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In this paper, we report the development of a label-free biosensor, based on surface plasmon resonance, for real-time monitoring of captured human CD4+T-cells, and their dynamic cytokine production upon specific antigen stimulation. Microarrays of CD4+T-cells, and interferon gamma (IFN-γ) specific antibody (Ab) spots were printed side by side onto the poly(OEGMA-co-HEMA) matrix. The placement of CD4+ T-cells near the anti IFN-γ Ab-coated spots ensured a high local concentration of secreted IFN-γ for detection. We have demonstrated that this approach enables the detection of tuberculosis (TB) infection in clinical samples, with an overall sensitivity of 85.5% and an overall specificity of 97.7%. [ABSTRACT FROM AUTHOR]

The requirements for the eradication of HIV in infected individuals are unknown. Intermittent administration of the immune activator interleukin-2 (IL-2) in combination with highly-active anti-retroviral therapy (HAART) has been suggested as an effective strategy to realize long-term control of HIV replication in vivo . However, potential latent virus reservoirs are considered to be a major impediment in achieving this goal. In this paper, a new mathematical model is designed and used to monitor the interactions between HIV, CD4+ T-cells, CD8+ T-cells, productively infected and latently infected CD4+ T-cells, and to evaluate therapeutic strategies during the first 3 years of HIV infection. The model shows that current anti-HIV therapies, including intermittent IL-2 and HAART, are insufficient in achieving eradication of HIV. However, it suggests that the HIV eradication may indeed be theoretically feasible if such therapy is administered continuously (without interruption) under some specified conditions. These conditions may realistically be achieved using an agent (such as a putative anti-HIV vaccine) that brings about a concomitant increase in the proliferation of HIV-specific CD4+ T- and CD8+ T-cells and the differentiation of CD8+ T-cells into anti-HIV cytotoxic T lymphocytes (CTLs). [ABSTRACT FROM AUTHOR]

Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-TCLPD) was reclassified in 2016 as a rare benign entity with an excellent prognosis, yet its clinical features and best treatments remain poorly defined. We collected clinical data, treatments, and treatment-responses from our institution's patients with PCSM-TCLPD through September 2018 and an identical PubMed review through June 2021. Among 36 cases (median-age 54 years; 58.3% head/neck), diagnostic biopsy resulted in sustained complete remission (CR) in 13/33 punch/shave biopsies and 3/3 excisional biopsies. The remaining 20 patients further required topical corticosteroids (n = 5); intralesional corticosteroids (n = 1); surgical-excision (n = 5); electron-beam-radiation (n = 6); or brachytherapy (n = 3). All patients ultimately achieved CR, excluding one patient continuing treatment at end-of-study. 57/59 (96.6%) of institutional and literature-reported radiation-treated patients experienced CR. No institutional cases progressed beyond skin; 5/209 (2.4%) literature-reported cases progressed to systemic/extracutaneous involvement, all pre-reclassification. PCSM-TCLPD responds well to local-directed therapy including radiation, and only rarely if ever progresses. [ABSTRACT FROM AUTHOR]

Hepatic ischemia-reperfusion injury (IRI) is a severe complication frequently encountered in liver surgery, seriously affecting the therapeutic effects, tissue function. Various immune cells are involved in hepatic IRI, including macrophages, NKT cells, DCs, CD4 + T cells, and CD8 + T cells, among which CD4 + T cells play a critical role in this process. This article aims to summarize the functions and changes in various CD4 + T cell type counts and related cytokine levels in hepatic IRI and to review the possible mechanisms of mutual conversion between T cell types. We have covered the functions and changes that occur in Th1, Th17, and Treg cells in liver IRI, as well as the pathways and factors associated with them. We also discuss the prospects of clinical application and future directions for therapeutic advances. This section explores the current clinical trials involving CD4 + T cells, especially Tregs, explains the limitations of their application, and summarizes the future development trends of cell engineering and their combination with the CAT technology. We also provide new ideas and therapeutic targets for alleviating liver IRI or other liver inflammatory diseases. [ABSTRACT FROM AUTHOR]

The article reviews developments in the research of regulatory Treg (T) cells in the treatment of autoimmunity. A research paper in the issue on attempts to improve the isolation of Treg cells through the addition of CD8-depletion techniques to those currently being practiced is mentioned. The author describes the possible benefits that can arise from Treg cell transfers and the clinical trials that should be performed to evaluate them.

