scholarly journals The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Laia Gorchs ◽  
Sultan Ahmed ◽  
Chanté Mayer ◽  
Alisa Knauf ◽  
Carlos Fernández Moro ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Surveillance ◽  
Tumour Cell Line ◽  
Prostaglandin E ◽  
Cell Mediated Immunity ◽  
Pancreatic Tumour ◽  
The Impact

Abstract The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D3 analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E2, IL-6, periostin, and leukemia inhibitory factor. However, calcipotriol promoted PD-L1 upregulation, which could influence T cell mediated tumour immune surveillance. Calcipotriol reduced T cell proliferation and production of IFN-γ, granzyme B and IL-17, but increased IL-10 secretion. These effects were even more profound in the presence of CAFs in 2D cultures and in the presence of CAFs and pancreatic tumour cell line (PANC-1) spheroids in 3D cultures. Functional assays on tumour infiltrating lymphocytes also showed a reduction in T cell activation by calcipotriol. This suggests that calcipotriol reduces the tumour supportive activity of CAFs but at the same time reduces T cell effector functions, which could compromise the patients’ tumour immune surveillance. Thus, vitamin D3 analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications.

scholarly journals Vitamin D Supplementation Modulates T Cell–Mediated Immunity in Humans: Results from a Randomized Control Trial

2016 ◽  
Vol 101 (2) ◽  
pp. 533-538 ◽  
Author(s):  
Gauree Gupta Konijeti ◽  
Pankaj Arora ◽  
Matthew R. Boylan ◽  
Yanna Song ◽  
Shi Huang ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cell ◽  
Vitamin D Deficiency ◽  
T Cell Activation ◽  
Vitamin D3 ◽  
Cell Activation ◽  
Atp Release ◽  
High Dose ◽  
Cell Mediated Immunity ◽  
Ancillary Study

Abstract Context: Although studies have linked vitamin D deficiency with immune-mediated diseases, data demonstrating a direct effect on T-cell function are sparse. Objective: Our objective was to determine whether oral vitamin D3 influences T-cell activation in humans with vitamin D deficiency. Design: This was a single-center ancillary study within Vitamin D Therapy in Individuals at High Risk of Hypertension, a double-blind, multicenter, randomized controlled trial. Setting: This study was undertaken in a single academic medical center. Participants: Adults with vitamin D deficiency and untreated pre- or early stage I hypertension were included. Intervention: In Vitamin D Therapy in Individuals at High Risk of Hypertension, participants were randomized to either low- (400 IU daily) or high- (4000 IU daily) dose oral vitamin D3 for 6 months. In this ancillary study of 38 patients, we measured CD4+ T-cell activation estimated by intracellular ATP release after stimulation of whole blood with plant lectin phytohemagglutinin collected at baseline (pretreatment) and 2-month follow-up. Main Outcome Measure: Determining whether ATP level changes were significantly different between treatment groups was the main outcome measure. Results: Treatment with 4000 IU of vitamin D3 decreased intracellular CD4+ ATP release by 95.5 ng/ml (interquartile range, −219.5 to 105.8). In contrast, 400 IU of vitamin D3 decreased intracellular CD4+ ATP release by 0.5 ng/ml (interquartile range, −69.2 to 148.5). In a proportional odds model, high-dose vitamin D3 was more likely than low-dose vitamin D3 to decrease CD4+ ATP release (odds ratio, 3.43; 95% confidence interval, 1.06–1.11). Conclusions: In this ancillary study of a randomized controlled trial, we found that high-dose vitamin D3 significantly reduced CD4+ T-cell activation compared to low-dose vitamin D3, providing human evidence that vitamin D can influence cell-mediated immunity.

scholarly journals Cell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 852 ◽  
Author(s):  
Michael F. Coleman ◽  
Alyssa J. Cozzo ◽  
Alexander J. Pfeil ◽  
Suhas K. Etigunta ◽  
Stephen D. Hursting
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Metabolism ◽  
Immune Surveillance ◽  
Therapy Outcomes ◽  
Host Metabolism ◽  
The Impact

Immune checkpoint inhibitor (ICI) therapy has shown extraordinary promise at treating cancers otherwise resistant to treatment. However, for ICI therapy to be effective, it must overcome the metabolic limitations of the tumor microenvironment. Tumor metabolism has long been understood to be highly dysregulated, with potent immunosuppressive effects. Moreover, T cell activation and longevity within the tumor microenvironment are intimately tied to T cell metabolism and are required for the long-term efficacy of ICI therapy. We discuss in this review the intersection of metabolic competition in the tumor microenvironment, T cell activation and metabolism, the roles of tumor cell metabolism in immune evasion, and the impact of host metabolism in determining immune surveillance and ICI therapy outcomes. We also discussed the effects of obesity and calorie restriction—two important systemic metabolic perturbations that impact intrinsic metabolic pathways in T cells as well as cancer cells.

