scholarly journals P2X7 Receptor at the Crossroads of T Cell Fate

2020 ◽  
Vol 21 (14) ◽  
pp. 4937 ◽  
Author(s):  
Elizabeth Rivas-Yáñez ◽  
Carlos Barrera-Avalos ◽  
Brian Parra-Tello ◽  
Pedro Briceño ◽  
Mariana V. Rosemblatt ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
T Cell Activation ◽  
P2x7 Receptor ◽  
Cell Activation ◽  
Receptor Activation ◽  
Extracellular Nucleotides ◽  
Inflammasome Activation ◽  
Membrane Pore ◽  
P2x7 Receptor Activation

The P2X7 receptor is a ligand-gated, cation-selective channel whose main physiological ligand is ATP. P2X7 receptor activation may also be triggered by ARTC2.2-dependent ADP ribosylation in the presence of extracellular NAD. Upon activation, this receptor induces several responses, including the influx of calcium and sodium ions, phosphatidylserine externalization, the formation of a non-selective membrane pore, and ultimately cell death. P2X7 receptor activation depends on the availability of extracellular nucleotides, whose concentrations are regulated by the action of extracellular nucleotidases such as CD39 and CD38. The P2X7 receptor has been extensively studied in the context of the immune response, and it has been reported to be involved in inflammasome activation, cytokine production, and the migration of different innate immune cells in response to ATP. In adaptive immune responses, the P2X7 receptor has been linked to T cell activation, differentiation, and apoptosis induction. In this review, we will discuss the evidence of the role of the P2X7 receptor on T cell differentiation and in the control of T cell responses in inflammatory conditions.

847 Inflammasome activation in M2 macrophage restrain the immune suppressive function

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A900-A900
Author(s):  
Ronghua Zhang ◽  
Tienan Wang ◽  
Qing Lin
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Culture System ◽  
Cell Activation ◽  
Macrophage Polarization ◽  
Inflammasome Activation ◽  
M2 Macrophage ◽  
M1 Macrophage ◽  
Suppressive Phenotype

BackgroundMacrophage is an important component in tumor microenvironment (TME) and plays multiple roles in tumor initiation, progression and metastases. In response to various stimuli within TME, macrophage exhibits high level of functional heterogeneity. There are two distinct groups of macrophages: M1 macrophage exhibits pro-inflammatory phenotype with high levels of TNF-a, IL-6, and IL-1ß, while M2 macrophage displays immune suppressive phenotype with high levels of anti-inflammatory cytokines such as IL-10 and TGF-ß. In response to the M2 cytokines, myeloid cells within the TME further acquire higher expression of PD-L1 and thus inactivate T cells. M2 cytokines can also directly inhibit T cell activation. As a result, re-polarizing M2 macrophages becomes a key concept for cancer immunotherapy. The NLRP3 inflammasome is acquired by macrophages to fight against endogenous danger signals. Macrophage NLRP3 activation has been observed in several tumor models, but the function of NLRP3 on macrophage polarity remains controversial. Inflammasome activation with IL-1ß/IL-18 secretion was reported to promote M1 polarization. However, NLRP3 activation was also reported to promote M2 polarity through up-regulation of IL4 in asthma modelMethodsHere, we have established an in vitro human macrophage NLRP3 activation system (figure 1), coupled with M2 macrophage polarization assay, to dissect the role of NLRP3 in macrophage phenotype.ResultsOur results indicate that NLRP3 activation restrained M2 phenotype and further enhanced T cell activation in an M2/T cell co-culture system (figure 2).Abstract 847 Figure 1Inflammasome activation polarize M2 macrophage intUse LPS/ATP to stimulate NLRP3 in M2 macrophage and demonstrate NLRP3 activation could reduce CD163 and increase CD86Abstract 847 Figure 2Inflammasome in M2 rescue T cell activationestablish M2/T co-culture system in vitro to demonstrate M2 could suppress T activation while Inflammatory M2 could partial rescue the suppressive phenotypeConclusionsInflammasome could be the potential target for cancer by modulating T cell activation through macrophage polarization regulation

Crucial role of P2X7 receptor for effector T cell activation in experimental autoimmune uveitis

