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Background: It has been reported that programmed death‐ligand 1 (PD‐L1) is highly expressed in cells during viral infection, which helps the virus escape host immunity. However, the relationship between human papillomavirus (HPV) and PD‐L1 in condyloma acuminatum and whether they participate in immunosuppression have not been reported. In this paper, we aimed to explore the expression and significance of PD‐L1 in condyloma acuminatum. Methods: The expression of PD‐L1 in the wart of condyloma acuminatum patients and the foreskin of healthy individuals was evaluated. Lentivirus transfection was used to introduce the HPV11‐E7 gene into HaCaT cells to investigate whether HPV infection could affect the expression of PD‐L1. The successfully constructed HPV11‐E7 HaCaT cells were cocultured with Jurkat cells, and Jurkat cell apoptosis and proliferation as well as the Jurkat cell cycle were evaluated by flow cytometry and cell counting kit‐8 (CCK‐8) assays. Results: PD‐L1 was highly expressed in keratinocytes of genital warts. Through the construction of a cell model, we found that HPV11‐E7 could upregulate the expression of PD‐L1 in HaCaT cells. Furthermore, HPV11‐E7 HaCaT cells can promote the apoptosis of Jurkat cells, inhibit the proliferation of Jurkat cells and mediate the cell cycle arrest of Jurkat cells through the PD‐1/PD‐L1 signalling pathway. Conclusions: HPV infection may upregulate PD‐L1 expression in the keratinocytes of genital warts and participate in the inhibition of local T‐cell function. [ABSTRACT FROM AUTHOR]

Immunohistochemical staining is a common technique to study tissue morphology and in situ protein expression. With the rise of immunotherapy, more and more markers in the tumor microenvironment have been discovered. In this paper, the multiplex immunofluorescence staining method was used to stain paraffin sections of 35 cases of gastric adenocarcinoma tissue and 35 cases of colorectal adenocarcinoma tissue and its adjacent tissue. The infiltration of CD8+ T cells and CD103+CD8+ T cells in the slices was detected by using the slice scanner to form the map and CaseViewer2.0 software analysis. The experimental results in this paper showed that compared with adjacent tissues, the infiltration degree of CD8+ T cells in gastric adenocarcinoma tissue was significantly lower (Z = 2.244 , P = 0.025 , P < 0.05), and the infiltration degree of cells was significantly lower (Z = 2.785 , P = 0.005 , P < 0.05). In gastric adenocarcinoma tissue, the infiltration of CD8+ T cells was correlated with the tumor diameter of gastric adenocarcinoma (P = 0.002). There was a statistically significant difference. The degree of CD103+CD8+ T cell infiltration was related to the survival of patients with gastric adenocarcinoma (P = 0.002) and the degree of tumor differentiation (P = 0.004). The infiltration of CD103+CD8+ T cells in gastric cancer tissue and colorectal cancer tissue is related to the survival of patients. CD103+CD8+ T cells are thought to play a role in the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma. Experiments have shown that the more the CD103+CD8+ T cells, the better the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma, so the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma can be improved by increasing CD103+CD8+ T cells. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing (scRNA-seq) data has been widely used for cell trajectory inference, with the assumption that cells with similar expression profiles share the same differentiation state. However, the inferred trajectory may not reveal clonal differentiation heterogeneity among T cell clones. Single-cell T cell receptor sequencing (scTCR-seq) data provides invaluable insights into the clonal relationship among cells, yet it lacks functional characteristics. Therefore, scRNA-seq and scTCR-seq data complement each other in improving trajectory inference, where a reliable computational tool is still missing. We developed LRT, a computational framework for the integrative analysis of scTCR-seq and scRNA-seq data to explore clonal differentiation trajectory heterogeneity. Specifically, LRT uses the transcriptomics information from scRNA-seq data to construct overall cell trajectories and then utilizes both the TCR sequence information and phenotype information to identify clonotype clusters with distinct differentiation biasedness. LRT provides a comprehensive analysis workflow, including preprocessing, cell trajectory inference, clonotype clustering, trajectory biasedness evaluation, and clonotype cluster characterization. We illustrated its utility using scRNA-seq and scTCR-seq data of CD8+ T cells and CD4+ T cells with acute lymphocytic choriomeningitis virus infection. These analyses identified several clonotype clusters with distinct skewed distribution along the differentiation path, which cannot be revealed solely based on scRNA-seq data. Clones from different clonotype clusters exhibited diverse expansion capability, V-J gene usage pattern and CDR3 motifs. The LRT framework was implemented as an R package 'LRT', and it is now publicly accessible at https://github.com/JuanXie19/LRT. In addition, it provides two Shiny apps 'shinyClone' and 'shinyClust' that allow users to interactively explore distributions of clonotypes, conduct repertoire analysis, implement clustering of clonotypes, trajectory biasedness evaluation, and clonotype cluster characterization. Author summary: Understanding the dynamic changes behind biological processes is important for determining molecular mechanisms underlying normal tissue formulation, developmental disorders and pathologies. Usually, a biological process can be characterized by identifying a trajectory, a path that goes through the various cellular states associated with the process. Since cells in different states may express different sets of genes, researchers often infer cell trajectory via capturing transcriptomics changes. Dozens of methods have been developed for cell trajectory inference, and scRNA-seq data is predominantly utilized. However, cells from different clones may exist distinct differentiation patterns, while methods based only on scRNA-seq data cannot capture this heterogeneity. T cells play a key role in the immune system, and their high antigen recognition specificity is largely determined by their TCR sequences. Thanks to the advent of scTCR-seq technology, we can now identify the group of cells coming from the same clone. This paper describes our novel computational framework, namely LRT, and demonstrates that by complementing scRNA-seq data with the clonal information from scTCR-seq data using LRT, we are able to examine the clonal differentiation heterogeneity that cannot be revealed solely based on scRNA-seq data. [ABSTRACT FROM AUTHOR]