In this article, time to immune recovery during antiretroviral therapy was estimated and compared between HIV-infected children with and without tuberculosis (TB). CD4 T-cell restoration was used as a criterion for determining immune recovery. The median residual lifetime function, which is more intuitive and robust compared to the frequently used measures of lifetime data, was used to estimate time to CD4 T-cell restoration. The median residual lifetime is not influenced by extreme observations and heavy-tailed distributions which are commonly encountered in clinical studies. Permutation-based methods were used to compare the CD4 T-cell restoration times between the two groups of patients. Our results indicate that children with TB had uniformly higher median residual lifetimes to immune recovery compared to those without TB. Although TB was associated with slower CD4 T-cell restoration, the differences between the restoration times of the two groups were not statistically significant. [ABSTRACT FROM AUTHOR]

Objective: We compared the frequency of peripheral blood Treg cells in women with pre-eclampsia (PE) and in those without, and investigated whether the frequency of Treg cells in women with high-risk factor for PE changed during pregnancy.Methods: We examined the frequency of CD4+FoxP3+Treg cells in the peripheral blood using flow cytometry. Eleven women with PE and 10 women without PE (controls) were included. Every control had any risk factors for PE, such as high blood pressure, bilateral notching or a past history of PE or gestational hypertension. Blood sampling was conducted 1–3 times in the controls.Results: No significant differences were observed in the frequency of Treg cells between women with PE and the controls [mean ± SE (%): 5.74 ± 0.91 versus 5.48 ± 0.94,p = 0.843]. In five controls with serial sampling, the frequency of Treg cells significantly decreased from 5.83 ± 1.20 to 2.99 ± 0.54 (p = 0.046) (week of the first sampling to that of the last sampling [mean ± SD]: 21.5 ± 1.6 weeks to 31.2 ± 2.5 weeks).Conclusion: The frequency of Treg cells in women with PE was almost identical to that in the controls. The frequency of Treg cells in the controls was reduced by half from the second trimester to the third trimester. These results suggested that the levels of Treg cells in a high-risk pregnant cohort were decreased to those in women with PE in the third trimester irrespective of the occurrence of PE. [ABSTRACT FROM PUBLISHER]

CD4+ T cells and many cytokines play critical roles in the pathogenesis of Guillain–Barré Syndrome (GBS), an immune-mediated inflammatory disease. However, the role of IL-35, a novel member of the IL-12 cytokine family, in this kind of disease has not yet been elucidated. In this study, we investigated the functional changes of CD4+ T cells from GBS patients with IL-35 treatmentin vitro. This study involved 21 GBS patients and an equal number of healthy controls (HCs). The results indicated that the average concentration of IL-35 in the plasma of GBS patients was lower than that of healthy controls (HCs). Increased levels of STAT1, STAT3 and STAT4 proteins and T-bet, ROR γt, IFN-γ and IL-17A mRNA were observed in CD4+ T cells from GBS patients. In contrast, the levels of STAT5 and STAT6 proteins and GATA3, Foxp3, IL-4 and TGF-β1 mRNAs were decreased in GBS patients in comparison with those of HCs. In addition, treatment of CD4+ T cells from GBS patients with IL-35 upregulated IL-35, STAT5 and STAT6 protein and T-bet, GATA3, Foxp3, IFN-γ, IL-4, IL-17A and TGF-β1 mRNA while inhibited levels of STAT3 and STAT4 protein and RORγt and IL-17A mRNA. These results indicate that IL-35 might play a potential role in GBS pathogenesis. Further studies are required in order to evaluate its role in GBS. [ABSTRACT FROM PUBLISHER]

Aims: To determine the number of CD4+CD25-Foxp3+, CD4+CD25+Foxp3+ and CD4+CXCR5+Foxp3+ T cells in renal transplant recipients that are transplanted stable (TS), or experiencing accelerated rejection (ALR), or acute rejection (AR). Methods: Renal transplantation was conducted in 28 patients with end-stage renal failure (ESRF). The number of peripheral CD4+CD25-Foxp3+, CD4+CD25+Foxp3+, or CD4+CXCR5+Foxp3+ T cells and the serum levels of interleukin-10 (IL-10) were measured in pre- and post-transplant patients and these results were compared to 10 healthy controls (HC). Correlation between CD4+CD25+Foxp3+ and estimated glomerular filtration rate (eGFR), CD4+CD25-Foxp3+ and serum creatinine (Cr) levels, or Cr and IL-10 levels in TS patients was also determined. Results: The number of CD4+CD25-Foxp3+ T cells was significantly increased in patients with ESRF, as compared to HC. Stratification analysis demonstrated that TS patients contained greater numbers of CD4+CD25+Foxp3+ and CD4+CXCR5+Foxp3+ T cells, higher levels of serum IL-10, and fewer numbers of CD4+CD25-Foxp3+ T cells than ESRF patients. In contrast, ALR and AR patients contained fewer numbers of CD4+CD25+Foxp3+ and CD4+CXCR5+Foxp3+ T cells, greater numbers of CD4+CD25-Foxp3+ T cells, and lower levels of serum IL-10 than ESRF patients. In TS patients, the numbers of CD4+CD25+Foxp3+ and CD4+CD25-Foxp3+ T cells were positively correlated with eGFR and serum Cr levels, respectively. Conclusion: An imbalance of different types of CD4+Foxp3+ T cells might be involved in renal transplant rejection. [ABSTRACT FROM AUTHOR]

