scholarly journals PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity

2021 ◽  
Vol 118 (31) ◽  
pp. e2010053118
Author(s):  
Alessandro Poli ◽  
Shidqiyyah Abdul-Hamid ◽  
Antonio Enrico Zaurito ◽  
Francesca Campagnoli ◽  
Valeria Bevilacqua ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
Late Onset ◽  
Cell Activity ◽  
Peripheral Tolerance ◽  
Immunosuppressive Activity ◽  
Pharmacological Inhibition ◽  
Human T Cell

Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P2. They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.

scholarly journals Physiological strength electric fields modulate human T cell activation and polarisation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Christina E. Arnold ◽  
Ann M. Rajnicek ◽  
Joseph I. Hoare ◽  
Swechha Mainali Pokharel ◽  
Colin D. Mccaig ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Electric Fields ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Activity ◽  
Research Area ◽  
Functional Changes ◽  
Cell Functions ◽  
Human T Cell

AbstractThe factors and signals driving T cell activation and polarisation during immune responses have been studied mainly at the level of cells and chemical mediators. Here we describe a physical driver of these processes in the form of physiological-strength electric fields (EFs). EFs are generated at sites where epithelium is disrupted (e.g. wounded skin/bronchial epithelia) and where T cells frequently are present. Using live-cell imaging, we show human primary T cells migrate directionally to the cathode in low strength (50/150 mV/mm) EFs. Strikingly, we show for the first time that EFs significantly downregulate T cell activation following stimulation with antigen-activated APCs or anti-CD3/CD28 antibodies, as demonstrated by decreased IL-2 secretion and proliferation. These EF-induced functional changes were accompanied by a significant dampening of CD4+ T cell polarisation. Expression of critical markers of the Th17 lineage, RORγt and IL-17, and the Th17 polarisation mediator phospho-STAT3 were reduced significantly, while STAT1, ERK and c-Jun phosphorylation were comparatively unaffected suggesting STAT3 modulation by EFs as one mechanism driving effects. Overall, we identify electrical signals as important contributors to the co-ordination and regulation of human T cell functions, paving the way for a new research area into effects of naturally occurring and clinically-applied EFs in conditions where control of T cell activity is paramount.

Measuring human T-lymphocyte function

1998 ◽  
Vol 1 (6) ◽  
pp. 1-20 ◽  
Author(s):  
Julian K. Hickling
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cell Activity ◽  
T Cell Response ◽  
Lymphocyte Function ◽  
Human T Cell ◽  
Model Animal ◽  
Human T Lymphocyte ◽  
Qualitative Nature

T lymphocytes (T cells) play critical roles in the regulation of immune responses, and are responsible for mediating many of the effector mechanisms of the immune system. For this reason, there has always been a need for assays to measure accurately the activity of populations of T cells, both in model (animal) systems and in humans. The expansion of the biotechnology industry has led to a dramatic increase in the number of novel immunotherapeutics that are being developed for the treatment of cancer, autoimmune disorders and infectious diseases. This increase in activity in the field of immunotherapy, coupled with the expense of clinical trials, has led to renewed interest in methods that accurately assess T-cell function, as researchers seek to maximise the amount of information that can be obtained from each clinical study. Assessing the quantitative and qualitative nature of a T-cell response, for example following vaccination or immunosuppressive therapy, can provide valuable information about the efficacy of a treatment, in place of a clinical endpoint. This article reviews some of the established methods that are used to monitor human T-cell activity, and describes some new approaches that are in development to increase the speed, sensitivity and relevance of such methods.