Distinct Neopterin Excretion Patterns after Vaccination

Pteridines ◽  
1990 ◽  
Vol 2 (3) ◽  
pp. 147-149 ◽  
Author(s):  
Dietmar Fuchs ◽  
Arno Hausen ◽  
Gilbert Reibnegger ◽  
Ernst R. Werner ◽  
Gabriele Werner-Felmayer ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cellular Immunity ◽  
Tetanus Toxoid ◽  
Cell Activation ◽  
Cell Mediated Immunity ◽  
Soluble Antigen ◽  
Human Monocytes ◽  
Mumps Vaccine ◽  
Urinary Neopterin

Summary To compare the involvement of cellular immunity in response to vaccination we have investigated urinary neopterin levels in daily follow-ups of children after vaccination with live measles/mumps vaccine and of adults after boosting with the soluble antigen tetanus toxoid. Neopterin levels distinctly peaked 8 - 11 days after vaccination with measles/mumps vaccine. In contrast, after boosting with soluble antigen tetanus toxoid neopterin levels remained unaffected. Large amounts of neopterin are produced by human monocytes/ macro phages on stimulation with gamma interferon. In patients neopterin concentrations reflect activation of cell mediated immunity. The data imply that distinct pathways of T cell activation are triggered in humans after immunization with live vaccine and with soluble antigen .

scholarly journals The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy

AIDS ◽  
2013 ◽  
Vol 27 (13) ◽  
pp. 2101-2110 ◽  
Author(s):  
Judith J. Lok ◽  
Peter W. Hunt ◽  
Ann C. Collier ◽  
Constance A. Benson ◽  
Mallory D. Witt ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
The Impact

scholarly journals SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity

Science ◽  
2021 ◽  
Vol 372 (6543) ◽  
pp. eaba4220 ◽  
Author(s):  
Tao Yue ◽  
Xiaoming Zhan ◽  
Duanwu Zhang ◽  
Ruchi Jain ◽  
Kuan-wen Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cell Mediated Immunity ◽  
Activated T Cells ◽  
Granule Formation

Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support T cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response that leads to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) to protect them from cleavage by the ribonuclease angiogenin. T cell–specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress-granule formation. Interleukin-2 receptor β (IL-2Rβ) and IL-2Rγ fail to be translationally up-regulated after T cell receptor stimulation, rendering SLFN2-deficient T cells insensitive to interleukin-2’s mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting the robust protein synthesis necessary for T cell expansion and immunity.

scholarly journals Brucella Peptide Cross-Reactive MHC I Presentation Activates SIINFEKL-Specific TCR Expressing T Cells

2018 ◽  
Author(s):  
Jerome S. Harms ◽  
Mike Khan ◽  
Cherisse Hall ◽  
Gary A. Splitter ◽  
E. Jane Homan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Pathogenic Bacteria ◽  
Cell Activation ◽  
Immune Surveillance ◽  
Cross Reactivity ◽  
Near Neighbor ◽  
Target Cells ◽  
Mhc I

ABSTRACTBrucella spp are intracellular pathogenic bacteria remarkable in their ability to escape immune surveillance and therefore inflict a state of chronic disease within the host. To enable further immune response studies, Brucella were engineered to express the well characterized chicken ovalbumin (OVA). Surprisingly, we found that CD8 T cells bearing T cell receptors (TCR) nominally specific for the OVA peptide SIINFEKL (OT-1) reacted to parental Brucella-infected targets as well as OVA-expressing Brucella variants in cytotoxicity assays. Furthermore, splenocytes from Brucella immunized mice produced IFN-γ and exhibited cytotoxicity in response to SIINFEKL-pulsed target cells. To determine if the SIINFEKL-reactive OT-1 TCR could be cross-reacting to Brucella peptides, we searched the Brucella proteome using an algorithm to generate a list of near-neighbor nonamer peptides that would bind to H2Kb. Selecting five Brucella peptide candidates, along with controls, we verified that several of these peptides mimicked SIINFEKL resulting in T cell activation through the “SIINFEKL-specific” TCR. Activation was dependent on peptide concentration as well as sequence. Our results underscore the complexity and ubiquity of cross-reactivity in T cell recognition. This cross-reactivity may enable microbes such as Brucella to escape immune surveillance by presenting peptides similar to the host, and may also lead to the activation of autoreactive T cells.

scholarly journals Diacylglycerol kinase ζ limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes

2020 ◽  
Vol 8 (2) ◽  
pp. e001521
Author(s):  
Javier Arranz-Nicolás ◽  
Miguel Martin-Salgado ◽  
Cristina Rodríguez-Rodríguez ◽  
Rosa Liébana ◽  
Maria C Moreno-Ortiz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Tumor Rejection ◽  
Cytotoxic T Cell ◽  
Adenocarcinoma Cells ◽  
The Impact

BackgroundThe inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize antitumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8+ T cells achieving hyporesponsive states from which recovery is hardly feasible. Dysfunctional T cell phenotypes are favored by a sustained imbalance in the diacylglycerol (DAG)- and Ca2+-regulated transcriptional programs. In mice, DAG kinase ζ (DGKζ) facilitates DAG consumption, limiting T cell activation and cytotoxic T cell responses. DGKζ deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. Despite its therapeutic potential, little is known about DGKζ function in human T cells, and no known inhibitors target this isoform.MethodsWe used a human triple parameter reporter cell line to examine the consequences of DGKζ depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKζ deficiency on PD-1 expression dynamics, as well as the impact of DGKζ absence on the in vivo growth of MC38 adenocarcinoma cells.ResultsWe demonstrate that DGKζ depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGKζ loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8+ T cell populations. This is observed even in immunosuppressive milieus, and correlates with the reduced ability of MC38 adenocarcinoma cells to form tumors in DGKζ-deficient mice.ConclusionsOur results, which define a role for DGKζ in the control of PD-1 expression, confirm DGKζ potential as a therapeutic target as well as a biomarker of CD8+ T cell dysfunctional states.

scholarly journals MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain

2018 ◽  
Vol 92 (8) ◽  
Author(s):  
E. Kip ◽  
J. Staal ◽  
L. Verstrepen ◽  
H. G. Tima ◽  
S. Terryn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Rabies Virus ◽  
T Cell Activation ◽  
Therapeutic Target ◽  
Cell Activation ◽  
Wild Type ◽  
The Impact ◽  
The Brain

ABSTRACTMALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1−/−mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1−/−mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1−/−mice at 10 dpi compared to MALT1+/+infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1+/+mice. Moreover, MALT1−/−mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain.IMPORTANCERabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protein involved in innate and adaptive immunity and is an interesting therapeutic target because MALT1-deregulated activity has been associated with autoimmunity and cancers. The role of MALT1 in viral infection is, however, largely unknown. Here, we study the impact of MALT1 on virus infection in the brain, using the attenuated ERA rabies virus in different models of MALT1-deficient mice. We reveal the importance of MALT1-mediated inflammation and T cell activation to control ERA virus, providing new insights in the biology of MALT1 and rabies virus infection.

scholarly journals Allergen-Induced C5a/C5aR1 Axis Activation in Pulmonary CD11b+ cDCs Promotes Pulmonary Tolerance through Downregulation of CD40

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 300 ◽  
Author(s):  
Konstantina Antoniou ◽  
Fanny Ender ◽  
Tillman Vollbrandt ◽  
Yves Laumonnier ◽  
Franziska Rathmann ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
C5a Receptor ◽  
The Impact

Activation of the C5/C5a/C5a receptor 1 (C5aR1) axis during allergen sensitization protects from maladaptive T cell activation. To explore the underlying regulatory mechanisms, we analyzed the impact of C5aR1 activation on pulmonary CD11b+ conventional dendritic cells (cDCs) in the context of house-dust-mite (HDM) exposure. BALB/c mice were intratracheally immunized with an HDM/ovalbumin (OVA) mixture. After 24 h, we detected two CD11b+ cDC populations that could be distinguished on the basis of C5aR1 expression. C5aR1− but not C5aR1+ cDCs strongly induced T cell proliferation of OVA-reactive transgenic CD4+ T cells after re-exposure to antigen in vitro. C5aR1− cDCs expressed higher levels of MHC-II and CD40 than their C5aR1+ counterparts, which correlated directly with a higher frequency of interactions with cognate CD4+ T cells. Priming of OVA-specific T cells by C5aR1+ cDCs could be markedly increased by in vitro blockade of C5aR1 and this was associated with increased CD40 expression. Simultaneous blockade of C5aR1 and CD40L on C5aR1+ cDCs decreased T cell proliferation. Finally, pulsing with OVA-induced C5 production and its cleavage into C5a by both populations of CD11b+ cDCs. Thus, we propose a model in which allergen-induced autocrine C5a generation and subsequent C5aR1 activation in pulmonary CD11b+ cDCs promotes tolerance towards aeroallergens through downregulation of CD40.

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