Simple Summary: Every year, cervical cancer affects more than 500,000 women worldwide. The persistent infection caused by the human papillomavirus (HPV) is the main risk factor for the development of this type of cancer. Conventional treatments for cervical cancer are often associated with resistance and side effects. Therefore, it is necessary to find new targets for the development of more effective therapeutic approaches. In recent years, an increasing number of studies have been concerned with developing immunotherapeutic strategies for treating cancer. Thus, it is important to investigate new targets, such as the various molecules and cells that are involved in the cancer-immunity cycle (CIC). This process consists of the release of cancer antigens and their destruction by cytotoxic T-cells. Hence, in this review, we discuss the molecular changes that occur at each stage of the CIC for cervical cancer, including the impact of variables such as histological subtype and HPV infection. Moreover, we explore the latest immunotherapeutic approaches that have been adopted, together with their benefits and limitations. In this scenario, current studies are opening up new horizons in clinical practice for a personalized treatment of cervical cancer. Cervical cancer (CC) is the fourth most common cancer in women worldwide, with more than 500,000 new cases each year and a mortality rate of around 55%. Over 80% of these deaths occur in developing countries. The most important risk factor for CC is persistent infection by a sexually transmitted virus, the human papillomavirus (HPV). Conventional treatments to eradicate this type of cancer are accompanied by high rates of resistance and a large number of side effects. Hence, it is crucial to devise novel effective therapeutic strategies. In recent years, an increasing number of studies have aimed to develop immunotherapeutic methods for treating cancer. However, these strategies have not proven to be effective enough to combat CC. This means there is a need to investigate immune molecular targets. An adaptive immune response against cancer has been described in seven key stages or steps defined as the cancer-immunity cycle (CIC). The CIC begins with the release of antigens by tumor cells and ends with their destruction by cytotoxic T-cells. In this paper, we discuss several molecular alterations found in each stage of the CIC of CC. In addition, we analyze the evidence discovered, the molecular mechanisms and their relationship with variables such as histological subtype and HPV infection, as well as their potential impact for adopting novel immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

T-cell intracellular antigen 1 (TIA1)-related/like (TIAR/TIAL1) protein is a multifunctional RNA-binding protein (RBP) involved in regulating many aspects of gene expression, independently or in combination with its paralog TIA1. TIAR was first described in 1992 by Paul Anderson's lab in relation to the development of a cell death phenotype in immune system cells, as it possesses nucleolytic activity against cytotoxic lymphocyte target cells. Similar to TIA1, it is characterized by a subcellular nucleo-cytoplasmic localization and ubiquitous expression in the cells of different tissues of higher organisms. In this paper, we review the relevant structural and functional information available about TIAR from a triple perspective (molecular, cellular and pathophysiological), paying special attention to its expression and regulation in cellular events and processes linked to human pathophysiology. [ABSTRACT FROM AUTHOR]

Simple Summary: Primary liver cancer, also known as Hepatocellular carcinoma (HCC), is considered to be a major global health challenge. Due to delays in diagnosis at early asymptomatic stages, HCC reaches a severe aggressive stage, thereby having a significant negative impact on patient survival. In addition, HCC shows marked resistance to conventional cancer treatments such as chemo- and radiotherapy. A variety of new and advanced therapies are continuously being evaluated to acquire a breakthrough in HCC treatment to enhance overall and recurrence-free survival. Appropriate identification and selection of target genes and utilization of safe and effective therapeutic approaches, such as gene therapy or immunotherapy, are key strategies for the effective treatment for HCC. This review paper intends to provide a perspective on emerging approaches as avenues towards more effective and safer therapies for HCC. Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment. [ABSTRACT FROM AUTHOR]

Despite recent breakthroughs of immune-checkpoint inhibitors in the management of bladder cancer (BC), only 20% of patients with non-muscle invasive BC (NMIBC) completely respond, leaving room for improvement. Due to challenges in developing a preclinical model which reflects the heterogeneity and biology of bladder tumors, patient-derived xenograft (PDX) models were created. PDX models involve implanting tumor extracted from patients into immunocompromised mice, which therefore keep the morphology and genomic fidelity of their parental patient cancers. The state of immunodeficiency, however, precludes study of immunotherapy and consequently humanized mice models engrafted with a human immune system were developed, though this led to spontaneous xenogenic graft vs host disease (GVHD). As a potential solution to GVHD in humanized mouse models, this paper describes successful creation of a double-humanized mouse (DHM) by simultaneously engrafting human immune cells and human tumors from the same donor. BC tissue was processed +/- digested into single-cell suspensions (SCS, F0 tissue) and injected orthotopically or subcutaneously into flanks of NSG™ mice. Subsequent tumor growth (PDX-F1) was measured, and PDX-F1 tumors reaching >200mm3 were processed into SCS and reimplanted subcutaneously into a new NSG™ (PDX-F2). Continuous passages (PDX-Fn) were repeated.; Extra SCS-F1 and Fn was analyzed for human epithelial cell adhesion molecule (EpCAM) expression. From an individual F1, a stable cell line (PDX257S) was cultured, and also analyzed for EpCAM expression by flow cytometry. For the DHM model, autologous γδ T-cells expanded in vitro from PDX257S donors were injected with PDX257S cells (effector: target = 2:1) into the NSG™ flanks and were observed for body condition/hematuria for 45 days. Total RNA-sequencing was performed on F0, PDX-Fn and PDX257S cell line. Tumor growth curves were analyzed with 2-way analysis of variance (ANOVA). F0 tissue was obtained from 60 patients. Tumor acceptance in orthotopic injection was not observed in the first 11 suitable tumors, and this method was ceased. Subcutaneous tumor acceptance rate improved with digestion and processing of F0 rather than processing alone (11% vs 5%). EpCAM expression was 98% vs 70% in PDX257S vs its F1 tissue, and < 30% in F1 tissue from other donors that did not yield further passages. In the DHM, while tumor growth was significantly reduced compared to control group after 45 days (mean vol 200 mm3 vs 580 mm3, p=0.02) post injection, it was not completely suppressed. RNA sequencing revealed increased expression of genes including BCL2L1, KRAS, MYC, E2F1, and E2F4 in both PDX257 subcutaneous tumor and cell line compared with donor tumor tissue, and very low/no expression of CDKN2A and FHIT genes in both PDX257 cell line and donor tumor tissue. Creation of a double-humanized mouse model is feasible, and tumor growth is not completely suppressed with the addition of autologous γδ T-cells. PDX257S tumor and cell line is associated with increased EpCAM expression and on RNA sequencing, increased expression of BCL2L1, KRAS, MYC, E2F1, and E2F4. [ABSTRACT FROM AUTHOR]

