Abstract IA05: Selective pressure by activated T cells identifies de novo and adaptive resistance mechanisms in melanoma

2018 ◽  
Author(s):  
Keith T. Flaherty
Keyword(s):  
T Cells ◽  
Selective Pressure ◽  
De Novo ◽  
Resistance Mechanisms ◽  
Activated T Cells ◽  
Adaptive Resistance

scholarly journals NF-κB Is Involved in Regulation of CD40 Ligand Expression on Mycobacterium bovis Bacillus Calmette-Guérin-Activated Human T Cells

2003 ◽  
Vol 10 (3) ◽  
pp. 376-382 ◽  
Author(s):  
Patricia Méndez-Samperio ◽  
Hilda Ayala ◽  
Abraham Vázquez
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
De Novo ◽  
Cd40 Ligand ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
Cell Surface Expression ◽  
Membrane Expression ◽  
Activated T Cells ◽  
Cd40l Expression

ABSTRACT Interaction between CD40L (CD154) on activated T cells and its receptor CD40 on antigen-presenting cells has been reported to be important in the resolution of infection by mycobacteria. However, the mechanism(s) by which Mycobacterium bovis bacillus Calmette-Guérin (BCG) up-regulates membrane expression of CD40L molecules is poorly understood. This study was done to investigate the role of the nuclear factor κB (NF-κB) signaling pathway in the regulation of CD40L expression in human CD4+ T cells stimulated with BCG. Specific pharmacologic inhibition of the NF-κB pathway revealed that this signaling cascade was required in the regulation of CD40L expression on the surface of BCG-activated CD4+ T cells. These results were further supported by the fact that treatment of BCG-activated CD4+ T cells with these pharmacological inhibitors significantly down-regulated CD40L mRNA. In this study, inhibitor κBα (IκBα) and IκBβ protein production was not affected by the chemical protease inhibitors and, more importantly, BCG led to the rapid but transient induction of NF-κB activity. Our results also indicated that CD40L expression on BCG-activated CD4+ T cells resulted from transcriptional up-regulation of the CD40L gene by a mechanism which is independent of de novo protein synthesis. Interestingly, BCG-induced activation of NF-κB and the increased CD40L cell surface expression were blocked by the protein kinase C (PKC) inhibitors 1-[5-isoquinolinesulfonyl]-2-methylpiperazine and salicylate, both of which block phosphorylation of IκB. Moreover, rottlerin a Ca2+-independent PKC isoform inhibitor, significantly down-regulated CD40L mRNA in BCG-activated CD4+ T cells. These data strongly suggest that CD40L expression by BCG-activated CD4+ T cells is regulated via the PKC pathway and by NF-κB DNA binding activity.

scholarly journals Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules

2021 ◽  
Vol 12 ◽  
Author(s):  
Marlies J. W. Peeters ◽  
Pia Aehnlich ◽  
Adriano Pizzella ◽  
Kasper Mølgaard ◽  
Tina Seremet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Oxidative Phosphorylation ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Activated T Cells ◽  
Inhibition Of Proliferation ◽  
Effector Molecules ◽  
Pyrimidine Synthesis

T-cell activation upon antigen stimulation is essential for the continuation of the adaptive immune response. Impairment of mitochondrial oxidative phosphorylation is a well-known disruptor of T-cell activation. Dihydroorotate dehydrogenase (DHODH) is a component of the de novo synthesis of pyrimidines, the activity of which depends on functional oxidative phosphorylation. Under circumstances of an inhibited oxidative phosphorylation, DHODH becomes rate-limiting. Inhibition of DHODH is known to block clonal expansion and expression of effector molecules of activated T cells. However, this effect has been suggested to be caused by downstream impairment of oxidative phosphorylation rather than a lower rate of pyrimidine synthesis. In this study, we successfully inhibit the DHODH of T cells with no residual effect on oxidative phosphorylation and demonstrate a dose-dependent inhibition of proliferation of activated CD3+ T cells. This block is fully rescued when uridine is supplemented. Inhibition of DHODH does not alter expression of effector molecules but results in decreased intracellular levels of deoxypyrimidines without decreasing cell viability. Our results clearly demonstrate the DHODH and mitochondrial linked pyrimidine synthesis as an independent and important cytostatic regulator of activated T cells.

scholarly journals Human T cell activation. III. Rapid induction of a phosphorylated 28 kD/32 kD disulfide-linked early activation antigen (EA 1) by 12-o-tetradecanoyl phorbol-13-acetate, mitogens, and antigens.

