scholarly journals HIV infection of primary human T cells is determined by tunable thresholds of T cell activation

2004 ◽  
Vol 34 (6) ◽  
pp. 1705-1714 ◽  
Author(s):  
Kyra Oswald-Richter ◽  
Stacy M. Grill ◽  
Mindy Leelawong ◽  
Derya Unutmaz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human T Cells

scholarly journals Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Peter A. Szabo ◽  
Hanna Mendes Levitin ◽  
Michelle Miron ◽  
Mark E. Snyder ◽  
Takashi Senda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interferon Response ◽  
Functional Responses ◽  
Multiple Tumor ◽  
Human T Cell ◽  
Human T Cells

Abstract Human T cells coordinate adaptive immunity in diverse anatomic compartments through production of cytokines and effector molecules, but it is unclear how tissue site influences T cell persistence and function. Here, we use single cell RNA-sequencing (scRNA-seq) to define the heterogeneity of human T cells isolated from lungs, lymph nodes, bone marrow and blood, and their functional responses following stimulation. Through analysis of >50,000 resting and activated T cells, we reveal tissue T cell signatures in mucosal and lymphoid sites, and lineage-specific activation states across all sites including distinct effector states for CD8+ T cells and an interferon-response state for CD4+ T cells. Comparing scRNA-seq profiles of tumor-associated T cells to our dataset reveals predominant activated CD8+ compared to CD4+ T cell states within multiple tumor types. Our results therefore establish a high dimensional reference map of human T cell activation in health for analyzing T cells in disease.

scholarly journals Non-voltage-gated L-type Ca2+Channels in Human T Cells

2004 ◽  
Vol 279 (19) ◽  
pp. 19566-19573 ◽  
Author(s):  
Leanne Stokes ◽  
John Gordon ◽  
Gillian Grafton
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Splice Variants ◽  
Antigen Receptor ◽  
Dominant Form ◽  
Voltage Gated ◽  
Antigen Receptor Signaling ◽  
Human T Cells

In T lymphocytes, engagement of the antigen receptor leads to a biphasic Ca2+flux consisting of a mobilization of Ca2+from intracellular stores followed by a lower but sustained elevation that is dependent on extracellular Ca2+. The prolonged Ca2+flux is required for activation of transcription factors and for subsequent activation of the T cell. Ca2+influx requires as yet unidentified Ca2+channels, which potentially play a role in T cell activation. Here we present evidence that human T cells express a non-voltage-gated Ca2+channel related to L-type voltage-gated Ca2+channels. Drugs that block classical L-type channels inhibited the initial phase of the antigen receptor-induced Ca2+flux and could also inhibit the sustained phase of the Ca2+signal suggesting a role for the L-type Ca2+channel in antigen receptor signaling. T cells expressed transcripts for the α11.2 and α11.3 pore-forming subunits of L-type voltage-gated Ca2+channels and transcripts for all four known β-subunits including several potential new splice variants. Jurkat T leukemia cells expressed a small amount of full-length α11.2 protein but the dominant form was a truncated protein identical in size to a truncated α11.2 protein known to be expressed in B lymphocytes. They further expressed a truncated form of the α11.3 subunit and auxiliary β1- and β3-subunit proteins. Our data strongly suggest that functional but non-voltage-gated L-type Ca2+channels are expressed at the plasma membrane in T cells and play a role in the antigen receptor-mediated Ca2+flux in these cells.

scholarly journals Interleukin-2-dependent phosphorylation of the retinoblastoma-susceptibility-gene product p110-115RB in human T-cells

1992 ◽  
Vol 282 (3) ◽  
pp. 759-764 ◽  
Author(s):  
G A Evans ◽  
L M Wahl ◽  
W L Farrar
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Gene Transcription ◽  
T Cell Activation ◽  
Cell Activation ◽  
Susceptibility Gene ◽  
Interleukin 2 ◽  
Human T Cells ◽  
Rb Phosphorylation