Today in reliability analysis, the most used distribution to describe the behavior of devices is the Weibull distribution. Nonetheless, the Weibull distribution does not provide an excellent fit to lifetime datasets that exhibit bathtub shaped or upside‐down bathtub shaped (unimodal) failure rates, which are often encountered in the performance of products such as electronic devices (ED). In this paper, a reliability model based on the exponentiated Weibull distribution and the inverse power law model is proposed, this new model provides a better approach to model the performance and fit of the lifetimes of electronic devices. A case study based on the lifetime of a surface‐mounted electrolytic capacitor is presented in this paper. Besides, it was found that the estimation of the proposed model differs from the Weibull classical model and that affects the mean time to failure (MTTF) of the capacitor under analysis. [ABSTRACT FROM AUTHOR]

Diagnosing acute leukemia is the necessary prerequisite to treating it. Multi-classification on the gene expression data of acute leukemia is help for diagnosing it which contains B-cell acute lymphoblastic leukemia (BALL), T-cell acute lymphoblastic leukemia (TALL) and acute myeloid leukemia (AML). However, selecting cancer-causing genes is a challenging problem in performing multi-classification. In this paper, weighted gene co-expression networks are employed to divide the genes into groups. Based on the dividing groups, a new regularized multinomial regression with overlapping group lasso penalty (MROGL) has been presented to simultaneously perform multi-classification and select gene groups. By implementing this method on three-class acute leukemia data, the grouped genes which work synergistically are identified, and the overlapped genes shared by different groups are also highlighted. Moreover, MROGL outperforms other five methods on multi-classification accuracy. [ABSTRACT FROM AUTHOR]

The expression of Programmed cell Death Ligand 1 (PD-L1) is observed in many malignant tumors and is associated with poor prognosis including Gastric Cancer (GC). The relationship between PD-L1 expression and prognosis, however, is controversial in GC. This paper purports to use a meta-analysis to investigate the relationship between PD-L1 expression and prognosis in GC. For this study, the following databases were searched for articles published from June 2003 until February 2017: PubMed, EBSCO, Web of Science and Cochrane Library. The baseline information extracted were: authors, year of publication, country where the study was performed, study design, sample size, follow-up time, baseline characteristics of the study population, pathologic data, overall survival (OS). A total of 15 eligible studies covering 3291 patients were selected for a meta-analysis based on specified inclusion and exclusion criteria. The analysis showed that the expression level of PD-L1 was associated with the overall survival in GC (Hazard Ratio, HR = 1.46, 95%CI = 1.08–1.98, P = 0.01, random-effect). In addition to the above, subgroup analysis showed that GC patients with deeper tumor infiltration, positive lymph-node metastasis, positive venous invasion, Epstein-Barr virus infection positive (EBV+), Microsatellite Instability (MSI) are more likely to expression PD-L1. The results of this meta-analysis suggest that GC patients, specifically EBV+ and MSI, may be prime candidates for PD-1 directed therapy. These findings support anti-PD-L1/PD-1 antibodies as a kind of immunotherapy which is promising for GC. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is a blood-borne pathogen which has chronically infected people worldwide. Therefore, it is of utmost importance to design prophylactic and therapeutic vaccine in order to control HCV infection. To date, several researchers have attempted to improve the efficiency of HCV vaccine by using different adjuvants. However, a few studies have focused on the synthetic immunomodulatory drugs as adjuvants for HCV vaccine. Recently, researchers have shown that lenalidomide, which is used to treat the patients with multiple myeloma, is capable of improving the immune system factors. In this paper, two doses of lenalidomide along with pcDNA3.1 + NS3 as HCV DNA vaccine were administrated in mice models and the percentage of regulatory T cells (Treg cells) and the cells with PD-1 + expression in spleen of mice model were investigated by flow cytometry method. Additionally, activities of CTL cells and NK cells were evaluated in spleen of prophylactic and therapeutic mice models via LDH method. Results of the Treg and PD-1 analysis showed that low dose of lenalidomide along with pcDNA3.1 + NS3 can noticeably decrease the percentage of Treg cells and the cells with PD-1 + expression, while lenalidomide can significantly increase the CTL and NK activity in mice models. Also, results of the therapeutic mice model, in which SP2/0 cells- challenged mice were treated with 5 mg/kg lenalidomide in combination with pcDNA3.1 + NS3, reasonably agreed with those of the prophylactic model. Finally, it was found that lenalidomide can reduce the level of Treg cells which results in lower the cells with PD-1 + expression and subsequently higher CTL and NK cell activities. This study concluded that lenalidomide possess the characteristics of an ideal adjuvant candidate for use in combination with HCV DNA vaccine in order to promote the immune response and vaccine efficiency. [ABSTRACT FROM AUTHOR]

MHC class I-related gene protein (MR1) is a non-polymorphic MHC class IB antigen-presenting molecule that is the restricting molecule for mucosal-associated invariant T (MAIT) cells, a prominent population of innate-like antibacterial T cells. The MAIT cell-MR1 axis represents a new paradigm in antigen presentation, with the MR1 ligand derived from vitamin B compounds or their metabolic precursors. Many bacteria and some fungi produce the activating ligand for MR1. In evolution, MR1 is highly conserved in most, but not all, mammals. In humans and rodents it is expressed in a broad range of cell types, both haematopoietic and non-haematopoietic, although cell surface expression has been difficult to detect. Although MR1 trafficking shares features with both the MHC class I and MHC class II pathways, it is distinct. Several strands of evidence suggest that the intracellular location where MR1 is loaded differs for soluble ligand and for ligand derived from intact bacteria. The regulation of MR1 surface expression may also vary between different cell types. This paper will review what is currently known about the expression and trafficking of MR1 and propose a model for the loading and trafficking of MR1. [ABSTRACT FROM AUTHOR]

