scholarly journals Lactobacillus paracasei subsp. paracasei B21060 Suppresses Human T-Cell Proliferation

2007 ◽  
Vol 75 (4) ◽  
pp. 1730-1737 ◽  
Author(s):  
Ilaria Peluso ◽  
Daniele Fina ◽  
Roberta Caruso ◽  
Carmine Stolfi ◽  
Flavio Caprioli ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Growth ◽  
Intracellular Ph ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Lactobacillus Paracasei ◽  
T Cell Proliferation ◽  
T Cell Growth

ABSTRACT Recent studies have shown that probiotics are beneficial in T-cell-mediated inflammatory diseases. The molecular mechanism by which probiotics work remains elusive, but accumulating evidence indicates that probiotics can modulate immune cell responses. Since T cells express receptors for bacterial products or components, we examined whether different strains of lactobacilli directly regulate the functions of human T cells. CD4+ T cells were isolated from blood and intestinal lamina propria (LP) of normal individuals and patients with inflammatory bowel disease (IBD). Mononuclear cells were also isolated from Peyer's patches. Cells were activated with anti-CD3/CD2/CD28 in the presence or absence of Lactobacillus paracasei subsp. paracasei B21060, L. paracasei subsp. paracasei F19, or L. casei subsp. casei DG. Cell proliferation and death, Foxp3, intracellular pH, and cytokine production were evaluated by flow cytometry. We showed that L. paracasei subsp. paracasei B21060 but neither L. paracasei subsp. paracasei F19 nor L. casei subsp. casei DG inhibited blood CD4+ T-cell growth. This effect was associated with no change in cell survival, expression of Foxp3, or production of gamma interferon, interleukin-4 (IL-4), IL-5, and IL-10. L. paracasei subsp. paracasei B21060-mediated blockade of CD4+ T-cell proliferation required a viable bacterium and was associated with decreased MCT-1 expression and low intracellular pH. L. paracasei subsp. paracasei B21060 also inhibited the growth of Peyer's patch mononuclear cells, normal lymphocytes, and IBD CD4+ LP lymphocytes without affecting cytokine production. The data show that L. paracasei subsp. paracasei B21060 blocks T-cell growth, thus suggesting a mechanism by which these probiotics could interfere with T-cell-driven immune responses.

scholarly journals Transient expression of interleukin 2 receptors. Consequences for T cell growth.

1983 ◽  
Vol 158 (6) ◽  
pp. 1895-1911 ◽  
Author(s):  
D A Cantrell ◽  
K A Smith
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Growth ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Receptor Expression ◽  
T Cell Proliferation ◽  
Immune Stimulation ◽  
T Cell Growth

T lymphocyte mitosis results from the interaction of interleukin 2 (IL-2) with specific receptors that appear only after appropriate immune stimulation. To assess the potential role of IL-2 receptor levels in determining the rate and magnitude of T cell proliferation, the expression of IL-2 receptors by lectin-stimulated human peripheral blood T cells was examined and correlated with T cell growth. Using biosynthetically radiolabeled IL-2 and anti-Tac, a monoclonal antibody that blocks IL-2 receptor binding, IL-2 receptors were found to accumulate slowly and asynchronously among lectin-stimulated T cells and to precede the onset of DNA synthesis. Moreover, a critical threshold of IL-2 receptor density appeared to be required before the commitment to cell cycle progression, as analyzed quantitatively by tritiated thymidine incorporation and flow cytometric analysis of cellular DNA content. Once maximal IL-2 receptor expression occurred, continued proliferation was IL-2 concentration dependent as assessed using homogenous immunoaffinity-purified IL-2. Upon removal of the activating lectin, IL-2 receptor levels progressively declined, and, in parallel, the rate of proliferation diminished. The decay of IL-2 receptors could not be attributed to IL-2-mediated down-regulation. Instead, renewed IL-2 receptor expression was dependent upon the reintroduction of the initial activating signal. Repetitive exposure to lectin resulted in a more rapid reexpression of maximal IL-2 receptor levels, which was then followed by an accelerated resumption of proliferation. Thus, the extent of T cell proliferation after immune stimulation depends upon the interplay of the IL-2 concentration available and the density of IL-2 receptors expressed, both of which are ultimately determined by antigen/lectin stimulation. The awareness of the transience and the antigen/lectin dependence of IL-2 receptor expression, together with the capacity to monitor T cell cultures for IL-2 receptor levels, should facilitate the initiation and maintenance of cloned, antigen-specific T cells in long-term culture. In addition, these findings suggest that, in vivo, the rapidity of acquisition of maximum IL-2 receptor levels by activated T cells and the duration of IL-2 receptor expression may well direct the magnitude of T cell clonal expansion and resultant immune responses.