The state of phosphorylation of the retinoblastoma-susceptibility gene product, p110-115RB, is thought to have fundamental importance in controlling the progression of the cell through the cell cycle. We have studied RB phosphorylation in human T-cells in the context of T-cell activation, stimulated by phytohaemagglutinin (PHA) and interleukin-2 (IL-2). We show that, of the signals associated with T-cell activation, only signals that directly lead to movement into S phase of the cell cycle are capable of stimulating RB phosphorylation. Cyclosporin A (CsA), a potent inhibitor of IL-2 synthesis and cellular proliferation, blocked RB phosphorylation, and this was recovered with exogenous IL-2, indicating a direct involvement of IL-2 in controlling RB phosphorylation. We found that PHA did not stimulate RB phosphorylation within 10 h of treatment, but IL-2 could effectively stimulate RB phosphorylation within 2 h, and this approached a maximum within 8-10 h of IL-2 treatment. Further, by using actinomycin D to inhibit new gene transcription following IL-2 stimulation, we found that early-cell-cycle phosphorylation of RB required IL-2-stimulated gene transcription. From these data we conclude that, in human T-cells, RB phosphorylation is not directly associated with T-cell receptor-mediated events, but requires the interaction of IL-2 and new gene transcription following IL-2 stimulation.

scholarly journals The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy

Blood ◽  
2018 ◽  
Vol 131 (1) ◽  
pp. 39-48 ◽  
Author(s):  
Sarah L. Buchan ◽  
Anne Rogel ◽  
Aymen Al-Shamkhani
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
High Profile ◽  
Cell Immunity ◽  
Human T Cells ◽  
Checkpoint Receptors ◽  
Tumor Types

In recent years, monoclonal antibodies (mAbs) able to reinvigorate antitumor T-cell immunity have heralded a paradigm shift in cancer treatment. The most high profile of these mAbs block the inhibitory checkpoint receptors PD-1 and CTLA-4 and have improved life expectancy for patients across a range of tumor types. However, it is becoming increasingly clear that failure of some patients to respond to checkpoint inhibition is attributable to inadequate T-cell priming. For full T-cell activation, 2 signals must be received, and ligands providing the second of these signals, termed costimulation, are often lacking in tumors. Members of the TNF receptor superfamily (TNFRSF) are key costimulators of T cells during infection, and there has been an increasing interest in harnessing these receptors to augment tumor immunity. We here review the immunobiology of 2 particularly promising TNFRSF target receptors, CD27 and OX40, and their respective ligands, CD70 and OX40L, focusing on their role within a tumor setting. We describe the influence of CD27 and OX40 on human T cells based on in vitro studies and on the phenotypes of several recently described individuals exhibiting natural deficiencies in CD27/CD70 and OX40. Finally, we review key literature describing progress in elucidating the efficacy and mode of action of OX40- and CD27-targeting mAbs in preclinical models and provide an overview of current clinical trials targeting these promising receptor/ligand pairings in cancer.

scholarly journals Nx-2127, a Degrader of BTK and IMiD Neosubstrates, for the Treatment of B-Cell Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Daniel W Robbins ◽  
Aileen Kelly ◽  
May Tan ◽  
Joel McIntosh ◽  
Jeffrey Wu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Oral Administration ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Publicly Traded ◽  
B Cell Malignancies ◽  
Human T Cells ◽  
Baseline Levels