T cell response is crucial to the pathogenesis and progression of rheumatoid arthritis (RA). IL-7/IL-7R axis has significant effect on CD4 + T cell response, including proliferation, differentiation, survival and migration. However, whether blockade of IL-7/IL-7R axis signaling can relieve RA and what is the potential treatment mechanisms are still remaining unclear. In this paper, we established collagen-induced arthritis (CIA) model and observed the effect of IL-7Rα antibody in the treatment of CIA mice. It is demonstrated that IL-7Rα antibody significantly alleviated clinical symptoms of CIA mice, accompanied with reduced CD4 + T cell number in both spleen and joints. Decreased CII-specific CD4 + T cell proliferation and reduced mRNA expression of inflammatory cytokines in IL-7Rα antibody-treated mice were observed. Subsequently, IL-7Rα antibody treatment in vivo downregulated the percentages of Th1 and Th17 cells and the mRNA expression of T-bet and RORγt gene. Moreover, it was found that IL-7 promoted Th1 cell differentiation in vitro, while having no effect on Th17 cell differentiation. In addition, administration of IL-7Rα antibody reduced the mRNA expression of chemokine receptors (CCR7, CXCR3, CXCR6 and XCR1) on CD4 + T cells and chemokine CXCL2 in joints. The results suggested that IL-7Rα antibody treated CIA mice via the inhibition of CII-specific CD4 + T cell proliferation, the reduction of Th1 cell differentiation and the restrain of CD4 + T cell migration to joint lesion site. This investigation indicates that IL-7Rα is a potential therapeutic target for RA. [ABSTRACT FROM AUTHOR]

This paper distinguishes a rare subset of myeloid dendritic-like cells found in mouse spleen from conventional (c) dendritic cells (DC) in terms of phenotype, function and gene expression. These cells are tentatively named “L-DC” since they resemble dendritic-like cells produced in longterm cultures of spleen. L-DC can be distinguished on the basis of their unique phenotype as CD11bhiCD11cloMHCII-CD43+Ly6C-Ly6G-Siglec-F- cells. They demonstrate similar ability as cDC to uptake and retain complex antigens like mannan via mannose receptors, but much lower ability to endocytose and retain soluble antigen. While L-DC differ from cDC by their inability to activate CD4+ T cells, they are capable of antigen cross-presentation for activation of CD8+ T cells, although less effectively so than the cDC subsets. In terms of gene expression, CD8- cDC and CD8+ cDC are quite distinct from L-DC. CD8+ cDC are distinguishable from the other two subsets by expression of CD24a, Clec9a, Xcr1 and Tlr11, while CD8- cDC are distinguished by expression of Ccnd1 and H-2Eb2. L-DC are distinct from the two cDC subsets through upregulated expression of Clec4a3, Emr4, Itgam, Csf1r and CD300ld. The L-DC gene profile is quite distinct from that of cDC, confirming a myeloid cell type with distinct antigen presenting properties. [ABSTRACT FROM AUTHOR]

Presents an abstract of the paper entitled `Intracellular Ca2+ Thresholds for Interleukin 2 Gene Expression in Single T Lymphocytes,' by Paul A. Negulescu, Nilabh Shastri and Michael D. Cahalan presented at the 1993 meeting of the Society of General Physiologists held at the Marine Biological Laboratory in Woods Hole, Massachusetts. Role of calcium ion in the regulation of interleukin 2.

Perforin (PFN) is one of the most important protein effectors of the immune system. It is produced by cytotoxic T lymphocytes and natural killer cells and helps with the clearance of virus-infected and tumor cells. PFN is a pore-forming protein that readily binds to the lipid membranes of target cells, oligomerizes at the cell surface and forms transmembrane pores that allow passage of ions and other larger molecules. Its characterization was hindered in the past by a lack of efficient and reliable expression systems that would result in pure and functional product. In this paper we present optimization of PFN expression in a baculovirus expression system. We optimized several parameters of murine PFN (mPFN) expression and purification and showed that the expressed product is pure and hemolytically active and that it forms pores in the plasma membranes of K562 cells. We could also observe circular pores formed on liposome membranes by cryo-electron microscopy (cryo-EM). Our protocol opens the door for further biochemical and biophysical assessment of PFN properties and interactions with small ligands and lipid membranes. [ABSTRACT FROM AUTHOR]

Aim To evaluate CD4+ CD28+ and CD8+ T-cell genes and the gene expression of IFN-γ, TNF-α, IL-1-β, IL-17A, IL-10, CCL-2/ MCP-1, CCL-4, CCL-5 ( RANTES), CXCR4, CCR5 and RANKL from cells in the periapical interstitial fluid from root canal infections in healthy patients ( HIV−) and HIV-positive individuals ( HIV+). Methodology Subjects included 20 HIV− and 23 HIV+ patients referred to the School of Dentistry at the Universidade Federal de Minas Gerais (Belo Horizonte, MG, Brazil). Almost all HIV+ patients were undergoing highly active antiretroviral therapy ( HAART). Clinical samples were taken from teeth with pulp necrosis, and no patients had acute periapical symptoms at the time of the appointments. After cleaning and drying, 3 paper points were introduced into the root canal, passing passively through the root apex (2 mm) into the periapical tissues for 1 min. The samples were collected immediately after root canal cleaning and 7 days later (restrained root canal bacterial load) to characterize those gene expressions using real-time PCR. Results Significantly higher levels of CD4+ CD28+ and CD8+ T cells in teeth with restrained bacterial loads (second collection) compared with the first collection were observed in both HIV− and HIV+ samples. In HIV− patients, an increase in IL-10 and CXCR4 expression was demonstrated as well as a decrease in pro-inflammatory cytokines such as RANKL, IFN-γ, IL1-β and CCL5. However, in HIV+ patients an increase in cytokines IFN-γ, IL-1-β, TNF-α and IL-17A, and chemokines CCL-2, CXCR4 and CCR5 were observed. The chemokine CCL-5 was not detected in HIV+ individuals. Conclusions These findings suggest that after reducing the root canal bacterial load in HIV− individuals an anti-inflammatory response is generated whilst in HIV+ patients a pro-inflammatory response is sustained in the periapical area. [ABSTRACT FROM AUTHOR]