Background: nAChRs play an important role in the regulation and modulation of immune cell proliferation, differentiation, migration and cell-cell interactions. The present study was to characterize the expression of α7nAChR on human peripheral blood mononuclear cells (hPBMC) and CD4+T lymphocytes, and to explore the change of Th17 expression after activation of α7nAChR on human CD4+T lymphocytes. Methods: A Ficoll gradient was used to separate hPBMC from whole blood, and then CD4+T lymphocytes were isolated by magnetic bead separation. The expression of α7nAChR on PBMC and CD4+T lymphocytes was analyzed using flow cytometry before and after stimulation with phytohemagglutinin (PHA). The effect of α7nAChR stimulation by nicotine or inhibition by α-bungarotoxin (α-BTX), as well as Th17 expression on the phenotype of CD4+T cells was evaluated using flow cytometric analysis. Results: The percentage of CD4+T cells in reduced PBMC, while the expression of α7nAChR increased when cells were stimulated by nicotine. This effect vanished when co-treated with nicotine and α-BTX. α7nAChR was found to expressed in about 90% of CD4+T cells. However, α7nAChR expression reduced to 80% on CD4+T cells after stimulation with PHA for 24 h. Stimulation of α7nAChR with nicotine increased the expression of Th17 cells, and this upregulation reduced when AChRα7 was inhibited by α-BTX. Conclusion: α7nAChR was ubiquitously expressed by CD4+T lymphocytes, which was correlated with the cell activation status. Meanwhile, activation of nAChRα7 by nicotine in CD4 cells reduced the Th17 response. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) lung disease is characterized by dysregulated inflammatory response in the airways. CD4+CD25+ regulatory T cells play a crucial role in maintaining the immune homeostasis. However their role in the disease pathogenesis of CF remains unexplored. Aim: To determine the percentage of circulating CD4+CD25high, FoxP3+ T cell expression in children with CF and controls. Furthermore to evaluate the relationship between CD4+CD25high, FOXP3 T cell % and the clinical status of the disease (lung function). Methods: CD4+CD25+, intracellular FoxP3 expression in peripheral blood were estimated using flowcytometry in 20 children with CF and 10 healthy controls. Spirometry was carried out according to the standard guidelines. Results: We observed a significant difference in CD4+CD25+T cell% in children with CF (5.2 ± 1.2) versus controls (6.8 ± 1.4, p < 0.05), CD4+CD25highTcell% in CF (1.72 ± 0.36) versus controls (2.59 + 0.42, p < 0.003). Similarly a significant difference was observed in FoxP3 T cell% CF: (60.7 ± 6.19) versus controls (76.8 ± 5.16), p < 0.001. A significant positive correlation between FoxP3 T cell% and FEV1 in children with CF(r = 0.822, p < 0.01) was observed.CD4+CD25high T cell% correlated positively with FEV1 (r = 0.742, p < 0.01). Conclusion: Our findings report the first evidence of a decreased expression of circulating CD4+CD25high FoxP3+ T cells in children with CF. Furthermore circulating CD4+ CD25high, FOXP3+ T cell percentage correlated with FEV1. [ABSTRACT FROM AUTHOR]

To determine the roles of CD4+ T-cell (Th) subsets, including Th17 cells, in the development of chronic graft-versus-host disease (cGVHD), we used a Th-dependent cGVHD model comprising B10.D2 donor and BALB/c recipient mice. The clinical GVHD score increased beginning at day +14, peaked at day +42, and remained elevated until day +70. In the skin, increased dermal thickness was apparent at day +14, and maintained with few changes until day +70. In contrast, the liver had peak pathologic scores at day +28, and the tissue damage began to improve at day +56. To determine possible associations between improvement of liver pathology and changes in Th subsets, we analyzed Th subsets using flow cytometry. Th1 frequencies in the livers were greater than other Th subsets throughout the disease course, but the frequencies decreased over time. Notably, Th17 cells were rarely detected during earlier periods, but emerged at day +56, which correlated with the improved hepatic inflammation. In contrast, other Th subsets (Th2 and regulatory T cells) did not change significantly during the disease course. These results indicate the association of attenuation on cGVHD with a later emergence of Th17 cells and concomitant decrease of Th1 cells. [ABSTRACT FROM AUTHOR]