Bruton's tyrosine kinase (BTK) plays a key role in cell survival in B cell malignancies, such as chronic lymphocytic leukemia (CLL). Covalent inhibitors of BTK, such as ibrutinib and acalabrutinib, while effective, have been associated with the occurrence of resistance mutations. The most prevalent site of mutation, C481, renders covalent BTK inhibitors unable to form a covalent bond with BTK leading to diminished efficacy and disease progression. Small molecule-induced protein degradation offers a unique approach to target BTK for the treatment of B-cell malignancies. Chimeric Targeting Molecules (CTMs) catalyze ubiquitylation and proteasomal degradation of target proteins and are comprised of a ubiquitin ligase binding element ("harness"), a linker, and a target binding element ("hook"). NX-2127 is a CTM that contains a BTK hook linked to a cereblon (CRBN) harness. NX-2127 degrades 50% of cellular BTK (DC50) at < 5 nM across multiple cancer cell lines and in human PBMCs. BTK CTMs impair viability in the BTK-dependent ABC-DLBCL cell line, TMD8 (EC50: < 15 nM after 72 hours). Importantly, NX-2127 induces degradation of the mutated BTK-C481S in cells and inhibits proliferation of BTK-C481S mutant TMD8 cells more effectively than ibrutinib (NX-2127 EC50 values of < 30 nM versus > 1 μM for ibrutinib). Oral administration of NX-2127 in mice leads to dose-proportional exposure in plasma and BTK degradation to <10% of baseline levels in circulating and splenic B cells. In both WT TMD8 and C481S mutant xenograft models, daily oral administration of NX-2127 resulted in superior tumor growth inhibition (TGI) as compared to ibrutinib. NX-2127 also demonstrates potent degradation of BTK in cynomolgus monkeys with oral administration. Following 14 days of once daily, oral dosing in cynomolgus monkey, BTK levels are suppressed to <10% of baseline levels at doses as low as 1 mg/kg. In addition to potent BTK degradation, NX-2127 possesses IMiD-like properties through the design of the CRBN binding harness that catalyzes the degradation of CRBN neosubstrates Aiolos (IKZF3) and Ikaros (IKZF1). This activity is associated with increased T cell activation and anti-tumor effects of the IMiD drugs lenalidomide and pomalidomide. In primary human T cells, NX-2127 catalyzes the degradation of Aiolos and Ikaros with of 25 nM and 54 nM, respectively, potencies which are similar to those of lenalidomide (20 nM and 343 nM, respectively). Corresponding with such degradation, NX-2127 stimulates T cell activation as measured by increased IL-2 production in primary human T Cells in a manner similar to lenalidomide and pomalidomide. The dual activity of BTK degradation combined with immunomodulation of NX-2127 supports its development for the treatment of B-cell malignancies. Disclosures Robbins: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kelly:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tan:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. McIntosh:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wu:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Konst:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kato:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Peng:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mihalic:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Weiss:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Perez:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tung:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kolobova:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Borodovsky:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rountree:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tenn-McClellan:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Noviski:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ye:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Basham:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ingallinera:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. McKinnell:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karr:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Powers:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Guiducci:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sands:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Hypoxia is a dominant remodeler of the CD8+ T cell surface proteome relative to activation and regulatory T cell-mediated suppression

2021 ◽  
Author(s):  
James Robert Byrnes ◽  
Amy M Weeks ◽  
Julia Carnevale ◽  
Eric Shifrut ◽  
Lisa Kirkemo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Metabolic Reprogramming ◽  
T Cell Function ◽  
Human T Cells ◽  
Surface Proteome

Immunosuppressive factors in the tumor microenvironment (TME) impair T cell function and limit the anti-tumor immune response. T cell surface receptors that influence interactions and function in the TME are already proven targets for cancer immunotherapy. However, surface proteome remodeling of primary human T cells in response to suppressive forces in the TME has never been characterized systematically. Using a reductionist cell culture approach with primary human T cells and SILAC-based quantitative cell surface capture glycoproteomics, we examined how two immunosuppressive TME factors, regulatory T cells (Tregs) and hypoxia, globally affect the activated CD8+ surface proteome (surfaceome). Surprisingly, the CD8+/Treg co-culture only modestly affected the CD8+ surfaceome, but did reverse several activation-induced surfaceomic changes. In contrast, hypoxia dramatically altered the CD8+ surfaceome in a manner consistent with both metabolic reprogramming and induction of an immunosuppressed state. The CD4+ T cell surfaceome similarly responded to hypoxia, revealing a novel hypoxia-induced surface receptor program. Our findings are consistent with the premise that hypoxic environments create a metabolic challenge for T cell activation, which may underlie the difficulty encountered in treating solid tumors with immunotherapies. Together, the data presented here provide insight into how suppressive TME factors remodel the T cell surfaceome and represent a valuable resource to inform future therapeutic efforts to enhance T cell function in the TME.

scholarly journals RNA-seq of Human T-Cells After Hematopoietic Stem Cell Transplantation Identifies Linc00402 as a Novel Regulator of T-Cell Alloimmunity

2020 ◽  
Author(s):  
Daniel Peltier ◽  
Molly Radosevich ◽  
Guoqing Hou ◽  
Cynthia Zajac ◽  
Katherine Oravecz-Wilson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Cell Responses ◽  
Human T Cells ◽  
Allogeneic Stimulation

