scholarly journals Pseurotin D Inhibits the Activation of Human Lymphocytes

2021 ◽  
Vol 22 (4) ◽  
pp. 1938
Author(s):  
Daniela Rubanova ◽  
Petra Dadova ◽  
Ondrej Vasicek ◽  
Lukas Kubala
Keyword(s):  
Immune Response ◽  
T Cells ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Biological Activities ◽  
Human Lymphocytes ◽  
Future Research ◽  
Activation Markers ◽  
Tnf Α

Background: Pseurotins, a family of secondary metabolites of different fungi characterized by an unusual spirocyclic furanone-lactam core, are suggested to have different biological activities including the modulation of immune response. Purpose: Complex characterization of the effects of pseurotin D on human lymphocyte activation in order to understand the potential of pseurotin to modulate immune response in humans. Methods: CD4+ and CD8+ T cells and CD19+ B cells isolated from human blood were activated by various activators simultaneously with pseurotin D treatment. The effects of pseurotin were tested on the basis of changes in cell viability, apoptosis, activation of signal transducers and activators of transcription (STAT) signaling pathways, production of tumor necrosis factor (TNF)-α by T cells, expression of activation markers CD69 and CD25 on T cells and Human Leukocyte Antigen–DR isotype (HLA-DR) on B cells, and the differentiation markers CD20, CD27, CD38, and immunoglobulin (Ig) D on B cells. Results: Pseurotin D significantly inhibited the activation of both CD4+ and CD8+ human T cells complemented by the inhibition of TNF-α production without significant acute toxic effects. The Pseurotin D-mediated inhibition of T-cell activation was accompanied by the induction of the apoptosis of T cells. This corresponded with the inhibited phosphorylation of STAT3 and STAT5. In human B cells, pseurotin D did not significantly inhibit their activation; however, it affected their differentiation. Conclusions: Our results advance the current mechanistic understanding of the pseurotin-induced inhibition of lymphocytes and suggest pseurotins as new attractive chemotypes for future research in the context of immune-modulatory drugs.

scholarly journals Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection

2020 ◽  
Author(s):  
Nina Le Bert ◽  
Hannah E Clapham ◽  
Anthony T Tan ◽  
Wan Ni Chia ◽  
Christine YL Tham ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Inflammatory Cytokines ◽  
T Cell Activation ◽  
Cellular Immune Response ◽  
Cell Activation ◽  
Tnf Α ◽  
Specific Cellular Immune Response ◽  
Ifn Γ ◽  
Cellular Immune

AbstractThe efficacy of virus-specific T cells in clearing pathogens involves a fine balance between their antiviral and inflammatory features. SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 infection without symptoms or disease could reveal non-pathological yet protective characteristics. We therefore compared the quantity and function of SARS-CoV-2-specific T cells in a cohort of asymptomatic individuals (n=85) with that of symptomatic COVID-19 patients (n=76), at different time points after antibody seroconversion. We quantified T cells reactive to structural proteins (M, NP and Spike) using ELISpot assays, and measured the magnitude of cytokine secretion (IL-2, IFN-γ, IL-4, IL-6, IL-1β, TNF-α and IL-10) in whole blood following T cell activation with SARS-CoV-2 peptide pools as a functional readout. Frequencies of T cells specific for the different SARS-CoV-2 proteins in the early phases of recovery were similar between asymptomatic and symptomatic individuals. However, we detected an increased IFN-γ and IL-2 production in asymptomatic compared to symptomatic individuals after activation of SARS-CoV-2-specific T cells in blood. This was associated with a proportional secretion of IL-10 and pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2 infected individuals are not characterized by a weak antiviral immunity; on the contrary, they mount a robust and highly functional virus-specific cellular immune response. Their ability to induce a proportionate production of IL-10 might help to reduce inflammatory events during viral clearance.

scholarly journals Lysis of malignant B cells from patients with B-chronic lymphocytic leukemia by autologous T cells activated with CD3 x CD19 bispecific antibodies in combination with bivalent CD28 antibodies

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1803-1812 ◽  
Author(s):  
H Bohlen ◽  
T Hopff ◽  
O Manzke ◽  
A Engert ◽  
D Kube ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Bispecific Antibodies ◽  
Autologous Tumor ◽  
Activation Markers