The incidence of reflux-related esophageal disease - Barrett's esophagus and esophageal adenocarcinoma - is rising, and the prognosis remains poor. Evidence exists that 1,25-dihydroxyvitamin D may augment the course of colon, breast and prostate cancer but little knowledge exists regarding its impact on disease of the esophagus. Important immune cells involved in reflux-related esophageal disease include CD4+ T cells, macrophages and dendritic cells, and key signaling pathways include Wnt, Hedgehog, NFκ-B and IL-6-JAK-STAT. There is an interrelationship between these entities and 1,25-dihydroxyvitamin D, which has been described in animal models and some human tissue. Despite this, there is an incomplete understanding of how the immune cell population and signaling pathways contribute to the course and prognosis of Barrett's esophagus and esophageal adenocarcinoma. More investigation with a focus on the clinical outcomes of patients with Barrett's esophagus and esophageal adenocarcinoma and the immune cell population and cell signaling activity in the diseased esophagus is necessary to determine the immunomodulatory role of 1,25-dihydroxyvitamin D in the pathogenesis of esophageal diseases. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate and determine the potential mechanisms of As2O3 in accelerated rejection mediated by alloreactive CD4+ memory T cells. Vascularized heterotopic cardiac transplantation from C57BL/6 mice to nude mice (pre-transferred CD4+ memory T cells) was performed on Day 0, and As2O3 was administered to recipient mice from Day 0 to 10. As a result, As2O3 could reduce the proliferation of allo-primed CD4+ memory T cells in vitro in MLR and the baseline rate of proliferation was restored by the addition of exogenous IL-2. In vivo, compared with the control[+] group, the mean survival time of cardiac allografts in the As2O3 group was prolonged from 5.8 ± 0.7 to 14.2 ± 2.5 days. Five days after transplantation, the relative gene expression of IL-2, IFN-γ and Foxp3 was reduced in the grafts by As2O3 treatment, but the expression of IL-10 and TGF-β was increased. Correspondingly, the proportions of CD4+ T cells, CD4+ memory T cells and regulatory T cells (Tregs), both in recipient spleens and lymph nodes, were lowered. These results indicate the potential of As2O3 as a novel immunosuppressant targeting CD4+ memory T cells. [ABSTRACT FROM AUTHOR]

Although double negative T (DNT) cells (CD3+CD4-CD8-) share some characteristics with T regulatory cells, the relationship between DNT cells and disease progression in HIV infection is unclear. In this study, we analyzed the relationship between DNT cells and disease progression during the first 2 years of HIV infection. We found that DNT cell numbers tended to decrease with disease progression. There was a positive correlation between DNT cells and CD4 counts. The DNT cell numbers were significantly lower in the high viral load group compared with the low viral load group. Therefore, we conclude that DNT cells correlated with disease progression in HIV infection. These data provide valuable information for further understanding of the role of DNT cells during HIV infection. [ABSTRACT FROM AUTHOR]

The suppressor effect of T regulatory lymphocytes in co-cultures with T effector cells obtained by magnetic columns from healthy donors and activated by CD3/CD28 was measured by a proliferation assay using BrdU incorporation and an ELISA test. Tritiated thymidine incorporation was used as a reference since it is the gold standard for proliferation assays. Both methods were used simultaneously in the same samples in order to compare them. Correlation between them was statistically significant (p < 0.001). The purification using magnetic columns was very efficient since CD4+CD25+ cells were also FOXP3+ therefore; they were identified as suppressor T cells. The use of BrdU incorporation in suppression assays is an excellent method that avoids the use of radioactive contaminating materials. [ABSTRACT FROM AUTHOR]

The differential diagnosis between malignant and tuberculous exudative pleural effusions is an important clinical problem. The aim of current study is to evaluate the frequencies of T-regulatory cells (Treg) on the basis of distinct phenotypes in the differential diagnosis between malignant and tuberculous pleural effusion. In addition, to evaluate Interferon-gamma (IFN- γ) and interleukin-16 (IL-16) levels and their correlation to Treg cells in malignant and tuberculous pleural effusions. Sixty patients with pleural effusion (26 tuberculous and 34 malignant) and 20 healthy controls were included in the study. Pleural fluid and peripheral blood were assessed for frequencies of T regs, IL-16, and IFN-γ. Pleural effusions from both tuberculous and malignant groups represented significantly higher levels (more in TB) for the following cell populations than peripheral blood: total lymphocytes, CD3+lymphocyte, CD4+CD25+lymphocyte and Treg (CD4+ CD25+FoxP3+). Levels of IL-16 and IFN-γ in tuberculous group were significantly higher than that in malignant group. Regulatory T cells, INF-γ and IL-16 are new important tools for differentiation between tuberculous and malignant pleural effusion. [ABSTRACT FROM AUTHOR]