ABSTRACTMechanisms governing allogeneic T-cell responses after allogeneic hematopoietic stem cell (HSC) and solid organ transplantation are incompletely understood. Long non-coding RNAs (lncRNA) do not code for, but control gene expression with tissue specificity. However, their role in T-cell alloimmunity is unknown. We performed RNA-seq on donor T-cells from HSCT patients and found that increasing strength of allogeneic stimulation caused greater differential expression of lncRNAs. The differential expression was validated in an independent patient cohort, and also following ex vivo allogeneic stimulation of healthy human T-cells. Linc00402, a novel, conserved lncRNA, was identified as the most differentially expressed and was enriched 88 fold in human T-cells. Mechanistically, it was mainly located in the cytoplasm, and its expression was rapidly reduced following T-cell activation. Consistent with this, tacrolimus preserved the expression of Linc00402 following T-cell activation, and lower levels of Linc00402 were found in patients who subsequently went on to develop acute graft versus host disease (GVHD). The dysregulated expression of Linc00402 was also validated in murine T-cells, both in vitro and in vivo. Functional studies using multiple modalities to deplete Linc00402 in both mouse and human T-cells, demonstrated a critical role for Linc00402 in the T-cell proliferative response to an allogeneic stimulus but not a non-specific anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a novel, conserved regulator of allogeneic T-cell function. Because of its T-cell specific expression and its impact on allogeneic T-cell responses, targeting Linc00402 may improve outcomes after allogeneic HSC and solid organ transplantation.One sentence summaryLncRNAs are differentially expressed by allogeneic antigen-stimulated T-cells, and the novel lncRNA, Linc00402, is a specific regulator of mouse and human allogeneic T-cells.

Abstract P167: Title: Prediction of Arterial Stiffness from Early T-cell Activation among HIV and HCV Co-infected Women in the Women's Interagency HIV Study (WIHS)

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Roksana Karim ◽  
Naoko Kono ◽  
Robert Kaplan ◽  
Wendy J Mack ◽  
Howard N Hodis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Arterial Stiffness ◽  
Hiv Infection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Infection Status ◽  
Activation Markers ◽  
Color Flow ◽  
The Impact

Introduction: Activation of T-lymphocytes, a hallmark of HIV infection, reaches a set point early in HIV infection and persists even after viral suppression with highly active antiretroviral therapy (HAART). Early T-cell activation predicts subsequent CD4 depletion, progression to AIDS and survival. HIV-infected subjects are at high risk for premature atherosclerosis. Little is known regarding the impact of early T cell activation on arterial stiffness. While Kaplan et al. (2011) were the first and only group to show a cross-sectional association, we investigate here if early T cell activation can predict future arterial stiffness. Hypothesis: High early T cell activation will predict increased arterial stiffness, measured 5.5 (IQR=2.5-7.5) years later, in HIV and HCV co-infected women. Methods: A longitudinal study nested within the WIHS, an ongoing prospective cohort study. Percentages of CD4 and CD8 T cell activation, assessed by CD38 and HLA-DR co-expression using 3-color flow cytometry, were measured on average 5.5 years before arterial stiffness assessments (carotid artery distensibility, and Young’s elastic modulus for elasticity) using B-mode carotid ultrasound. Multiple linear regression models evaluated the association between log-transformed T cell activation markers (independent variables) and arterial stiffness (dependent variable). Analyses were stratified by HCV co-infection status and by pre- and post-HAART assessment of T cell activation. Results: A total of 376 HIV+ women (185 HCV+) were included in the analysis. Participants were on average 46(SD=9) years old, 59% Black, and 49% were current smokers. Activation of both CD4 and CD8 T cells significantly univariately predicted reduced distensibility and elasticity among HIV-infected women. CD4 activation continued to significantly predict distensibility (β(SEM)= −3.51(1.30) 10 −6* N −1* m 2 , p=0.01), and elasticity (0.11(0.04)10 5* N * m 2 , p=0.004) with adjustment for age, race, BMI, smoking, ART, CD4 count, and HIV RNA. CD8 activation was no longer associated after adjustment. When stratified by HCV co-infection status, the prediction of arterial stiffness parameters from early CD4 activation was somewhat stronger among the HIV+/HCV+ women compared to HIV+/HCV- women (β(SEM)= −4.44(1.93), p=0.02 vs. −3.04(1.84), p=0.10 for distensibility, and 0.17(0.06), p=0.003 vs. 0.09(0.05), p=0.09 for elasticity); however the test for interaction was not statistically significant. In a subset of 188 women, CD4 activation measured both pre- and post-HAART significantly predicted later arterial stiffness. Conclusions: CD4 activation level predicts future arterial stiffness in HIV-infected women, perhaps more markedly among HCV co-infected women. These data confirm the proinflammatory impact of activated T cells that can cause vascular dysfunction and shed light on the early onset of atherogenesis.

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