cells help balance T effector (Teff) cells through their suppressive function during an immune response and keep autoimmunity in check. Both of these cell types bind to interleukin 2 (IL2), a cytokine which promotes the differentiation, expansion and activation of these cell populations. Treg cells possess a high affinity epitope of the IL2 receptor. With a low dose of IL2, the Treg population outcompetes the Teff cells, leading to an increase in activation and number. The increased suppressive activity may induce tolerance in hemophilia A mice treated with FVIII plasmid.Hemophilia A mice were hydrodynamically injected with either 2 µg or 5 µg IL2 plasmid and 50 µg FVIII plasmid, either sequentially (1 week apart) or simultaneously. Both plasmids were driven by a liver-specific promoter (hAAT-HCR). Cell staining data showed a marked increase in Treg cell population and activation, demonstrating that a small amount of IL2 plasmid incorporated into liver cells is enough to dramatically increase the Treg population. A larger increase of Teff cells were observed in mice treated with 5 µg IL2 plasmid than in mice treated with 2 µg IL2 plasmid. Importantly, Treg/Teff ratio was significantly increased in the 2 µg IL2 plasmid group in the first 3 weeks and maintained at increased levels over several weeks afterwards. ELISA showed an initial higher level of IL2 production; IL2 expression dropped and maintained at low levels after one week. On Day 28-post FVIII plasmid injection, control mice had started to develop inhibitors associated with significant decrease of FVIII expression, while mice treated with IL2 plasmid showed no inhibitor development with persistent FVIII gene expression. The treated mice are monitored to determine the potential long term tolerance effects induced by low dose IL2 plasmid. Using gene therapy to slightly increase the amount of a cytokine in patients could provide a better treatment option than existing drug regimens. FVIII protein is also extremely expensive, especially in the amounts needed for treating hemophilia A patients. Combined gene transfer of FVIII and IL2 plasmids has the potential to produce therapeutic FVIII and simultaneously prevent inhibitory antibody formation, therefore reducing the amount of expensive reagents needed, the number of doctor visits required, and the overall cost, potential morbidity and stress to the patient.

Reduced IL-2R signaling in T1D subjects is pervasive in the memory CD4 T effector compartment and is mediated through intrinsic mechanisms

Abstract The IL-2/IL-2R pathway is strongly implicated in type 1 diabetes (T1D). Yet, identifying the functional significance and underlying mechanisms of altered IL-2R signaling in T1D has been challenging due to variance in the subjects, cell types and the assays utilized. We performed a large, well-matched, cross-sectional study of control and T1D subjects (n&amp;gt;75 subjects per group), with an optimized IL-2/pSTAT5 assay (internal control CoV &amp;lt;7%). We found reduced responses to IL-2 in memory CD4 Treg and Teff cell populations of T1D subjects relative to controls. Known genetic risk alleles accounted for some, but not all, of the reduction in pSTAT5. To determine additional factors underlying reduced IL-2R signaling, we interrogated CD4 Teff cells of control and T1D subjects held constant for risk alleles associated with IL-2R signaling. IL-2 signaling in T1D memory CD4 Teff cells remained significantly lower than controls after in vitro activation and proliferation, suggesting a role for intrinsic factors. These intrinsic factors were not caused by divergence to MAPK or Akt signaling pathways, as measured by western blot. Instead, differences in basal activation state prior to in vitro activation correlated with IL-2 response, as measured by targeted flow and qPCR of activation and negative regulation. Thus, multiple factors including genetics, disease and activation state contribute to natural variation in IL-2 responsiveness, requiring precise assays and well-defined cohorts to reach solid conclusions. These findings offer a better understanding of the mechanisms contributing to reduced IL-2R signaling in T1D and have implications for development of more targeted IL-2-based therapies and stratification of patients for therapy.

T-Cell Cytokines as Predictive Markers of the Risk of Allograft Rejection.