T-CELL GROWTH FACTOR-MEDIATED T-CELL PROLIFERATION

1979 ◽  
Vol 332 (1 Subcellular F) ◽  
pp. 423-432 ◽  
Author(s):  
Kendall A. Smith ◽  
Steven Gillis ◽  
Paul E. Baker ◽  
Douglas McKenzie ◽  
Francis W. Ruscetti
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Growth Factor ◽  
Cell Growth ◽  
T Cell Proliferation ◽  
T Cell Growth ◽  
T Cell Growth Factor

siRNA silencing of PD-L1 and PD-L2 on dendritic cells augments expansion and function of minor histocompatibility antigen–specific CD8+ T cells

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4501-4511 ◽  
Author(s):  
Willemijn Hobo ◽  
Frans Maas ◽  
Niken Adisty ◽  
Theo de Witte ◽  
Nicolaas Schaap ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cytokine Production ◽  
Memory T Cells ◽  
Interleukin 2 ◽  
Histocompatibility Antigen ◽  
T Cell Proliferation ◽  
Minor Histocompatibility Antigen

Tumor relapse after human leukocyte antigen–matched allogeneic stem cell transplantation (SCT) remains a serious problem, despite the long-term presence of minor histocompatibility antigen (MiHA)–specific memory T cells. Dendritic cell (DC)–based vaccination boosting MiHA-specific T-cell immunity is an appealing strategy to prevent or counteract tumor recurrence, but improvement is necessary to increase the clinical benefit. Here, we investigated whether knockdown of programmed death ligand 1 (PD-L1) and PD-L2 on monocyte-derived DCs results in improved T-cell activation. Electroporation of single siRNA sequences into immature DCs resulted in efficient, specific, and long-lasting knockdown of PD-L1 and PD-L2 expression. PD-L knockdown DCs strongly augmented interferon-γ and interleukin-2 production by stimulated T cells in an allogeneic mixed lymphocyte reaction, whereas no effect was observed on T-cell proliferation. Moreover, we demonstrated that PD-L gene silencing, especially combined PD-L1 and PD-L2 knockdown, resulted in improved proliferation and cytokine production of keyhole limpet hemocyanin–specific CD4+ T cells. Most importantly, PD-L knockdown DCs showed superior potential to expand MiHA-specific CD8+ effector and memory T cells from leukemia patients early after donor lymphocyte infusion and later during relapse. These data demonstrate that PD-L siRNA electroporated DCs are highly effective in enhancing T-cell proliferation and cytokine production, and are therefore attractive cells for improving the efficacy of DC vaccines in cancer patients.

scholarly journals Screening of FDA-Approved Drug Library Identifies Adefovir Dipivoxil as Highly Potent Inhibitor of T Cell Proliferation

2021 ◽  
Vol 11 ◽  
Author(s):  
Linda Voss ◽  
Karina Guttek ◽  
Annika Reddig ◽  
Annegret Reinhold ◽  
Martin Voss ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Adefovir Dipivoxil ◽  
Cytokine Production ◽  
T Cell Proliferation ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Approved Drugs

Repositioning of approved drugs for identifying new therapeutic purposes is an alternative, time and cost saving strategy to classical drug development. Here, we screened a library of 786 FDA-approved drugs to find compounds, which can potentially be repurposed for treatment of T cell-mediated autoimmune diseases. Investigating the effect of these diverse substances on mitogen-stimulated proliferation of both, freshly stimulated and pre-activated (48 h) peripheral blood mononuclear cells (PBMCs), we discovered Adefovir Dipivoxil (ADV) as very potent compound, which inhibits T cell proliferation in a nanomolar range. We further analyzed the influence of ADV on proliferation, activation, cytokine production, viability and apoptosis of freshly stimulated as well as pre-activated human T cells stimulated with anti-CD3/CD28 antibodies. We observed that ADV was capable of suppressing the proliferation in both T cell stimulation systems in a dose-dependent manner (50% inhibition [IC50]: 63.12 and 364.8 nM for freshly stimulated T cells and pre-activated T cells, respectively). Moreover, the drug impaired T cell activation and inhibited Th1 (IFN-γ), Th2 (IL-5), and Th17 (IL-17) cytokine production dose-dependently. Furthermore, ADV treatment induced DNA double-strand breaks (γH2AX foci expression), which led to an increase of p53-phospho-Ser15 expression. In response to DNA damage p21 and PUMA are transactivated by p53. Subsequently, this caused cell cycle arrest at G0/G1 phase and activation of the intrinsic apoptosis pathway. Our results indicate that ADV could be a new potential candidate for treatment of T cell-mediated autoimmune diseases. Prospective studies should be performed to verify this possible therapeutic application of ADV for such disorders.