Regulatory T cells play an important role in the progression of atherosclerosis. GARP is a newly biological membrane molecule existed on activated Tregs, which is related to the release of TGF-β. The antiatherosclerosis effects of statins partly depend on their multiple immune modulatory potencies. In this paper, we present that atorvastatin could upregulate the expression of GARP and TGF-β in CD4+ T cells and increase the numbers of CD4+LAP+ and CD4+Foxp3+ regulatory T cells in ApoE−/− mice. Also, we indicate that atorvastatin promotes the aggregation of GARP+ and Foxp3+ cells and secretory of the TGF-β1 in atherosclerotic plaques. Furthermore, we prove that atorvastatin could delay the procession of atherosclerosis and improve the stability of atherosclerotic plaques. Interestingly, we report that inhibition of GARP distinctly inhibits the anti-inflammatory effects of atorvastatin. We conclude that atorvastatin improves the inflammatory response in atherosclerosis partly by upregulating the expression of GARP on regulatory T cells. [ABSTRACT FROM AUTHOR]

Helicobacter pylori ( H. pylori ) infection is regarded as the major cause of various gastric diseases (gastritis, peptic ulcers and gastric cancer) and induces the production of several cytokines. Interleukin-17 (IL-17) is recently recognized as an important player in the pathophysiology of infectious and immune-mediated gastrointestinal diseases. H. pylori infection increases IL-17 in the gastric mucosa of humans. IL-17 usually causes secretion of IL-8 through activation of ERK 1/2 MAP kinase pathway. The released IL-8 attracts neutrophils promoting inflammation. T regulatory cells (Tregs) suppress the inflammatory reaction driven by IL-17, there by favoring bacterial persistence in H. pylori -infection. The pathogenesis of H. pylori -induced inflammation is not well understood. Inflammation is promoted by both host factors and H. pylori factors, such as the proteins cytotoxin associated gene A (cagA) and vacuolating cytotoxin A (vacA). IL-1β, IL-6, tumor necrosis factor (TNF)-α, TGF-β1, IL-17, IL-18, IL-21 and IL-22 have been reported to be involved in H. pylori -induced gastric mucosal inflammation, but the details and relation to different patterns of inflammation remain unclear. Numerous studies have demonstrated important functions of IL-17 in acute and chronic inflammatory processes. This paper reviews the role of IL-17 in gastritis, peptic ulcers and gastric cancer related to H. pylori . [ABSTRACT FROM AUTHOR]

Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70), a member of Syk family (non-receptor protein tyrosine kinase family), has an imperative function in the immune cell signaling in T cells. Its role in T-cell development has been established by the severe combined immune deficiency syndrome in ZAP-70 deficient humans. Moreover, defects in T-cell activation and downstream signaling events were observed in T-cells that lack ZAP-70. Thus, the crucial role of ZAP-70 in the development and activation of T-cell and its predominant expression in T-cells make it a logical target for the treatment of pathological conditions related to abnormal T-cell responses. The present review article portrays the domain structure of ZAP-70 along with its implication in T-cell signaling. Additionally, varied ZAP-70 inhibitors published in different patents and papers have also been reviewed. [ABSTRACT FROM AUTHOR]

CD2BP2 (CD2 cytoplasmic tail binding protein 2), one of several proteins interacting with the cytoplasmic tail of CD2, plays a crucial role in CD2-triggered T cell activation and nuclear splicing. The studies on CD2BP2 have tended to be confined to a few mammals, and little information is available to date regarding fish CD2BP2. In this paper, a CD2BP2 gene (On-CD2BP2) was cloned from Nile tilapia, Oreochromis niloticus. Sequence analysis showed that the full length of On-CD2BP2 cDNA was 1429 bp, containing a 5'untranslated region (UTR) of 111 bp, a 3'-UTR of 193 bp and an open reading frame of 1125 bp which is encoding 374 amino acids. Two important structural features, a GYF domain and a consensus motif GPFXXXXMXXWXXXGYF were detected in the deduced amino acid sequence of On-CD2BP2, and the deduced genomic structure of On-CD2BP2 was similar to the known CD2BP2. The mRNA expression of On-CD2BP2 in various tissues of Nile tilapia was analyzed by fluorescent quantitative real-time PCR. In healthy Nile tilapia, the On-CD2BP2 transcripts were mainly detected in the head kidney and spleen. While vaccinated with inactivated Streptococcus agalactiae, the On-CD2BP2 mRNA expression was significantly up-regulated in the head kidney, spleen and brain 48 h post immunization. Moreover, there was a clear time-dependent expression pattern of On-CD2BP2 after immunization and the expression reached the highest level at 24 h in the brain and 48 h in the head kidney and spleen. This is the first report of proving the presence of a CD2BP2 ortholog in fish, and investigating its tissue distribution and expression profile in response to bacterial stimulus. These findings indicated that On-CD2BP2 may play an important role in the immune response to bacteria in Nile tilapia. [ABSTRACT FROM AUTHOR]