1986 ◽  
Vol 164 (6) ◽  
pp. 1988-2005 ◽  
Author(s):  
T Hara ◽  
L K Jung ◽  
J M Bjorndahl ◽  
S M Fu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Activated T Cells ◽  
Early Activation ◽  
Human T Cell ◽  
Activated Monocytes ◽  
Activation Antigen

With human T cells activated by 12-o-tetradecanoyl phorbol-13-acetate (TPA) as immunogen, an IgG2a mAb, early activation antigen 1 (EA 1), was generated against a 60-kD protein with disulfide-linked 28-kD and 32-kD subunits. Both subunits were phosphorylated. The antigen, EA 1, was readily detected on approximately 60% of isolated and cryopreserved thymocytes, as determined by indirect immunofluorescence. A low level of EA 1 expression was detectable on 6-7% of blood lymphocytes. TPA-activated T cells expressed EA 1 as early as 30 min after activation. By 1 h, 85-90% of the T cells stained with mAb EA 1. By 3-4 h, the expression of EA 1 was detected in greater than 95% of the T cells. Although the percentages of EA 1+ T cells did not change, the intensity of staining increased slightly. After 18-24 h, both the percentage of EA 1+ cells and the intensity of staining decreased gradually. TPA-induced EA 1 expression was independent of monocytes. EA 1 expression was slightly delayed in T cells that were isolated without the rosette selection and treated with TPA. Nevertheless, greater than 85% of these T cells expressed EA 1 within 1 h, and the maximal number of EA 1+ T cells was also detected at 3-4 h. In T cell populations with 1-2% monocytes, about 50-90% of the PHA- or Con A-activated T cells expressed EA 1 with a slower kinetics. EA 1 expression preceded that of IL-2-R in these activation processes. Similarly, T cells activated by soluble antigens (tetanus toxoid and PPD) and alloantigens in MLR also expressed EA 1 after a longer incubation. Approximately 20% of the T cells stained for EA 1 at day 6. EA 1 expression was not limited to activated T cells. B cells activated by TPA or anti-IgM antibody plus B cell growth factor expressed EA 1. The kinetics of EA 1 expression was markedly slower and the staining was less intense. Repeated attempts to detect EA 1 on resting and TPA-activated monocytes and granulocytes have not been successful. However, the detection of EA 1 in nonlymphoid cell lines would indicate that EA 1 may have a broader cell distribution. EA 1 expression was due to de novo synthesis, as the induction of EA 1 was blocked by cycloheximide and actinomycin D.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity

2020 ◽  
Vol 10 ◽  
Author(s):  
Johannes Sam ◽  
Sara Colombetti ◽  
Tanja Fauti ◽  
Andreas Roller ◽  
Marlene Biehl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Resistance Mechanisms ◽  
Bispecific Antibodies ◽  
Great Promise ◽  
Tumor Escape ◽  
Blocking Antibody ◽  
Adaptive Resistance ◽  
Anti Tumor Activity

T-cell Bispecific Antibodies (TCBs) elicit anti-tumor responses by cross-linking T-cells to tumor cells and mediate polyclonal T-cell expansion that is independent of T-cell receptor specificity. TCBs thus offer great promise for patients who lack antigen-specific T-cells or have non-inflamed tumors, which are parameters known to limit the response of checkpoint inhibitors. The current study deepens the understanding of TCB mode of action and elaborates on one of the adaptive resistance mechanisms following its treatment in vivo in humanized mice and syngeneic pre-clinical tumor models. Single-agent TCB treatment reduced tumor growth compared with controls and led to a 2–10-fold increase in tumor-infiltrating T-cells, regardless of the baseline tumor immune cell infiltration. TCB treatment strongly induced the secretion of CXCL10 and increased the frequency of intra-tumor CXCR3+ T-cells pointing to the potential role of the CXCL10-CXCR3 pathway as one of the mechanisms for T-cell recruitment to tumors upon TCB treatment. Tumor-infiltrating T-cells displayed a highly activated and proliferating phenotype, resulting in the generation of a highly inflamed tumor microenvironment. A molecular signature of TCB treatment was determined (CD8, PD-1, MIP-a, CXCL10, CXCL13) to identify parameters that most robustly characterize TCB activity. Parallel to T-cell activation, TCB treatment also led to a clear upregulation of PD-1 on T-cells and PD-L1 on tumor cells and T-cells. Combining TCB treatment with anti-PD-L1 blocking antibody improved anti-tumor efficacy compared to either agent given as monotherapy, increasing the frequency of intra-tumoral T-cells. Together, the data of the current study expand our knowledge of the molecular and cellular features associated with TCB activity and provide evidence that the PD-1/PD-L1 axis is one of the adaptive resistance mechanisms associated with TCB activity. This mechanism can be managed by the combination of TCB with anti-PD-L1 blocking antibody translating into more efficacious anti-tumor activity and prolonged control of the tumor outgrowth. The elucidation of additional resistance mechanisms beyond the PD-1/PD-L1 axis will constitute an important milestone for our understanding of factors determining tumor escape and deepening of TCB anti-tumor responses in both solid tumors and hematological disorders.