The pathology of relapsing-remitting multiple sclerosis (RR-MS) is largely attributed to activated autoreactive effector T lymphocytes. The influence of microRNAs on the immune response has been shown to occur in different pathways of lymphocyte differentiation and function. Here, the expression of the miRNAs miR-15a/16-1 in PBMC, CD4+, and CD8+ from RR-MS patients has been investigated. BCL2, a known miR-15a/16-1 target, has also been analyzed. The results have shown that miR-15a/16-1 is downregulated in CD4+ T cells, whereas BCL2 is highly expressed in RR-MS patients only. Our data suggest that miR-15a/16-1 can also modulate the BCL2 gene expression in CD4+ T cells from RR-MS patients, thereby affecting apoptosis processes. [ABSTRACT FROM AUTHOR]

Background. Dysregulation of CD4 ++ T cell subsets participates in the pathogenesis of IgA nephropathy (IgAN). FoxP3 ++ regulatory T cells (Treg) and Th17 cells are two novel subsets of CD4 ++ T cells. This study aims to investigate Treg/Th17 balance in IgAN patients. Methods. Peripheral frequencies of Th17 and Treg functional subsets - CD45RA ++ FoxP3low resting Treg (rTreg) and CD45RA-FoxP3high activated Treg (aTreg) were assessed in 63 adult IgAN patients. Expression of transcription factors (FoxP3 and RORγt) and related cytokines of Treg and Th17 were analysed. Renal expression of FoxP3 and IL-17A were detected by immunohistochemistry. Results. Compared with normal controls, IgAN patients had decreased frequency of CD45RA-FoxP3high aTreg subset ( p < 0.05), increased frequency of Th17 ( p < 0.05) and decreased ratio of Treg/Th17 ( p < 0.05). Frequency of aTreg subset correlated with SBP(r == − 0.57, p < 0.05), DBP (r == − 0.50, p < 0.05), eGFR (r == 0.68, p < 0.05) and 24 h proteinuria (r == − 0.58, p < 0.05). RORγtmRNA/FoxP3mRNA ratio increased in IgAN ( p < 0.05). Serum IL-17A, IL-21, IL-23, IL-1β and IL-6 elevated while IL-10 decreased in IgAN ( p < 0.05), and serum IL-17A correlated with 24 h proteinuria (r == 0.35, p < 0.05). Serum TGF-β1 wasn't different between the two groups. Renal interstitial infiltration of FoxP3 ++ mononuclear cells were observed in IgAN patients, particularly prominent in those with > 25% tubular atrophy/interstitial fibrosis. Tubular IL-17A expression was found in 34 out of 63 IgAN patients. Compared with 29 patients without IL-17A expression, these patients had lower renal function, greater proteinuria, and more severe tubulointerstitial damage. Conclusions. Imbalance of Treg/Th17 found in IgAN may play a role in disease pathogenesis and progression. [ABSTRACT FROM AUTHOR]

Recent development in antiretroviral treatment against HIV can help AIDS patients to fight against HIV. But the question that whether the disease is to be partially or totally eradicated from HIV infected individuals still remains unsolved. Usually, the most effective treatment for the disease is HAART which can only control the disease progression. But as the immune system becomes weak, the patients can not fight against other diseases. Immune cells are activated and proliferated by IL-2 after the identification of antigen. IL-2 production is impaired in HIV positive patients and intermitted administration of immune activator IL-2 together with HAART which is a more effective treatment to fight against the disease. Thus, its expediency is essential and is yet to be explored. In this article we anticipated a mathematical model of the effect of IL-2 together with RTIs therapy in HIV positive patients. Our analytical as well as numerical study shows that the optimal schedule of treatment for best result is to be obtained by systematic drug therapy. But at the last stage of treatment, the infection level raises again due to minimisation of drug dosage. Thus we study the perfect adherence of the drugs and found out if RTIs are taken with sufficient interval then for fixed interval of IL-2 therapy, certain amount of drug dosages may be able to sustain the immune system at pre-infection stage and the infected CD4+T cells are going towards extinction. [ABSTRACT FROM AUTHOR]

A key component of the immune system is its ability to establish and maintain peripheral tolerance. Naturally occurring CD4++CD25++Foxp3++ regulatory T (nTreg) cells represent an important means by which this is accomplished, through their potent ability to suppress the actions of both CD4++ and CD8++ effector (Teff) cells in vitro and in vivo. We hypothesized that direct contact between nTreg and Teff cells is sufficient for nTreg cell-contact suppression. We first show that nTreg cell suppression is independent of APCs and their derived co-stimulatory signals. We then used a two-colour, lipid dye labelling and quantification approach to formally demonstrate that nTreg cells specifically form cell conjugates with responding T (Tresp) cells only under TCR activating conditions. Strikingly, activated CD4++ nTreg cells undergo progressive trogocytosis, a process by which membrane fragments are transferred from one cell subset to another, with Tresp cells more readily than Teff cells. These results are the first to show that nTreg cell cognate interactions with Tresp cells leads to trogocytosis between the cells, and the first to relate the degree of trogocytosis with the level of nTreg-mediated suppression. [ABSTRACT FROM AUTHOR]