Lenalidomide (CC5013, Revlimid®) Promotes T Helper-1 Function Bias and Increases Responsiveness to Autologous Bone Marrow Antigens in Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2659-2659
Author(s):  
Edna Ku ◽  
JianXiang Zou ◽  
Fanqi Bai ◽  
Jeffrey S. Painter ◽  
Alan F. List ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Autologous Bone Marrow ◽  
T Cell Proliferation ◽  
T Helper 1 ◽  
Th 1

Abstract Background: The myelodysplastic syndromes (MDS) comprise a spectrum of stem cell malignancies with natural histories that vary from indolent mild cytopenias to rapid transformation to acute leukemia. MDS patients have impaired T cell antigen-induced proliferation and reduced T helper-1 (Th-1) cytokine production. Lenalidomide, an immuno-modulatory drug structurally-related to thalidomide, is FDA-approved for the treatment of MDS with chromosome 5q deletion; however, its mechanism of action is not fully characterized. We hypothesize that immune modulation by lenalidomide will be an effective adjunct to vaccine therapy for patients with MDS. Methods: The immunoregulatory effects of lenalidomide were investigated both in vitro and in vivo. Peripheral blood mononuclear cells (PBMCs) from MDS patients and normal controls were stimulated with anti-CD3 cross-linking, allogeneic dendritic cells (allo-DCs), autologous dendritic cells (auto-DCs), and patient-derived autologous bone marrow mononuclear cells (BM-MNC) as antigen sources in the presence of DMSO (vehicle control) and lenalidomide [0.625 μM to 40 μM]. Proliferation of specific CD4+ and CD8+ T cell populations was assessed by Brdu incorporation and intracellular cytokine production by flow cytometry. Preliminary studies were performed to examine the combined effects of the GMCSF/K562 “bystander” vaccine (gift of Dr. I. Borrello, Johns Hopkins University) and lenalidomide on antigen-induced T cell proliferation in PBMC from both normal donors and MDS patients. Results: Lenalidomide augmented a Th-1-biased cytokine (IFN-γ, TNF-α and IL-2) response from normal donors (n=5) and MDS patients (n=5). The Th-1-biased increase in cytokine production accompanied erythroid response in MDS patients treated with 10 mg of lenalidomide for 16 weeks (n=4 responders and 3 non-responders) (List et al, NEJM2005;351:549). Augmentation of antigen-dependent proliferation accompanied cytokine responses both in vitro and in vivo. Next, we examined the effects of lenalidomide on in vitro response to autologous and allogeneic antigens. We found that pre-treatment T cell proliferation in response to auto-DC priming was not distinguishable from background. However, proliferation in response to auto-BM-MNCs used as a source of autologous tumor antigens was significantly increased by lenalidomide in CD3+, CD4+, and CD8+ T cell populations (P=0.002, 0.04, and 0.04, respectively). Proliferation after allo-DC exposure was also significantly enhanced by lenalidomide treatment (P<0.05). GMCSF/K562 “bystander” vaccine-increased proliferation to allo-DC antigens in CD4+ and CD8+ T cells without exposure to lenalidomide (n=4) (167% increase vs. 245% increase, respectively). When allo-DC-stimulated PBMCs were treated with lenalidomide alone, CD4+ and CD8+ proliferation was increased by 47% and 39% respectively. The combination of lenalidomide and the GMCSF/K562 vaccine further enhanced T cell proliferation to allo-DC stimulation (325% and 397% for CD4+ and CD8+ populations, respectively). Conclusion: Lenalidomide significantly augments T cell immune function in MDS, and potentiates immune response to the GMCSF/K562 “bystander” vaccine. We conclude that lenalidomide represents an attractive adjunct to vaccines for clinical investigation in MDS.