Over the last decade, several biomarkers and surrogate markers have surfaced as promising predictive markers of risk of rejection in solid organ transplantation. The monitoring of these markers can help to improve graft and recipient care by personalizing immunomodulatory therapies. The complex immune system response against an implanted graft can change during long-term follow-up, and the dynamic balance between effector and regulatory T-cell populations is a crucial factor in antidonor response, risk of rejection, and immunosuppression requirements. Therefore, at any time before and after transplantation, T-effector activity, which is associated with increased production and release of proinflammatory cytokines, can be a surrogate marker of the risk of rejection and need for immunosuppression. In addition, immunosuppressive drugs may have a different effect in each individual patient. The pharmacokinetics and pharmacodynamics of these drugs show high interpatient variability, and pharmacodynamic markers, strongly associated with the specific mechanism of action, can potentially be used to measure individual susceptibility to a specific immunosuppressive agent. The monitoring of a panel of valid biomarkers can improve patient stratification and the selection of immunosuppressive drugs. After transplantation, therapy can be adjusted based on the prediction of rejection episodes (maintained alloreactivity), the prognosis of allograft damage, and the individual's response to the drugs. This review will focus on current data indicating that changes in the T-cell production of the intracellular cytokines interferon-γ and interleukin-2 could be used to predict the risk of rejection and to guide immunosuppressive therapy in transplant recipients.

OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer.

The tumor microenvironment of squamous cell carcinoma of the head and neck (SCCHN) has been shown to be immune suppressive. Therefore, strategies aimed at overcoming this issue could have a positive therapeutic impact. Hence, we investigated the expression of the known immune-modulatory proteins OX40, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in SCCHN on different T-cell subsets of tumor-infiltrating lymphocytes (TIL) to ascertain whether these proteins could potentially be targeted alone or in combination for future clinical trials. T cells from peripheral blood (PBL) and tumor were analyzed for the expression of OX40, PD-1 and CTLA-4 in 29 patients undergoing surgery. These proteins were all expressed significantly higher in T-cell subsets isolated from tumors compared with PBL of the same patient. OX40 expression was significantly greater in the TIL regulatory T-cell (Treg) population relative to conventional CD4 and CD8 TIL or the Treg isolated from PBL. PD-1 expression was increased in all T-cell subsets relative to PBL. CTLA-4 was also increased in all TIL subsets relative to blood, and similar to OX40, its highest level of expression was observed in the Treg TIL. The highest frequency of PD-1, CTLA-4 and OX40 triple-positive cells were found in the Treg population isolated from the tumor. We analyzed both human papilloma virus-positive and -negative patients and found similar levels and expression patterns of these two patient populations for all three proteins. These data suggest that there may be therapeutic advantages of targeting these pathways independently or in combination for patients with this disease.

Association of T-regulatory cells and CD23/CD21 expression with vitamin D in children with asthma

BackgroundChildren with asthma have low vitamin D levels; however, we do not know whether low vitamin D is associated with impaired T-regulatory (Treg) cell population or high IgE receptors (CD23 and CD21) on B cells. ObjectiveTo examine Treg cell function, CD23 and CD21 receptors, vitamin D, and vitamin D–regulating enzymes in children with asthma. MethodsSixty children (2–6 years old) with asthma and 60 age-matched healthy children were selected as study participants. After collecting demographic and clinical data, blood samples were collected. Treg cells and CD23/CD21 expressions were evaluated by flow cytometry, 25-hydroxyvitamin D3 (25[OH]D3) was quantified by high-performance liquid chromatography, and cytokines and total IgE were estimated by enzyme-linked immunosorbent assay. Messenger RNA (mRNA) expressions of FOXP3, CD23, CD21, vitamin D receptors, and vitamin D–regulating enzymes were assessed by reverse transcription–polymerase chain reaction. ResultsThe 25(OH)D3 concentrations and proportion of Treg cells were lower (P < .05) among children with asthma. In contrast, the proportions of B cells with CD23 and CD21 expression were higher (P < .05) in patients with asthma compared with controls. Interleukin 10 and transforming growth factor β were also altered in asthma. The mRNA expression of CD23, CD21, and vitamin D receptors was up-regulated, whereas mRNA expression of vitamin D–regulating enzymes, CYP2R1, CYP27B1, and vitamin D binding protein (except CYP24A1) were up-regulated among children with asthma. ConclusionThe current study found impaired Treg cell population and high numbers of B cells with IgE receptors (CD23 and CD21) and altered regulatory cytokines in children with asthma, suggesting impaired immune regulation.