2018 ◽  
Vol 62 (3) ◽  
pp. 398-406 ◽  
Author(s):  
Atsunobu Takeda ◽  
Hisakata Yamada ◽  
Eiichi Hasegawa ◽  
Mitsuru Arima ◽  
Shoji Notomi ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Crucial Role ◽  
P2x7 Receptor ◽  
Cell Activation ◽  
Experimental Autoimmune Uveitis ◽  
Autoimmune Uveitis ◽  
Effector T Cell ◽  
Experimental Autoimmune

scholarly journals Abortive Proliferation of Rare T Cells Induced by Direct or Indirect Antigen Presentation by Rare B Cells In Vivo

1998 ◽  
Vol 187 (10) ◽  
pp. 1611-1621 ◽  
Author(s):  
Sarah E. Townsend ◽  
Christopher C. Goodnow
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Presentation ◽  
Cell Fate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Antigen Presenting

Antigen-specific B cells are implicated as antigen-presenting cells in memory and tolerance responses because they capture antigens efficiently and localize to T cell zones after antigen capture. It has not been possible, however, to visualize the effect of specific B cells on specific CD4+ helper T cells under physiological conditions. We demonstrate here that rare T cells are activated in vivo by minute quantities of antigen captured by antigen-specific B cells. Antigen-activated B cells are helped under these conditions, whereas antigen-tolerant B cells are killed. The T cells proliferate and then disappear regardless of whether the B cells are activated or tolerant. We show genetically that T cell activation, proliferation, and disappearance can be mediated either by transfer of antigen from antigen-specific B cells to endogenous antigen-presenting cells or by direct B–T cell interactions. These results identify a novel antigen presentation route, and demonstrate that B cell presentation of antigen has profound effects on T cell fate that could not be predicted from in vitro studies.

scholarly journals Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by the Interplay Between ORAI1 and InsP3 Receptors

2021 ◽  
Vol 12 ◽  
Author(s):  
Diana Gil ◽  
Andreas H. Guse ◽  
Geneviève Dupont
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Three Dimensional ◽  
Receptor Activation ◽  
Reaction Diffusion Model ◽  
Activated State ◽  
T Cell Adhesion

Ca2+ signaling plays an essential role in T cell activation, which is a key step to start an adaptive immune response. During the transition from a quiescent to a fully activated state, Ca2+ microdomains characterized by reduced spatial and temporal extents are observed in the junctions between the plasma membrane (PM) and the endoplasmic reticulum (ER). Such Ca2+ responses can also occur in response to T cell adhesion to other cells or extracellular matrix proteins in otherwise unstimulated T cells. These non-TCR/CD3-dependent Ca2+ microdomains rely on d-myo-inositol 1,4,5-trisphosphate (IP3) signaling and subsequent store operated Ca2+ entry (SOCE) via the ORAI/STIM system. The detailed molecular mechanism of adhesion-dependent Ca2+ microdomain formation remains to be fully elucidated. We used mathematical modeling to investigate the spatiotemporal characteristics of T cell Ca2+ microdomains and their molecular regulators. We developed a reaction-diffusion model using COMSOL Multiphysics to describe the evolution of cytosolic and ER Ca2+ concentrations in a three-dimensional ER-PM junction. Equations are based on a previously proposed realistic description of the junction, which is extended to take into account IP3 receptors (IP3R) that are located next to the junction. The first model only considered the ORAI channels and the SERCA pumps. Taking into account the existence of preformed clusters of ORAI1 and STIM2, ORAI1 slightly opens in conditions of a full ER. These simulated Ca2+ microdomains are too small as compared to those observed in unstimulated T cells. When considering the opening of the IP3Rs located near the junction, the local depletion of ER Ca2+ allows for larger Ca2+ fluxes through the ORAI1 channels and hence larger local Ca2+ concentrations. Computational results moreover show that Ca2+ diffusion in the ER has a major impact on the Ca2+ changes in the junction, by affecting the local Ca2+ gradients in the sub-PM ER. Besides pointing out the likely involvement of the spontaneous openings of IP3Rs in the activation of SOCE in conditions of T cell adhesion prior to full activation, the model provides a tool to investigate how Ca2+ microdomains extent and interact in response to T cell receptor activation.