Abstract Bispecific antibodies (bi-MABs) can be used to target T cells to autologous tumor cells. It has been shown that the activation of resting human T cells requires two independent signals, namely the cross-linking of the T-cell receptor (TCR)-CD3 complex together with the CD28 homodimer. In the present study, we demonstrate the activation of T cells from patients with chronic lymphocytic leukemia (CLL) using bi-MABs against the CD3 and CD19 antigens (CD3 x CD19) in combination with monospecific, bivalent antibodies against the CD28 antigen. Mononuclear cells from patients with CLL were cultured with the bi-MAB CD3 x CD19 and monospecific CD28 antibodies. The CD3 x CD19 bi-MABs were isolated by the hybridoma-hybridoma fusion technique and purified by hydrophobic interaction chromatography. T-Cell activation as demonstrated by increased proliferation, upregulation of T-cell activation markers (CD25, CD38), and cytotoxicity against autologous CLL cells and allogeneic B cells was shown in seven of eight CLL specimens. The stimulation with CD3 x CD19 bi-MABs with CD28 antibodies preferentially induced proliferation of CD4+ T cells. The effective dose of purified antibodies required for optimal T-cell activation was 100 ng/mL in vitro, which suggests that this antibody combination may be useful for immunotherapy of patients with B-CLL.

scholarly journals Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection

2021 ◽  
Vol 218 (5) ◽  
Author(s):  
Nina Le Bert ◽  
Hannah E. Clapham ◽  
Anthony T. Tan ◽  
Wan Ni Chia ◽  
Christine Y.L. Tham ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell Activation ◽  
Cellular Immune Response ◽  
Cell Activation ◽  
Asymptomatic Infection ◽  
Tnf Α ◽  
Specific Cellular Immune Response ◽  
Ifn Γ ◽  
Cellular Immune

The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between antiviral and inflammatory features. SARS-CoV-2–specific T cells in individuals who clear SARS-CoV-2 without symptoms could reveal nonpathological yet protective characteristics. We longitudinally studied SARS-CoV-2–specific T cells in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion. We quantified T cells reactive to structural proteins (M, NP, and Spike) using ELISpot and cytokine secretion in whole blood. Frequencies of SARS-CoV-2–specific T cells were similar between asymptomatic and symptomatic individuals, but the former showed an increased IFN-γ and IL-2 production. This was associated with a proportional secretion of IL-10 and proinflammatory cytokines (IL-6, TNF-α, and IL-1β) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2–specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2–infected individuals are not characterized by weak antiviral immunity; on the contrary, they mount a highly functional virus-specific cellular immune response.

Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 178-178
Author(s):  
Nadeem A. Sheikh ◽  
Johnna D. Wesley ◽  
Nikole Perdue ◽  
Frances P. Stewart ◽  
Lawrence Fong
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cellular Therapy ◽  
Localized Prostate Cancer ◽  
Activation Markers ◽  
Immune System Activation

178 Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in subjects with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Methods: Subjects with localized prostate cancer were enrolled in an open-label, Phase 2 study (P07-1; NCT00715104 ) in which they received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to radical prostatectomy. All samples were evaluated for cellular composition and antigen presenting cell (APC) activation pre- and post-culture with PA2024, a fusion protein comprising prostatic acid phosphatase and granulocyte macrophage-colony stimulating factor. Additionally, cytokines within the culture supernatant were assessed, and T and B cell activation were evaluated pre- and post-culture using flow cytometry. Results: Of the 42 enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T. Consistent with previous trials in mCRPC, CD54 upregulation (APC activation) was greater at the second and third infusions relative to the first. While the percent of CD4+ and CD8+ T cells was unchanged with treatment, the expression of early T cell activation markers (CD134, CD137, CD278 and CD279) was increased in pre-culture cells obtained after the first infusion, and further increased post-culture. Similarly, while the percent of B cells was unchanged, there was a progressive increase in memory B cells (CD20+CD27+IgD−CD86+; pre- and post-culture) and activated mature B cells (CD20+CD27+IgD+CD86+; post-culture) following the first infusion. Activated T cell-associated cytokines were significantly elevated (TNF-α, P < 0.001; IFN-γ, P < 0.001; and IL-2, P < 0.001) in the second and third products. Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune system activation that included APCs, memory and activated mature B cells, and both CD4+ and CD8+ T cells. The patterns observed at the second and third infusions, relative to the first, are consistent with an immunological prime-boost profile.

scholarly journals Lysis of malignant B cells from patients with B-chronic lymphocytic leukemia by autologous T cells activated with CD3 x CD19 bispecific antibodies in combination with bivalent CD28 antibodies

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1803-1812
Author(s):  
H Bohlen ◽  
T Hopff ◽  
O Manzke ◽  
A Engert ◽  
D Kube ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Bispecific Antibodies ◽  
Autologous Tumor ◽  
Activation Markers