Nuclear factor of activated T cells as potential pharmacodynamic biomarker for the risk of acute and subclinical rejection in de novo liver recipients

2020 ◽  
Vol 40 (4) ◽  
pp. 931-946 ◽  
Author(s):  
Olga Millán ◽  
Pablo Ruiz ◽  
Virginia Fortuna ◽  
Miquel Navasa ◽  
Mercè Brunet
Keyword(s):  
T Cells ◽  
De Novo ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Subclinical Rejection

scholarly journals Resistance of Short Term Activated T Cells to CD95-Mediated Apoptosis Correlates with De Novo Protein Synthesis of c-FLIPshort

2004 ◽  
Vol 172 (4) ◽  
pp. 2194-2200 ◽  
Author(s):  
Ingo Schmitz ◽  
Heiko Weyd ◽  
Andreas Krueger ◽  
Sven Baumann ◽  
Stefanie C. Fas ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Synthesis ◽  
De Novo ◽  
Short Term ◽  
Activated T Cells ◽  
De Novo Protein Synthesis

scholarly journals Folding for the Immune Synapse: CCT Chaperonin and the Cytoskeleton

2021 ◽  
Vol 9 ◽  
Author(s):  
Noa Beatriz Martín-Cófreces ◽  
José María Valpuesta ◽  
Francisco Sánchez-Madrid
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Mrna Translation ◽  
Membrane Receptors ◽  
Microtubule Network ◽  
Activated T Cells ◽  
Immune Synapse

Lymphocytes rearrange their shape, membrane receptors and organelles during cognate contacts with antigen-presenting cells (APCs). Activation of T cells by APCs through pMHC-TCR/CD3 interaction (peptide-major histocompatibility complex-T cell receptor/CD3 complexes) involves different steps that lead to the reorganization of the cytoskeleton and organelles and, eventually, activation of nuclear factors allowing transcription and ultimately, replication and cell division. Both the positioning of the lymphocyte centrosome in close proximity to the APC and the nucleation of a dense microtubule network beneath the plasma membrane from the centrosome support the T cell’s intracellular polarity. Signaling from the TCR is facilitated by this traffic, which constitutes an important pathway for regulation of T cell activation. The coordinated enrichment upon T cell stimulation of the chaperonin CCT (chaperonin-containing tailless complex polypeptide 1; also termed TRiC) and tubulins at the centrosome area support polarized tubulin polymerization and T cell activation. The proteasome is also enriched in the centrosome of activated T cells, providing a mechanism to balance local protein synthesis and degradation. CCT assists the folding of proteins coming fromde novosynthesis, therefore favoring mRNA translation. The functional role of this chaperonin in regulating cytoskeletal composition and dynamics at the immune synapse is discussed.

scholarly journals Vaccinia Virus Tropism for Primary Hematolymphoid Cells Is Determined by Restricted Expression of a Unique Virus Receptor

2005 ◽  
Vol 79 (16) ◽  
pp. 10397-10407 ◽  
Author(s):  
Ann Chahroudi ◽  
Rahul Chavan ◽  
Natalia Koyzr ◽  
Edmund K. Waller ◽  
Guido Silvestri ◽  
...  
Keyword(s):  
T Cells ◽  
Vaccinia Virus ◽  
T Cell Activation ◽  
Cell Activation ◽  
Vaccine Development ◽  
De Novo ◽  
Human Cells ◽  
Cellular Receptor ◽  
Cell Infection ◽  
Activated T Cells