scholarly journals Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 3757-3766 ◽  
Author(s):  
Nicola J. Rowbotham ◽  
Ariadne L. Hager-Theodorides ◽  
Marek Cebecauer ◽  
Divya K. Shah ◽  
Ekati Drakopoulou ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Signal Strength ◽  
Clonal Deletion ◽  
Cell Fate Decisions ◽  
Repertoire Selection ◽  
Tcr Repertoire ◽  
Hh Signaling

Abstract TCR signal strength is involved in many cell fate decisions in the T-cell lineage. Here, we show that transcriptional events induced by Hedgehog (Hh) signaling reduced TCR signal strength in mice. Activation of Hh signaling in thymocytes in vivo by expression of a transgenic transcriptional-activator form of Gli2 (Gli2\#916;N2) changed the outcome of TCR ligation at many stages of thymocyte development, allowing self-reactive cells to escape clonal deletion; reducing transgenic TCR-mediated positive selection; reducing the ratio of CD4/CD8 single-positive (SP) cells; and reducing cell surface CD5 expression. In contrast, in the Shh\#8722;/\#8722; thymus the ratio of CD4/CD8 cells and both positive and negative selection of a transgenic TCR were increased, demonstrating that Shh does indeed influence TCR repertoire selection and the transition from double-positive (DP) to SP cell in a physiological situation. In peripheral T cells, Gli2\#916;N2 expression attenuated T-cell activation and proliferation, by a mechanism upstream of ERK phosphorylation.

scholarly journals Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation

2017 ◽  
Vol 25 (6) ◽  
pp. 1254-1268.e7 ◽  
Author(s):  
Tatyana N. Tarasenko ◽  
Susan E. Pacheco ◽  
Mary Kay Koenig ◽  
Julio Gomez-Rodriguez ◽  
Senta M. Kapnick ◽  
...  
Keyword(s):  
T Cell ◽  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Cell Fate ◽  
T Cell Activation ◽  
Oxidase Activity ◽  
Cell Activation ◽  
Cell Fate Decisions

PS1-05 Loss of P2X7 receptor expression on dn regulatory T-cell subsets through T-cell activation

Cytokine ◽  
2010 ◽  
Vol 52 (1-2) ◽  
pp. 18
Author(s):  
Julie Legrand ◽  
Sylvain Le Gall ◽  
Pierre Bobé ◽  
Michael Tovey
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Regulatory T Cell ◽  
P2x7 Receptor ◽  
Cell Activation ◽  
Receptor Expression ◽  
T Cell Subsets

scholarly journals Beta-1,3 Oligoglucans Specifically Bind to Immune Receptor CD28 and May Enhance T Cell Activation

2021 ◽  
Vol 22 (6) ◽  
pp. 3124
Author(s):  
Jeffrey Comer ◽  
Molly Bassette ◽  
Riley Burghart ◽  
Mayme Loyd ◽  
Susumu Ishiguro ◽  
...  
Keyword(s):  
Free Energy ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Binding Free Energy ◽  
Receptor Activation ◽  
Free Energy Calculations ◽  
Mrna Levels ◽  
Immunostimulatory Activity ◽  
Immune Receptor

Beta glucans are known to have immunomodulatory effects that mediated by a variety of mechanisms. In this article, we describe experiments and simulations suggesting that beta-1,3 glucans may promote activation of T cells by a previously unknown mechanism. First, we find that treatment of a T lymphoblast cell line with beta-1,3 oligoglucan significantly increases mRNA levels of T cell activation-associated cytokines, especially in the presence of the agonistic anti-CD3 antibody. This immunostimulatory activity was observed in the absence of dectin-1, a known receptor for beta-1,3 glucans. To clarify the molecular mechanism underlying this activity, we performed a series of molecular dynamics simulations and free-energy calculations to explore the interaction of beta-1,3 oligoglucans with potential immune receptors. While the simulations reveal little association between beta-1,3 oligoglucan and the immune receptor CD3, we find that beta-1,3 oligoglucans bind to CD28 near the region identified as the binding site for its natural ligands CD80 and CD86. Using a rigorous absolute binding free-energy technique, we calculate a dissociation constant in the low millimolar range for binding of 8-mer beta-1,3 oligoglucan to this site on CD28. The simulations show this binding to be specific, as no such association is computed for alpha-1,4 oligoglucan. This study suggests that beta-1,3 glucans bind to CD28 and may stimulate T cell activation collaboratively with T cell receptor activation, thereby stimulating immune function.