Mouse and human CD8(+) CD28(low) regulatory T lymphocytes differentiate in the thymus.

Regulatory T (Treg) lymphocytes play a central role in the control of immune responses and so maintain immune tolerance and homeostasis. In mice, expression of the CD8 co-receptor and low levels of the co-stimulatory molecule CD28 characterizes a Treg cell population that exerts potent suppressive function in vitro and efficiently controls experimental immunopathology in vivo. It has remained unclear if CD8(+) CD28(low) Treg cells develop in the thymus or represent a population of chronically activated conventional T cells differentiating into Treg cells in the periphery, as suggested by their CD28(low) phenotype. We demonstrate that functional CD8(+) CD28(low) Treg cells are present in the thymus and that these cells develop locally and are not recirculating from the periphery. Differentiation of CD8(+) CD28(low) Treg cells requires MHC class I expression on radioresistant but not on haematopoietic thymic stromal cells. In contrast to other Treg cells, CD8(+) CD28(low) Treg cells develop simultaneously with CD8(+) CD28(high) conventional T cells. We also identified a novel homologous naive CD8(+) CD28(low) T-cell population with immunosuppressive properties in human blood and thymus. Combined, our data demonstrate that CD8(+) CD28(low) cells can develop in the thymus of mice and suggest that the same is true in humans.

Human Umbilical Vein Endothelial Cells foster conversion of CD4+CD25-Foxp3- T cells into CD4+Foxp3+ Regulatory T Cells via Transforming Growth Factor-β.

Trans-placental cell trafficking is a naturally occurring process during pregnancy that results in the direct recognition of foreign maternal antigens by fetal tissue and vice versa. Immigration of potentially harmful allo-reactive maternal T cells into fetal circulation may provoke anti-fetal immune responses. However, the contact with fetal tissue may favor differentiation of maternal immune cells into cells with a regulatory phenotype. Human Umbilical Vein Endothelial Cells (HUVECs) possess immune-regulating properties and are one of the first fetal cells to get in contact with foreign maternal immune cells. Therefore, here we studied whether HUVECs induce the conversion of maternal T cells into regulatory T (Treg) cells. Moreover, we assessed whether this response is changing according to the sex of the HUVECs. Both female and male HUVECs induced the conversion of maternal T cells into Treg cells which is partially mediated via TGF-β. Female HUVECs showed a stronger capacity to induce Treg cells compared to male HUVECs. Our findings propose that HUVECs contribute to fetal-maternal tolerance by the increase of the Treg cell population. Sex-specific differences in Treg cell induction may partly account for the disparities on the incidence of infectious and autoimmune diseases between both sexes during early childhood.

Notch and its ligands in alloimmunity and rejection.

The Notch signaling pathway is known to play a pivotal role in T- and B-cell development and fate, presenting it as an attractive therapeutic target in alloimmunity. This review provides an overview of the mechanisms of Notch signaling, focusing on new insights into its diverse functions in T-cell activation, differentiation and memory subset formation, and the consequences thereof in transplantation. Recent evidence has shown that while not critical for early antigen-specific CD4 T-cell activation, Notch signaling regulates the survival of memory CD4 T cells via control of glycolytic metabolism; in contrast, Notch signaling is critical for the generation of short-lived CD8 effector T cells, but not memory CD8 cells. Transient, selective inhibition of various Notch receptors and ligands in models of solid organ transplantation has been shown to successfully modulate the alloimmune response, affecting the balance between effector and regulatory cells, with particular influence on the natural regulatory T-cell population. These studies reveal diverse roles for individual Notch receptors and ligands in peripheral immunity and indicate that selective targeting of the Notch pathway is a promising, novel approach for immune modulation in transplantation; the advent of therapeutic human antibodies to neutralize both the Notch ligands and the individual Notch receptors suggests that this approach could be efficiently developed.

Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer's disease.

BackgroundAlzheimer’s disease (AD) is a severe neuroinflammatory disease. CD4+Foxp3+ regulatory T cells (Tregs) modulate various inflammatory diseases via suppressing Th cell activation. There are increasing evidences that Tregs have beneficial roles in neurodegenerative diseases. Previously, we found the population of Treg cells was significantly increased by bee venom phospholipase A2 (bvPLA2) treatment in vivo and in vitro.MethodsTo examine the effects of bvPLA2 on AD, bvPLA2 was administered to 3xTg-AD mice, mouse model of Alzheimer’s disease. The levels of amyloid beta (Aβ) deposits in the hippocampus, glucose metabolism in the brain, microglia activation, and CD4+ T cell infiltration were analyzed to evaluate the neuroprotective effect of bvPLA2.ResultsbvPLA2 treatment significantly enhanced the cognitive function of the 3xTg-AD mice and increased glucose metabolism, as assessed with 18F-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) positron emission tomography (PET). The levels of Aβ deposits in the hippocampus were dramatically decreased by bvPLA2 treatment. This neuroprotective effect of bvPLA2 was associated with microglial deactivation and reduction in CD4+ T cell infiltration. Interestingly, the neuroprotective effects of bvPLA2 were abolished in Treg-depleted mice.ConclusionsThe present studies strongly suggest that the increase of Treg population by bvPLA2 treatment might inhibit progression of AD in the 3xTg AD mice.

Low Expression of CD4+CD25+ T Regulatory Cells is Associated with High Level of Immune Activation in HAART Na ïve HIV-1 Infected Persons

Regulatory T cells (Tregs) are a subset of T cells that play a key role in immunoregulation. The naturally occurring CD4+CD25+ Tregs constitute 2–10% of cluster of differentiation-4+ (CD4+) T cells in humans. Recent studies have shown that persistent immune activation drives human immunodeficiency virus (HIV) disease progression. The mechanisms leading to immune activation are not well understood, and strategies to dampen it are urgently needed. The current available information does not sufficiently describe whether CD4+CD25+ Treg cells are helpful in HIV infection by controlling immune activation. A better understanding of the mechanisms of T-cell activation in HIV infection, as well as the contribution of Tregs to its control might increase therapeutic options for HIV-infected persons and provide an alternative method for monitoring HIV disease progression. This study evaluated the expression of CD4+CD25+ Treg cell populations in HIV-infected patients and correlated it with level of CD8+ T-cell activation, absolute CD4+ count and viral load. The study design was cross sectional and descriptive with samples of 32 HIV-positive patients and 32 healthy controls. There was significantly lower CD4+CD25+ Treg populations in HIV-infected patients (median 1.04%) as compared with the control group (median 3.1%), p < 0.05. There was elevated CD8+ T-cell activation in the HIV-infected patients (median 3.8%) as compared with the control group (median 1.3%), p < 0.05. A significant negative correlation between CD4+CD25+Treg-cell population and level of CD8+ T-cell activation was observed among the patients in this study (rho =-0.798, p < 0.001). This correlation was, however, not significant in the healthy control group (rho =-0.411, p = 0.061). Correlations between CD8+ T-cell activation and viral load with CD4+ absolute counts were all significant (p < 0.001). However, the correlation was the strongest between CD4+ T-cell absolute count and CD8+ T-cell activation. HIV infection was characterised by low expression of CD4+CD25+ Treg cells and increased immune activation as well as a decline in absolute CD4+ T-cell count and increased viral replication. The level of CD8+ T-cell activation was a better predictor of CD4+ T-cell count decline than viral load.