Polarization of cell phenotypes, a common strategy to achieve cell type diversity in metazoa, results from binary cell-fate decisions in the branching pedigree of development. Such “either-or” fate decisions are controlled by two opposing cell fate-determining transcription factors. Each of the two distinct “master regulators” promotes differentiation of its respective sister lineage. But they also suppress one other, leading to their mutually exclusive expression in the two ensuing lineages. Thus, promiscuous coexistence of the antagonist regulators in the same cell, the hallmark of the common “undecided” progenitor of two sister lineages, is considered unstable. This antagonism ensures robust polarization into two discretely distinct cell types. But now the immune system's T-helper (Th) cells and their two canonical subtypes, Th1 and Th2 cells, tell a different story, as revealed in three papers recently published in PLOS Biology. The intermediate state that co-expresses the two opposing master regulators of the Th1 and Th2 subtypes, T-bet and Gata3, is highly stable and is not necessarily an undecided precursor. Instead, the Th1/Th2 hybrid cell is a robust new type with properties of both Th1 and Th2 cells. These hybrid cells are functionally active and possess the benefit of moderation: self-limitation of effector T cell function to prevent excessive inflammation, a permanent risk in host defense that can cause tissue damage or autoimmunity. Gene regulatory network analysis suggests that stabilization of the intermediate center in a polarizing system can be achieved by minor tweaking of the architecture of the mutual suppression gene circuit, and thus is a design option readily available to evolution. [ABSTRACT FROM AUTHOR]

Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8+, but not CD4+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Minor histocompatibility (H) Ags are classically described as self-peptides derived from intracellular proteins that are expressed at the cell surface by MHC class I and class II molecules and that induce T ceil alloresponses. We have isolated three different T cell populations from a skin biopsy of a patient suffering from acute graft-versus-host disease following sex-mismatched HLA-identical bone marrow transplantation. The first population was: 1) CD4+/CD8+ double-positive; 2) specific for an HLA class I-restricted autosomal Ag; 3) expressed a Trl profile with high levels of IL-10, but low IL-2 and IFN-γ; and 4) exerted regulatory function in the presence of recipient APCs. The second was CD8 positive, specific for an HLA class I-restricted autosomally encoded minor H Ag, but was only weakly cytotoxic. The third was CD4 single positive, specific for an HLA-DR7-restricted HY epitope and exerted both proliferative and cytotoxic functions. Identification of the peptide recognized by these latter cells revealed a new human HY epitope, TGKIINFIKFDTGNL, encoded by RPS4Y and restricted by HLA-DR7. In this paper, we show human CD4/CD8 double-positive, acute graft-versus-host disease-protective, minor H Ag-specific regulatory T cells and identify a novel HLA-DR7/ HY T cell epitope, encoded by RPS4Y, a potential new therapeutic target. [ABSTRACT FROM AUTHOR]

Genomes are spatially assembled into chromosome territories (CT) within the nucleus of living cells. Recent evidences have suggested associations between three-dimensional organization of CTs and the active gene clusters within neighboring CTs. These gene clusters are part of signaling networks sharing similar transcription factor or other downstream transcription machineries. Hence, presence of such gene clusters of active signaling networks in a cell type may regulate the spatial organization of chromosomes in the nucleus. However, given the probabilistic nature of chromosome positions and complex transcription factor networks (TFNs), quantitative methods to establish their correlation is lacking. In this paper, we use chromosome positions and gene expression profiles in interphase fibroblasts and describe methods to capture the correspondence between their spatial position and expression. In addition, numerical simulations designed to incorporate the interacting TFNs, reveal that the chromosome positions are also optimized for the activity of these networks. These methods were validated for specific chromosome pairs mapped in two distinct transcriptional states of T-Cells (naïve and activated). Taken together, our methods highlight the functional coupling between topology of chromosomes and their respective gene expression patterns. [ABSTRACT FROM AUTHOR]

Polysaccharides (PS) have historically been viewed as T cell-independent antigens. However, in this paper I propose a new concept, based on substantial data from my laboratory over the previous 10 years, that during infections with PS-encapsulated extracellular bacteria, PS-specific IgG responses are largely CD4+ T cell dependent. Thus, capsular PS is typically encountered by the immune system covalently attached to the underlying subcapsular bacterial domain. I speculate that noncovalent association of PS with immunogenic proteins within the bacterial particle leads to recruitment of protein-specific CD4+ T cell help for the anti-PS response. However, differences in the composition and/or structure of the subcapsular domain of different extracellular bacteria may result in distinct anti-PS responses as well as differential effects on the immune response to coimmunizing soluble antigens. CD4+ T cell help for IgG anti-PS responses during infections with extracellular bacteria is likely to promote opsonic clearance of these rapidly growing pathogens. However, the expression of immunosuppressive components by certain bacteria may also serve to dampen such responses. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Petukhova et al. (2011) B- and T-cell memory elicited by a seasonal live attenuated reassortant influenza vaccine: assessment of local antibody avidity and virus-specific memory T-cells using trogocytosis-based method. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750-2659.2011.00279.x. Purpose The main purpose of vaccination is to generate immunological memory providing enhanced immune responses against infectious pathogens. The standard and most commonly used assay for influenza vaccine immunogenicity evaluation is a hemagglutination inhibition assay (HAI). It is clear now that HAI assay is unable to properly assess the proven protective immunity elicited by live attenuated influenza vaccines (LAIV). New methods need to be developed for more accurate LAIV immunogenicity assessment and prediction of vaccine efficacy among target populations. Objective Randomized placebo-controlled study of memory B- and T-cell responses to intranasal LAIV in young adults. Methods A total of 56 healthy young adults 18-20 years old received seasonal monovalent LAIV. Mucosal memory B-cell responses were measured by IgA avidity assessment in nasal swabs. CD4 memory T cells in peripheral blood were examined by the expression of CD45RO marker and in functional test by the ability of virus-specific T cells to maintain the trogocytosis with antigen-loaded target cells. Results Intranasal LAIV immunization enhances mucosal IgA avidity even without reliable increases in antibody titers. At the day 21 after vaccination, up to 40% of subjects demonstrated significant increases in both total and virus-specific CD4 memory T cells that were observed regardless of seroconversion rate measured by HAI assay. Conclusion The data suggest that immunogenicity of LAIV vaccines should be evaluated on the mucosal and cellular immunity basis. The assays applied could be used to support influenza clinical trials through preliminary screening of volunteers and subsequent measurement of anti-influenza in immunity. [ABSTRACT FROM AUTHOR]