ABSTRACT The presumed broad tropism of poxviruses has stymied attempts to identify both the cellular receptor(s) and the viral determinant(s) for binding. Detailed studies of poxvirus binding to and infection of primary human cells have not been conducted. In particular, the determinants of target cell infection and the consequences of infection for cells involved in the generation of antiviral immune responses are incompletely understood. In this report, we show that vaccinia virus (VV) exhibits a more restricted tropism for primary hematolymphoid human cells than has been previously recognized. We demonstrate that vaccinia virus preferentially infects antigen-presenting cells (dendritic cells, monocytes/macrophages, and B cells) and activated T cells, but not resting T cells. The infection of activated T cells is permissive, with active viral replication and production of infectious progeny. Susceptibility to infection is determined by restricted expression of a cellular receptor that is induced de novo upon T-cell activation and can be removed from the cell surface by either trypsin or pronase treatment. The VV receptor expressed on activated T cells displays unique characteristics that distinguish it from the receptor used to infect cell lines in culture. The observed restricted tropism of VV may have significant consequences for the understanding of natural poxvirus infection and immunity and for poxvirus-based vaccine development.

scholarly journals MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function

2021 ◽  
Author(s):  
Ayaka Sugiura ◽  
Gabriela Andrejeva ◽  
Kelsey Voss ◽  
Darren R. Heintzman ◽  
Katherine L. Beier ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Fate ◽  
Th17 Cells ◽  
De Novo ◽  
Treg Cells ◽  
Metabolic Reprogramming ◽  
Delayed Type Hypersensitivity ◽  
Activated T Cells ◽  
Mtorc1 Signaling

SUMMARYAntigenic stimulation promotes T cells metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme Methylenetetrahydrofolate Dehydrogenase-2 (MTHFD2) is highly expressed in inflammatory diseases and induced in activated T cells to promote proliferation and produce inflammatory cytokines. In pathogenic Th17 cells, MTHFD2 also prevented aberrant upregulation of FoxP3 and suppressive capacity. Conversely, MTHFD2-deficiency enhanced lineage stability of regulatory T (Treg) cells. Mechanistically, MTHFD2 maintained cellular 10-formyltetrahydrofolate for de novo purine synthesis and MTHFD2 inhibition led to accumulation of the intermediate 5-aminoimidazole carboxamide ribonucleotide that was associated with decreased mTORC1 signaling. MTHFD2 was also required for proper histone de-methylation in Th17 cells. Importantly, inhibiting MTHFD2 in vivo reduced disease severity in Experimental Autoimmune Encephalomyelitis and Delayed-Type Hypersensitivity. MTHFD2 induction is thus a metabolic checkpoint for pathogenic effector cells that suppresses anti-inflammatory Treg cells and is a potential therapeutic target within 1C metabolism.

scholarly journals CD4+FoxP3+ regulatory T cells confer infectious tolerance in a TGF-β–dependent manner

2008 ◽  
Vol 205 (9) ◽  
pp. 1975-1981 ◽  
Author(s):  
John Andersson ◽  
Dat Q. Tran ◽  
Marko Pesu ◽  
Todd S. Davidson ◽  
Heather Ramsey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
De Novo ◽  
Cell Contact ◽  
Dependent Manner ◽  
Activated T Cells ◽  
Independent Manner

CD4+FoxP3+ regulatory T (T reg) cells comprise a separate lineage of T cells that are essential for maintaining immunological tolerance to self. The molecular mechanism(s) by which T reg cells mediate their suppressive effects remains poorly understood. One molecule that has been extensively studied in T reg cell suppression is transforming growth factor (TGF)-β, but its importance remains controversial. We found that TGF-β complexed to latency-associated peptide (LAP) is expressed on the cell surface of activated but not resting T reg cells. T reg cell LAP–TGF-β plays an important role in the suppression of the proliferation of activated T cells, but it is not required for the suppression of naive T cell activation. More importantly, T reg cell–derived TGF-β could generate de novo CD4+FoxP3+ T cells in vitro from naive precursors in a cell contact–dependent, antigen-presenting cell–independent and αV integrin–independent manner. The newly induced CD4+FoxP3+ T cells are suppressive both in vitro and in vivo. Transfer of activated antigen-specific T reg cells with naive antigen-specific responder T cells to normal recipients, followed by immunization, also results in induction of FoxP3 expression in the responder cells. T reg cell–mediated generation of functional CD4+FoxP3+ cells via this TGF-β–dependent pathway may represent a major mechanism as to how T reg cells maintain tolerance and expand their suppressive abilities.

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