scholarly journals HIP-55 Is Important for T-Cell Proliferation, Cytokine Production, and Immune Responses

2005 ◽  
Vol 25 (16) ◽  
pp. 6869-6878 ◽  
Author(s):  
Jin Han ◽  
Jr-Wen Shui ◽  
Xuejun Zhang ◽  
Biao Zheng ◽  
Shuhua Han ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Knockout Mice ◽  
Cytokine Production ◽  
Adaptor Protein ◽  
T Cell Proliferation ◽  
Tcr Signaling ◽  
Signaling Events

ABSTRACT Engagement of the T-cell receptor (TCR) triggers a series of signaling events that lead to the activation of T cells. HIP-55 (SH3P7 or mAbp1), an actin-binding adaptor protein, interacts with and is tyrosine phosphorylated by ZAP-70, which is a crucial proximal protein tyrosine kinase for TCR signaling. HIP-55 is important for JNK and HPK1 activation induced by TCR signaling. In this study, we report the generation and characterization of HIP-55 knockout mice. We found that HIP-55 knockout mice were viable and fertile but showed decreased body weight and increased occurrence of death within the first 4 weeks after birth. The lymphoid organs in HIP-55 knockout mice showed cellularity and T-cell development comparable to that of the wild-type mice. HIP-55 knockout T cells displayed defective T-cell proliferation, decreased cytokine production, and decreased up-regulation of the activation markers induced by TCR stimulation. TCR internalization was slightly increased in HIP-55 knockout T cells. These phenotypes were accompanied by reduced immune responses, including antigen-specific antibody production and T-cell proliferation in HIP-55 knockout mice. The TCR-induced signaling events, including LAT/phospholipase Cγ1 phosphorylation and HPK1/JNK activation, were partially defective in HIP-55 knockout T cells. These results demonstrate the importance of HIP-55 as an adaptor protein in the TCR signaling and immune system.

scholarly journals Regulatory T Cells Accumulate in the Lung Allergic Inflammation and Efficiently Suppress T-Cell Proliferation but Not Th2 Cytokine Production

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Lucas Faustino ◽  
Daniel Mucida ◽  
Alexandre Castro Keller ◽  
Jocelyne Demengeot ◽  
Karina Bortoluci ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cytokine Production ◽  
Allergic Inflammation ◽  
Peripheral Tolerance ◽  
Effector Memory ◽  
T Cell Proliferation ◽  
Th2 Cytokine

Foxp3+CD25+CD4+regulatory T cells are vital for peripheral tolerance and control of tissue inflammation. In this study, we characterized the phenotype and monitored the migration and activity of regulatory T cells present in the airways of allergic or tolerant mice after allergen challenge. To induce lung allergic inflammation, mice were sensitized twice with ovalbumin/aluminum hydroxide gel and challenged twice with intranasal ovalbumin. Tolerance was induced by oral administration of ovalbumin for 5 consecutive days prior to OVA sensitization and challenge. We detected regulatory T cells (Foxp3+CD25+CD4+T cells) in the airways of allergic and tolerant mice; however, the number of regulatory T cells was more than 40-fold higher in allergic mice than in tolerant mice. Lung regulatory T cells expressed an effector/memory phenotype (CCR4highCD62LlowCD44highCD54highCD69+) that distinguished them from naive regulatory T cells (CCR4intCD62LhighCD44intCD54intCD69−). These regulatory T cells efficiently suppressed pulmonary T-cell proliferation but not Th2 cytokine production.

scholarly journals Restricting Tumor Lactate Metabolism using Dichloroacetate Improves T Cell Functions

2021 ◽  
Author(s):  
Hosein Rostamian ◽  
Mohammad Khakpoor-Kooshe ◽  
Leila Jafarzadeh ◽  
Elham Masoumi ◽  
Keyvan Fallah-Mehrjardi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Lactic Acid ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cytokine Production ◽  
Redox System ◽  
T Cell Proliferation ◽  
And Function

Abstract Background:Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism.In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells. Result:We found that lactate could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactate by manipulatingglucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis. Conclusion:Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells.

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