The C-class chemokine, lymphotactin, impairs the induction of Th1-type lymphokines in human CD4+ T cells

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 420-428 ◽  
Author(s):  
Chantal Cerdan ◽  
Edgar Serfling ◽  
Daniel Olive
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Jurkat Cells ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Human T Cell

Abstract Chemokines are involved in the regulation of leukocyte migration and for some of them, T-cell costimulation. To date, the only direct property of lymphotactin (Lptn), the unique member of the C class of chemokines, consists of T-cell chemoattraction. This report describes a novel function for Lptn in human T-lymphocyte biology, by demonstrating the direct ability of Lptn to both inhibit and costimulate CD4+ and CD8+ T-cell activation, respectively. Lptn but not RANTES inhibited CD4+ T-cell proliferation, through a decreased production of Th1 (interleukin [IL]-2, interferon [IFN]-γ) but not Th2 (IL-4, IL-13) lymphokines, and decreased IL-2R expression. Transfections in Jurkat cells showed a Lptn-mediated transcriptional down-regulation of gene-promoter activities specific for Th1-type lymphokines, as well as of nuclear factor of activated T cells (NF-AT) but not AP-1 or NF-ΚB enhancer activities. This suppressive action of Lptn could be compensated by overexpression of NF-ATc but not NF-ATp. CD4+ T-cell proliferation was completely restored by exogenous IL-2 or reversed by pertussis toxin, wortmannin, and genistein, suggesting the involvement of multiple partners in Lptn signaling. In contrast to CD4+ cells, Lptn exerted a potent costimulatory activity on CD8+ T-cell proliferation and IL-2 secretion. These data provide important insights into the role of Lptn in differential regulation of normal human T-cell activation and its possible implication in immune response disorders.

A dimeric form of soluble recombinant sheep LFA-3(CD58) inhibits human T-cell proliferation by generating regulatory T cells

1997 ◽  
Vol 37 (2-3) ◽  
pp. 209-220 ◽  
Author(s):  
Kenji Yamashita ◽  
Tetsu Kakutani ◽  
Takehisa Ohashi ◽  
Toshiji Saibara
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Proliferation ◽  
Human T Cell ◽  
Dimeric Form

scholarly journals Human T cell activation. I. Monocyte-independent activation and proliferation induced by anti-T3 monoclonal antibodies in the presence of tumor promoter 12-o-tetradecanoyl phorbol-13 acetate.

1985 ◽  
Vol 161 (4) ◽  
pp. 641-656 ◽  
Author(s):  
T Hara ◽  
S M Fu
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Receptor Expression ◽  
T Cell Proliferation ◽  
Dependent Manner ◽  
Human T Cell

Three monoclonal antibodies (mAb), of IgG1, IgG2a, and IgM isotypes, raised against the T3 complex, were used to probe the activation of human T cells. The IgM antibody 235 was not mitogenic for peripheral blood mononuclear cells (PMC). It efficiently blocked the proliferation of PMC induced by T cell mitogens, alloantigens, and soluble antigens. The other two antibodies were mitogenic, and behaved similarly to Leu 4 and OKT3, respectively. In T cell preparations with less than 0.1% monocytes (as assayed by nonspecific esterase staining), all three mAb were not mitogenic. They failed to induce either interleukin 2 (IL-2) receptor expression or IL-2 secretion. Addition of IL-1 failed to collaborate with anti-T3 mAb to induce these T cells to proliferate, but IL-2 enhanced T cell proliferation slightly. Monocyte-depleted T cells, however, proliferated in response to all three anti-T3 mAb, when TPA was added, in a dose-dependent manner. TPA induced a low level of IL-2 receptor expression in monocyte-depleted T cells, without inducing IL-2 secretion. Anti-T3 plus TPA induced a marked enhancement in both quantity and intensity of IL-2 receptor expression. IL-2 secretion was also detected. These results indicate that anti-T3 IgM can deliver an inductive signal despite its blockage of T cell proliferation, and that two signals are necessary and perhaps sufficient to induce human T cell activation and proliferation.

scholarly journals Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T cells

2002 ◽  
Vol 32 (10) ◽  
pp. 2888-2896 ◽  
Author(s):  
Claire N. Manzotti ◽  
Helen Tipping ◽  
Laura C. A. Perry ◽  
Karen I. Mead ◽  
Patrick J. Blair ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Proliferation ◽  
Human T Cell

scholarly journals Alpha and Lambda Interferon Together Mediate Suppression of CD4 T Cells Induced by Respiratory Syncytial Virus