Induction of immune tolerance as therapeutic approach for autoimmune diseases constitutes a current research focal point. In this sense, we aimed to evaluate an altered peptide ligand (APL) for induction of peripheral tolerance in patients with rheumatoid arthritis (RA). A novel T-cell epitope from human heat-shock protein 60 (Hsp60), an autoantigen involved in the pathogenesis of RA, was identified by bioinformatics tools and an APL was design starting from this epitope. We investigated the ability of this APL for inducing regulatory T cells (Treg cells) in mice and evaluated the therapeutic effect of this peptide in an adjuvant-induced arthritis (AA) rat model. Clinical score, TNFαα levels and histopathology were monitored, as well as the capacity of this APL for inducing Treg cells. Finally, the potentialities of the APL for inducing Treg cells were evaluated in ex vivo assays using mononuclear cells isolated from peripheral blood (PBMC). The APL induced an increase of the proportions of Treg cells in the draining lymph nodes of the injected site in mice. The APL efficiently inhibited the course of AA, with significant reduction of the clinical and histopathology score. This effect was associated with an increase of the proportions of Treg cells and a decrease of TNFαα levels in spleen. Finally, stimulation of PBMCs from RA patients by the APL increases the proportions of the CD4++CD25highFoxP3++ Treg cells. These results indicate a therapeutic potentiality of APL and support further investigation of this candidate drug for treatment of RA. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a generalized connective tissue disorder, characterized by a wide spectrum of microvascular and immunological abnormalities, leading to a progressive thickening and fibrosis of the skin and other organs, such as the lungs, GI tract, heart and kidneys. SSc is thought to be an autoimmune disease owing to the presence of high affinity antibodies and possible clinical overlap with other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Autoimmune diseases arise because of a breakdown in immunological self tolerance. Self tolerance is maintained via multiple regulatory mechanisms within the immune system, including the thymic deletion of self-reactive T cells and mechanisms of peripheral tolerance. In recent years, the presence of CD4+CD25+FOXP3+ Tregs has been identified as a major mechanism of peripheral tolerance, and accumulating evidence indicates that alterations in Treg frequencies and/or function may contribute to autoimmune diseases. Here, we will review recent data on the percentage, function and phenotype of CD4+CD25+ Tregs in rheumatic disease, and discuss how recent developments may guide research in this area in SSc. INSET: Key issues. [ABSTRACT FROM AUTHOR]

Purpose: To determine the radiosensitivity difference of human Cluster of Differentiation (CD)4+CD25+ regulatory T cells (Treg) and effector T cells to low dose gamma ray and elucidate the underlying mechanisms in vitro. Materials and methods: Blood samples were collected from five health subjects and five patients with advanced hepatocellular carcinoma (HCC). Treg and CD4+CD25− T cells were selected using magnetic microbeads. The proliferative profiles, cytokine secretion, and differential expressions of apoptosis-related proteins in Treg and CD4+CD25− T cells were compared using [3H]-thymidine incorporation, Luminex assay and flow cytometry when treated with various low doses of γ-ray. Results: A dose-dependent reduction of proliferation in response to irradiation which paralleled the induction of apoptosis existed in Treg and CD4+CD25− T cells. Treg were more radiosensitive to low-dose irradiation (0.94 Gray [Gy]) than effector T cells. The interferon-γ (IFNγ) was significantly upregulated and interleukin 10 (IL-10) was significantly downregulated in irradiated Treg. An enhanced immune response to low dose gamma ray existed in the peripheral blood in patients with advanced HCC. Higher levels of active caspase-3, CD95, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax) expression were observed in Treg compared to CD4+CD25− T cells. In addition, gamma irradiation activated CD4+CD25− T cells to express CD25. Conclusions: These studies revealed that Treg were more radiosensitive than CD4+CD25− T cells to low dose irradiation. Higher expressions of apoptosis-related proteins such as caspase-3, CD95 and Bax were observed in Treg when compared to CD4+CD25− T cells. Our results suggest that treatment with low doses of gamma irradiation may be a viable strategy to enhance immune response in patients with advanced HCC. [ABSTRACT FROM AUTHOR]