scholarly journals Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shulan Tian ◽  
Henan Zhang ◽  
Pan Zhang ◽  
Michael Kalmbach ◽  
Jeong-Heon Lee ◽  
...  
Keyword(s):  
T Cell ◽  
Signaling Pathway ◽  
Cell Fate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Developmental Process ◽  
Wnt Signaling Pathway ◽  
Mechanistic Study ◽  
Prolymphocytic Leukemia ◽  
Genome Wide

AbstractT cell prolymphocytic leukemia (T-PLL) is a rare disease with aggressive clinical course. Cytogenetic analysis, whole-exome and whole-genome sequencing have identified primary structural alterations in T-PLL, including inversion, translocation and copy number variation. Recurrent somatic mutations were also identified in genes encoding chromatin regulators and those in the JAK-STAT signaling pathway. Epigenetic alterations are the hallmark of many cancers. However, genome-wide epigenomic profiles have not been reported in T-PLL, limiting the mechanistic study of its carcinogenesis. We hypothesize epigenetic mechanisms also play a key role in T-PLL pathogenesis. To systematically test this hypothesis, we generated genome-wide maps of regulatory regions using H3K4me3 and H3K27ac ChIP-seq, as well as RNA-seq data in both T-PLL patients and healthy individuals. We found that genes down-regulated in T-PLL are mainly associated with defense response, immune system or adaptive immune response, while up-regulated genes are enriched in developmental process, as well as WNT signaling pathway with crucial roles in cell fate decision. In particular, our analysis revealed a global alteration of regulatory landscape in T-PLL, with differential peaks highly enriched for binding motifs of immune related transcription factors, supporting the epigenetic regulation of oncogenes and genes involved in DNA damage response and T-cell activation. Together, our work reveals a causal role of epigenetic dysregulation in T-PLL.

scholarly journals 798 CDX-585, A bispecific antibody with dual targeting of ILT4 and PD-1 checkpoint pathways

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A833-A833
Author(s):  
Laura Vitale ◽  
Michael Murphy ◽  
Collin Xia ◽  
Zeyu Peng ◽  
Thomas O'Neill ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Clinical Chemistry ◽  
Primary Cultures ◽  
Resistance Mechanism ◽  
Myeloid Cell ◽  
Receptor Activation ◽  
Pilot Studies ◽  
Enhanced Production

BackgroundActivation of the ITIM-bearing ILT4/LILRB2 receptor by its cognate ligands (HLA-G and HLA Class I) has been postulated as a resistance mechanism for checkpoint blockade of PD-1 and CTLA-4. Dual inhibition of receptors that suppress myeloid and T cell compartments through the generation of bispecific antibodies (bsAbs) is a promising strategy to improve outcomes for patients whose tumors are resistant to checkpoint inhibition.MethodsWe describe the discovery and characterization of CDX-585 a bsAb developed from novel ILT4 and PD-1 antagonist mAbs that revert myeloid cell suppression by antagonizing ILT4 and activating T-cell responses through PD-1 inhibition. The bsAb was engineered as a tetravalent molecule using the PD-1 IgG1 mAb linked to scFv of the ILT4 mAb at the C-terminus of the heavy chain. A series of mutations were introduced in the Fc domain to eliminate Fcy receptor binding and increase affinity to the neonatal Fc receptor. CDX-585 has good biophysical characteristics and retains functional properties similar to, or better, than the parental mAbs.ResultsCDX-585 has sub-nanomolar affinity binding to ILT4 and PD-1 and is a potent competitor of their respective ligands. Primary cultures of human macrophages and dendritic cells treated with CDX-585 enhanced production of inflammatory cytokines/chemokines, which was further potentiated in the presence of toll like receptor activation with lipopolysaccharide (LPS). CDX-585 was particularly effective in promoting T cell activation as measured by mixed lymphocyte reactions, and in polarizing macrophages towards M1 based on their cytokine profile. Pilot studies in mice and cynomolgus macaques confirmed a favorable pharmacokinetic profile without adverse effects of treatment noted in clinical observations or clinical chemistry.ConclusionsCDX-585 effectively combines ILT4 and PD-1 blockade into one molecule with favorable biophysical and functional characteristics supporting the initiation of development activities including manufacturing and IND-enabling studies.

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