In an accompanying paper, we find specific localization of diabetogenic T cells only to islets of Langerhans bearing the specific antigen. Instrumental in the specific localization was the presence of intraislet dendritic cells bearing the β-cell-peptide-MHC complex. Here, we report that the entry of diabetogenic CD4 T cells very rapidly triggered inflammatory gene expression changes in islets and vessels by up-regulating chemokines and adhesion molecules. Vascular cell adhesion molecule-1 (VCAM-1) expression was notable in blood vessels, as was intercellular adhesion molecule-1 (ICAM-1). ICAM-1 was also found on β-cells. These expression changes induced the entry of nonspecific T cells that otherwise did not localize to the islets. In contrast to the entry of diabetogenic CD4 T cells, the entrance of nonspecific T cells required a chemokine response and VCAM-1 expression by the islets. IFN-γ was important for the early gene expression changes in the islets. By microarray analysis, we detected up-regulation of a group of IFN-inducible genes as early as 8 h post-T-cell transfer. These studies establish that entry of diabetogenic T cells induces a state of receptivity of islets to subsequent immunological insults. [ABSTRACT FROM AUTHOR]

Abstract: For decades Experimental Autoimmune Encephalitis (EAE) has remained as an unsurpassed multiple sclerosis (MS) animal model. C-Phycocyanin (C-Pc) has been reported to exhibit pharmacological properties that may be expected to symptomatically improve EAE and MS. However, in this paper we reveal a basic underlying mechanism that may provide a new approach to the rationale of the overall beneficial effect of this natural antioxidant. We demonstrate that C-Pc is able to trigger mechanisms preventing or downgrading EAE expression and induces a regulatory T cell (Treg) response, in peripheral blood mononuclear cells (PBMC) from MS patients. These results agree with reports suggesting that Treg limit acute MS attacks and that C-Pc may act as a neuroprotector and thereby reverts the organic and functional damage in neurodegenerative disorders of the central nervous system (CNS). Moreover, evidence is provided on the antioxidant activity of C-Pc within the CNS, intended to improve the myelin and axonal damage of EAE induced Lewis rats. Our results indicate that specific Treg activation may represent a central and essential mechanism in supporting the therapeutic potential of C-Pc for MS and may lead to new and more effective therapies; this property would then complement and enhance other proven active principles such as interferons (IFN), giving rise to combined therapies. [ABSTRACT FROM AUTHOR]

Background: Gene expression is regulated at both the DNA sequence level and through modification of chromatin. However, the effect of chromatin on tissue/cell-type specific gene regulation (TCSR) is largely unknown. In this paper, we present a method to elucidate the relationship between histone modification/variation (HMV) and TCSR. Results: A classifier for differentiating CD4+ T cell-specific genes from housekeeping genes using HMV data was built. We found HMV in both promoter and gene body regions to be predictive of genes which are targets of TCSR. For example, the histone modification types H3K4me3 and H3K27ac were identified as the most predictive for CpG-related promoters, whereas H3K4me3 and H3K79me3 were the most predictive for nonCpG-related promoters. However, genes targeted by TCSR can be predicted using other type of HMVs as well. Such redundancy implies that multiple type of underlying regulatory elements, such as enhancers or intragenic alternative promoters, which can regulate gene expression in a tissue/cell-type specific fashion, may be marked by the HMVs. Finally, we show that the predictive power of HMV for TCSR is not limited to protein-coding genes in CD4+ T cells, as we successfully predicted TCSR targeted genes in muscle cells, as well as microRNA genes with expression specific to CD4+ T cells, by the same classifier which was trained on HMV data of protein-coding genes in CD4+ T cells. Conclusion: We have begun to understand the HMV patterns that guide gene expression in both tissue/cell-type specific and ubiquitous manner. [ABSTRACT FROM AUTHOR]

Abstract Introduction  The immune response is controlled by several inhibitory mechanisms. These mechanisms include regulatory T cells, which exist in multiple classes. Notable among these are Foxp3-expressing regulatory T cells (Treg), NKT cells, and Tr1 cells. Common to these mechanisms are inhibitory cytokines such as interleukin-10 and transforming growth factor-beta (TGF-β). TGF-β and Foxp3-expressing Treg cells are critical in maintaining self-tolerance and immune homeostasis. Discussions  The immune suppressive functions of TGF-β and Treg cells are widely acknowledged and extensively studied. Nonetheless, recent studies revealed the positive roles for TGF-β and Treg cells in shaping the immune system and the inflammatory responses. In this paper, we will discuss the role of these mechanisms in the control of immunity and autoimmunity and the mechanisms that underlie how these molecules control these responses. [ABSTRACT FROM AUTHOR]

CCL27 (also named CTACK, ALP, ILC and ESkine) is a CC chemokine primarily expressed by keratinocytes of the skin. The cognate receptor of CCL27 named CCR10 (GPR-2), is also expressed in skin-derived cells, and in addition by a subset of peripheral blood T-cells and in a variety of other tissues. In this paper, we report the cloning of porcine CCL27 cDNA and investigation of CCL27 mRNA expression in Staphylococcus hyicus infected piglets. At the protein level, 77 and 74% homology was found to human and mouse CCL27 sequences, respectively. The results of the expression analyses show that CCL27 mRNA is upregulated in the skin of infected piglets and to a lesser extent in piglets recovered from disease and without clinical signs of infection, indicating a role for CCL27 both during inflammation and after recovery from an infection. [Copyright &y& Elsevier]

The TCL1 (T-cell leukemia 1) protooncogene is highly expressed in many human B-cell leukemias and two recent papers show that TCL1 overexpression causes rapid development of B-cell lymphomas in mice. Other recent work showing that the TCL1 protein enhances the activation of the pro-survival kinase Akt has revealed a potential mechanism underlying the development of B-cell leukemias and raised new questions about the regulation of Akt. [Copyright &y& Elsevier]