Donor-reactive CD4+memory T cells threaten the survival of transplanted organs. In this study, we used anti-CD44 monoclonal antibody (mAb) to inhibit adoptively transferred B6-reactive CD4+memory Tcells (BALB/c origin) and to induce tolerance of B6 hearts in nude mice. The median survival time (MST) of the grafts was 6 days in the isotype group, and more than 100 days in the group treated with 8 doses of anti-CD44 at four-day intervals. Histological analysis revealed that the mean rejection level was Grade 3 in the isotype group, and Grade 0 or 1 in the multi-dose anti-CD44 treatment group. Compared with the isotype group, the multiply treated anti-CD44 group had significantly decreased IL-2 and IFN-γ expressions, while IL-10 and TGF-β were increased in the serum and the graft. Foxp3 in the graft was also increased. These data demonstrate that alloreactive CD4+ memory T cells mediate the destruction of allografts, and the adhesion molecule CD44 plays an important role in this course. Anti-CD44 mAb may promote the reduction of CD4+memory T cells and the production of regulatory T cells (Tregs). Furthermore, Tregs are maintained at a certain level while suppressing cellular immunity and inducing the grafts long-term survival in transplant recipients. [ABSTRACT FROM AUTHOR]

Objective. To determine circulating levels of CD4+CD25high regulatory T (Treg) cells and transforming growth factor-β (TGF-β) in patients with adult-onset Still's disease (AOSD) and to examine the associations with disease activity and clinical course of this disease. Methods. The frequencies of circulating CD4+CD25high Treg cells in 52 active AOSD patients, 42 active systemic lupus erythematosus (SLE) patients, and 22 healthy controls (HCs) were determined using flow cytometry analysis. Levels of serum TGF-β and soluble interleukin-2 receptor (sIL-2R) were measured by enzyme-linked immunosorbent assay. Results. Significantly lower levels of circulating CD4+CD25high Treg cells and serum TGF-β were found in AOSD patients and SLE patients than those found in HCs. Levels of circulating CD4+CD25high Treg cells and TGF-β were inversely correlated with disease activity scores for AOSD patients and SLE patients. Circulating CD4+CD25high Treg cell frequencies were positively correlated with serum TGF-β levels for patients with both diseases. Levels of circulating CD4+CD25high Treg cells and TGF-β significantly increased, paralleling clinical remission and the decrease in levels of C-reactive protein and soluble interleukin-2 receptor after effective therapy in AOSD patients. AOSD patients with monocyclic course had significantly higher levels of circulating CD4+CD25high Treg cells and TGF-β compared to those with polycyclic and chronic articular course. Conclusion. Diminished levels of circulating CD4+CD25high Treg cells and TGF-β, and inverse correlation with disease activity in patients with AOSD and SLE might be involved in the pathogenesis of both diseases. Increased levels of circulating CD4+CD25high Treg cells or TGF-β might be associated with a favorable clinical course in AOSD patients. [ABSTRACT FROM AUTHOR]

The prognostic value of the number of T cells and NK cells at diagnosis in CLL was analyzed in a cohort of 256 patients with CLL diagnosed between 1997 and 2007. Patients with leukemia showed elevated NK cells and T cell populations and CD4/CD8 ratio was inverted in 39.7% cases. Prognostic significance of lymphocytes was analyzed as a ratio of relative number of T cells to the size of the malignant monoclonal B-cell pool (T/NK cells:Malignant monoclonal B-cells ratio). Patients showed higher relative number of CD4 ( p = 0.03), CD8 ( p = 0.02), and NK cells ( p = 0.01) in early Rai stage of disease. The multivariate Cox analysis identified the relative number of CD8 (hazard ratio (HR) = 1.464; p = 0.006) and CD4 T cells (HR = 0.091; p < 0.01) as independent predictors for survival. Additionally, patients with relative CD8 count > 0.074 or CD4 count > 0.1 had higher 10-year overall survival than patients with CD8 count ≤ 0.074 or CD4 count ≤ 0.1 ( p = 0.002). Higher CD8 count was associated with significantly higher median time of survival of patients (149.33 vs. 82.06 months). Finally, association of the good prognostic factor of leukemia cells (CD38−) with high relative CD8 count identified a group of patients with an indolent clinical course with an overall survival probability at 10 years of 95%. [ABSTRACT FROM AUTHOR]

Purpose: Our previous study showed that radiation exposure reduced the diversity of repertoires of memory thymus-derived cells (T cells) with cluster of differentiation (CD)- 4 among atomic-bomb (A-bomb) survivors. To evaluate the maintenance of T-cell memory within A-bomb survivors 60 years after radiation exposure, we examined functionally distinct memory CD4 T-cell subsets in the peripheral blood lymphocytes of the survivors. Methods: Three functionally different subsets of memory CD4 T cells were identified by differential CD43 expression levels and measured using flow cytometry. These subsets consist of functionally mature memory cells, cells weakly responsive to antigenic stimulation, and those cells functionally anergic and prone to spontaneous apoptosis. Results: The percentages of these subsets within the peripheral blood CD4 T-cell pool all significantly increased with age. Percentages of functionally weak and anergic subsets were also found to increase with radiation dose, fitting to a log linear model. Within the memory CD4 T-cell pool, however, there was an inverse association between radiation dose and the percentage of functionally mature memory cells. Conclusion: These results suggest that the steady state of T cell memory, which is regulated by cell activation and/or cell survival processes in subsets, may have been perturbed by prior radiation exposure among A-bomb survivors. [ABSTRACT FROM AUTHOR]