Bispecific antibodies (bi-MABs) can be used to target T cells to autologous tumor cells. It has been shown that the activation of resting human T cells requires two independent signals, namely the cross-linking of the T-cell receptor (TCR)-CD3 complex together with the CD28 homodimer. In the present study, we demonstrate the activation of T cells from patients with chronic lymphocytic leukemia (CLL) using bi-MABs against the CD3 and CD19 antigens (CD3 x CD19) in combination with monospecific, bivalent antibodies against the CD28 antigen. Mononuclear cells from patients with CLL were cultured with the bi-MAB CD3 x CD19 and monospecific CD28 antibodies. The CD3 x CD19 bi-MABs were isolated by the hybridoma-hybridoma fusion technique and purified by hydrophobic interaction chromatography. T-Cell activation as demonstrated by increased proliferation, upregulation of T-cell activation markers (CD25, CD38), and cytotoxicity against autologous CLL cells and allogeneic B cells was shown in seven of eight CLL specimens. The stimulation with CD3 x CD19 bi-MABs with CD28 antibodies preferentially induced proliferation of CD4+ T cells. The effective dose of purified antibodies required for optimal T-cell activation was 100 ng/mL in vitro, which suggests that this antibody combination may be useful for immunotherapy of patients with B-CLL.

scholarly journals CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

2021 ◽  
Author(s):  
Yan Yan ◽  
Wei Zhao ◽  
Wei Liu ◽  
Yan Li ◽  
Xu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Crucial Role ◽  
Cell Activation ◽  
Hbv Infection ◽  
Host Immune System ◽  
Tnf Α ◽  
Ifn Γ ◽  
High Level

Abstract Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

scholarly journals Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Colado ◽  
Esteban Enrique Elías ◽  
Valeria Judith Sarapura Martínez ◽  
Gregorio Cordini ◽  
Pablo Morande ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Immunomodulatory Effects ◽  
Immunoglobulin Preparations

AbstractHypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

scholarly journals CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 580-588 ◽  
Author(s):  
Kathrin Gollmer ◽  
François Asperti-Boursin ◽  
Yoshihiko Tanaka ◽  
Klaus Okkenhaug ◽  
Bart Vanhaesebroeck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Early Time ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

scholarly journals TRPM2 Is Not Required for T-Cell Activation and Differentiation

2022 ◽  
Vol 12 ◽  
Author(s):  
Niels C. Lory ◽  
Mikolaj Nawrocki ◽  
Martina Corazza ◽  
Joanna Schmid ◽  
Valéa Schumacher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
Activation Markers

Antigen recognition by the T-cell receptor induces a cytosolic Ca2+ signal that is crucial for T-cell function. The Ca2+ channel TRPM2 (transient receptor potential cation channel subfamily M member 2) has been shown to facilitate influx of extracellular Ca2+ through the plasma membrane of T cells. Therefore, it was suggested that TRPM2 is involved in T-cell activation and differentiation. However, these results are largely derived from in vitro studies using T-cell lines and non-physiologic means of TRPM2 activation. Thus, the relevance of TRPM2-mediated Ca2+ signaling in T cells remains unclear. Here, we use TRPM2-deficient mice to investigate the function of TRPM2 in T-cell activation and differentiation. In response to TCR stimulation in vitro, Trpm2-/- and WT CD4+ and CD8+ T cells similarly upregulated the early activation markers NUR77, IRF4, and CD69. We also observed regular proliferation of Trpm2-/- CD8+ T cells and unimpaired differentiation of CD4+ T cells into Th1, Th17, and Treg cells under specific polarizing conditions. In vivo, Trpm2-/- and WT CD8+ T cells showed equal specific responses to Listeria monocytogenes after infection of WT and Trpm2-/- mice and after transfer of WT and Trpm2-/- CD8+ T cells into infected recipients. CD4+ T-cell responses were investigated in the model of anti-CD3 mAb-induced intestinal inflammation, which allows analysis of Th1, Th17, Treg, and Tr1-cell differentiation. Here again, we detected similar responses of WT and Trpm2-/- CD4+ T cells. In conclusion, our results argue against a major function of TRPM2 in T-cell activation and differentiation.

scholarly journals Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19

2020 ◽  
Author(s):  
Anno Saris ◽  
Tom D.Y. Reijnders ◽  
Esther J. Nossent ◽  
Alex R. Schuurman ◽  
Jan Verhoeff ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Effector Memory ◽  
Activated T Cells ◽  
Immune Profile ◽  
Prolonged Icu Stay

AbstractOur understanding of the coronavirus disease-19 (COVID-19) immune response is almost exclusively derived from studies that examined blood. To gain insight in the pulmonary immune response we analysed BALF samples and paired blood samples from 17 severe COVID-19 patients. Macrophages and T cells were the most abundant cells in BALF. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells and expressed higher levels of the exhaustion marker PD-1 than in peripheral blood. Prolonged ICU stay associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. In conclusion, the bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood.SummaryThe bronchoalveolar immune response in severe COVID-19 strongly differs from the peripheral blood immune profile. Fatal COVID-19 associated with T cell activation blood, but not in BALF.

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