Simple Summary: This review paper here describes the recent progress that has been made in chimeric antigen receptor (CAR) -based therapies for treatment of tumors and the role of metabolism in the tumor microenvironment in relation to these therapies. Moreover, this manuscript also discusses role of different CAR-based cells for treatment of solid tumors, which is a major challenge in the CAR immunotherapy field. Chimeric antigen receptor (CAR) T cell-based therapies have shown tremendous advancement in clinical and pre-clinical studies for the treatment of hematological malignancies, such as the refractory of pre-B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and large B cell lymphoma (LBCL). However, CAR T cell therapy for solid tumors has not been successful clinically. Although, some research efforts, such as combining CARs with immune checkpoint inhibitor-based therapy, have been used to expand the application of CAR T cells for the treatment of solid tumors. Importantly, further understanding of the coordination of nutrient and energy supplies needed for CAR T cell expansion and function, especially in the tumor microenvironment (TME), is greatly needed. In addition to CAR T cells, there is great interest in utilizing other types of CAR immune cells, such as CAR NK and CAR macrophages that can infiltrate solid tumors. However, the metabolic competition in the TME between cancer cells and immune cells remains a challenge. Bioengineering technologies, such as metabolic engineering, can make a substantial contribution when developing CAR cells to have an ability to overcome nutrient-paucity in the solid TME. This review introduces technologies that have been used to generate metabolically fit CAR-immune cells as a treatment for hematological malignancies and solid tumors, and briefly discusses the challenges to treat solid tumors with CAR-immune cells. [ABSTRACT FROM AUTHOR]

MRL-+, MRL-lpr and B6-lpr have been shown to be useful models in studying systemic lupus erythematosus. MRL-lpr and B6-lpr differ from their congenic counterparts by the presence and expression of the homozygous recessive lymphoproliferation (Ipr) gene. One manifestation of this gene is a massive Tall proliferation that results in a generalized lymphadenopathy in older animals. A paradox that has developed out of the work utilizing the congenic mice is that the gene responsible for lymphoproliferation also appears to be responsible for the inability of T cells to respond to proliferative signals in vitro. In this paper we investigate the basis for this hypo responsiveness in antigen-induced activation of proliferation and antibody synthesis. We have demonstrated that spleen cells from both MRL-+ and MRL-lpr mice gave minimal stimulation in a one-way mixed lymphocyte reaction against allogeneic T cells. These findings were extended to include antigen-specific proliferation involving antigen that must be processed and presented to responder lymphocytes in a H-2 restricted manner. Thus, MRL- + and MRL-lpr spleen cells pulsed with ferredoxin also failed to stimulate ferredoxin-primed T cells from B10.Br animals in vitro. We then investigated whether any T-cell defect(s) was also contributing to this proliferative hyporesponsiveness. T lymphocytes from the spleen of MRL- +, 2-month-old MRL-lpr, and 6-month-old MRL-lpr were tested in a one-way mixed lymphocyte reaction. It was found that only the MRL- + T cells gave responses approaching normal, suggesting lpr gene involvement in T-cell non-responsiveness. This was confirmed by the demonstration of an age-onset T-cell proliferative hyporesponsiveness in B6. lpr mice. This lpr gene-linked non-responsiveness was also shown to extend to T-cell helper function in a positive allogeneic effect assay. We can conclude from these studies that antigenic non-responsiveness in MRL congenic mice can be explained by two defects: (i) the failure of antigen-presenting cells in MRL- + and MRL-lpr mice to provide the necessary signal(s) to immunocompetent T cells, this defect not being associated with the lpr gene, and (ii) the Ip gene controlled outgrowth of a unique T-cell population that cannot respond in our assay systems. [ABSTRACT FROM AUTHOR]

IL-6, an important mediator of the acute phase response, has been implicated in the pathogenesis of rheumatoid arthritis (RA). Many cell types including macrophages, T cells. H cells, endothelial cells and fibroblasts can produce this cytokine and production is largely regulated at the level of gene transcription or mRNA stabilization. In this paper we have first measured the levels of IL-6 activity in synovial fluid (SF) and serum from patients with RA and then localized IL-6-producing cells in the synovium by in situ hybridization combined with immunophenotyping. Patients with RA had raised levels of IL-6 in both SF and serum compared with patients with osteoarthritis and age-matched healthy controls. in individual RA patients tested serially after admission to hospital, serum IL6 was initially raised and, unexpectedly. increased with clinical improvement, in situ hybridization of IL-6 mRNA showed positive cells both in the lymphocyte-rich aggregates and adjacent to small blood vessels. With immunophenotyping it was found that cells containing IL-6 mRNA were often in contact with CD 14+ tissue macrophages and double immunophenotyping revealed that immuno- reactive IL-6 was often associated with synovial T cells. [ABSTRACT FROM AUTHOR]

Notch signaling is essential for the development of T cell progenitors through the interaction of NOTCH1 receptor on their surface with the ligand, Delta-like 4 (DLL4), which is expressed by the thymic epithelial cells. Notch signaling is quickly shut down once the cells pass β-selection, and CD4/CD8 double positive (DP) cells are unresponsive to Notch. Over the past two decades a number of papers reported that over-activation of Notch signaling causes T cell acute lymphoblastic leukemia (T-ALL), a cancer that prominently features circulating monoclonal CD4/CD8 double positive T cells in different mouse models. However, the possible outcomes of Notch over-activation at different stages of T cell development are unknown, and the fine timing of Notch signaling that results in T-ALL is poorly understood. Here we report, by using a murine model that ectopically expresses DLL4 on developing T cells, that the T-ALL onset is highly dependent on a sustained Notch activity throughout the DP stage, which induces additional mutations to further boost the signaling. In contrast, a shorter period of Notch activation that terminates at the DP stage causes a polyclonal, non-transmissible lymphoproliferative disorder that is also lethal. These observations resolved the discrepancy of previous papers on DLL4 driven hematological diseases in mice, and show the critical importance of the timing and duration of Notch activity. [ABSTRACT FROM AUTHOR]

The article presents research highlights from the field of T cell differentiation based on the original research paper "T. Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-γ and interleukin-12," by E.G. Schulz, L. Mariani, A. Radbruch, and T. Höfer that appeared in the April 30, 2009 issue of "Immunity." Subjects discussed include cell phenotype stabilization, cell signalling, and gene expression.