Folate receptor 4 (FR4) is recently found as a lymphoid tissue specific protein. In this study, we have identified an alternative splicing variant of the FR4 gene from murine splenocytes, termed FR4v, which is almost identical to FR4 cDNA sequence except with the retained 108 bp intron 3 between exon 3 and 4 of FR4 gene. FR4v mRNA encodes a larger protein than FR4 and is constitutively expressed on CD4+CD25+ regulatory T cell (Treg) membrane via a GPI anchor mechanism. Whether FR4v plays a redundant or unique functional role in Tregs should be investigated further in the future. [ABSTRACT FROM AUTHOR]

Background Ulcerative colitis (UC) is an intractable disease; therefore new therapies need to be developed. CD4+ CD25high regulatory T cells (Treg) significantly ameliorate colitis in animal models. In active UC patients, although Treg are functionally preserved, their proportion in peripheral blood decreases. Thus Treg transfer therapy is expected to be efficacious for UC. During leukapheresis for UC, Treg are depleted, as well as colitogenic effector leukocytes. We therefore designed a leukapheresis/Treg transfer therapy in which Treg are isolated from leukapheresis products and transfused to patients, and studied large-scale germ-free methods of Treg preparation. Methods Using the CliniMACS cell selection system, we conducted Treg isolation experiments from leukapheresis products in which B and CD8+ T cells were depleted, followed by positive selection of CD25+ cells. In some experiments, isolated Treg or non-Treg were expanded with interleukin-2 (IL-2) ± transforming growth factor (TGF)-β1. Expression of a Treg-specific marker, FOXP3, and gut-homing receptors, and suppressor activity of isolated or cultured cells, were analyzed. Results CD4+ CD25high T cells were collected and efficiently enriched with a good recovery rate. Isolated cells preferentially expressed FOXP3 and significantly suppressed T-cell proliferation in vitro. In addition, isolated Treg could be efficiently expanded, and Treg could be induced from non-Treg with TGF-β1 in vitro. TGF-β1 significantly up-regulated αEβ7 and α4β7 integrins. Discussion We have established a method of Treg isolation from leukapheresis products that can be used clinically; therefore, Treg transfer therapy is feasible in combination with leukapheresis for UC. Expansion or induction of Treg in vitro may be another approach to Treg-based immunotherapy. [ABSTRACT FROM AUTHOR]

CD4+ helper T (Th) cells play crucial role in priming, expansion and survival of CD8+ cytotoxic T lymphocytes (CTLs). However, how CD4+ Th cell's help is delivered to CD8+ T cells in vivo is still unclear. We previously demonstrated that CD4+ Th cells can acquire ovalbumin (OVA) peptide/major histocompatibility complex (pMHC I) and costimulatory CD80 by OVA-pulsed DC (DCOVA) stimulation, and then stimulate OVA-specific CD8+ CTL responses in C57BL/6 mice. In this study, we further investigated CD4+ Th cell's effect on stimulation of CD8 CTL responses in major histocompatibility complex (MHC II) gene knockout (KO) mice and transgenic rat insulin promoter (RIP)-mOVA mice with moderate expression of self OVA by using CD4+ Th cells or Th cells with various gene deficiency. We demonstrated that the in vitro DCOVA-activated CD4+ Th cells (3 × 106 cells/mouse) can directly stimulate OVA-specific CD8+ T-cell responses in wild-type C57BL/6 mice and MHC II gene KO mice lacking CD4+ T cells. A large amount of CD4+ Th cells (12 × 106 cells/mouse) can even overcome OVA-specific immune tolerance in transgenic RIP-mOVA mice, leading to CD8+ CTL-mediated mouse pancreatic islet destruction and diabetes. The stimulatory effect of CD4+ Th cells is mediated by its IL-2 secretion and CD40L and CD80 costimulations, and is specifically delivered to OVA-specific CD8+ T cells in vivo via its acquired pMHC I complexes. Therefore, the above elucidated principles for CD4+ Th cells will have substantial implications in autoimmunity and antitumor immunity, and regulatory T-cell-dependent immune suppression. [ABSTRACT FROM AUTHOR]

CD4+T cells represent an entire arm of the immune system that has hitherto been incompletely understood, but their potential to act as both helper and effector may make them optimal protagonists in immunotherapeutic approaches to treat cancer. Cytokine therapy can activate this population in a manner that ensures maximal diversification of effector function for a robust immune response. [ABSTRACT FROM PUBLISHER]