2006 ◽  
Vol 80 (10) ◽  
pp. 5032-5040 ◽  
Author(s):  
Bo Chi ◽  
Harold L. Dickensheets ◽  
Kirsten M. Spann ◽  
Marc A. Alston ◽  
Cindy Luongo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Respiratory Syncytial Virus ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Types ◽  
T Cell Proliferation ◽  
Live Virus ◽  
Human T Cell ◽  
Syncytial Virus

ABSTRACT The mechanism by which respiratory syncytial virus (RSV) suppresses T-cell proliferation to itself and other antigens is poorly understood. We used monocyte-derived dendritic cells (MDDC) and CD4 T cells and measured [3H]thymidine incorporation to determine the factors responsible for RSV-induced T-cell suppression. These two cell types were sufficient for RSV-induced suppression of T-cell proliferation in response to cytomegalovirus or Staphylococcus enterotoxin B. Suppressive activity was transferable with supernatants from RSV-infected MDDC and was not due to transfer of live virus or RSV F (fusion) protein. Supernatants from RSV-infected MDDC, but not MDDC exposed to UV-killed RSV or mock conditions, contained alpha interferon (IFN-α; median, 43 pg/ml) and IFN-λ (approximately 1 to 20 ng/ml). Neutralization of IFN-α with monoclonal antibody (MAb) against one of its receptor chains, IFNAR2, or of IFN-λ with MAb against either of its receptor chains, IFN-λR1 (interleukin 28R [IL-28R]) or IL-10R2, had a modest effect. In contrast, blocking the two receptors together markedly reduced or completely blocked the RSV-induced suppression of CD4 T-cell proliferation. Defining the mechanism of RSV-induced suppression may guide vaccine design and provide insight into previously uncharacterized human T-cell responses and activities of interferons.

scholarly journals Collagen density regulates the activity of tumor-infiltrating T cells

2018 ◽  
Author(s):  
Dorota E Kuczek ◽  
Anne Mette H Larsen ◽  
Marco Carretta ◽  
Adrija Kalvisa ◽  
Majken S Siersbæk ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Density Matrix ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Cell Activity ◽  
High Density ◽  
Collagen Density ◽  
Whole Transcriptome

AbstractBackgroundTumor progression is accompanied by dramatic remodeling of the surrounding extracellular matrix leading to the formation of a tumor-specific ECM, which is often more collagen-rich and of increased stiffness. The altered ECM of the tumor supports cancer growth and metastasis, but it is unknown if this effect involves modulation of T cell activity. To investigate if a high-density tumor-specific ECM could influence the ability of T cells to kill cancer cells, we here studied how T cells respond to 3D culture in different collagen densities.MethodsT cells cultured in 3D conditions surrounded by a high or low collagen density were imaged using confocal fluorescent microscopy. The effects of the different collagen densities on T cell proliferation, survival, and differentiation were examined using flow cytometry. Cancer cell proliferation in similar 3D conditions was also measured. Triple-negative breast cancer specimens were analyzed for the number of infiltrating CD8+ T cells and for the collagen density. Whole-transcriptome analyses were applied to investigate in detail the effects of collagen density on T cells. Computational analyses were used to identify transcription factors involved in the collagen density-induced gene regulation. Observed changes were confirmed by qRT-PCR analysis.ResultsT cell proliferation was significantly reduced in a high-density matrix compared to a low-density matrix and prolonged culture in a high-density matrix led to a higher ratio of CD4+ to CD8+ T cells. The proliferation of cancer cells was unaffected by the surrounding collagen-density. Consistently, we observed a reduction in the number of infiltrating CD8+ T-cells in mammary tumors with high collagen-density indicating that collagen-density has a role in regulating T cell abundance in human breast cancer.Whole-transcriptome analysis of 3D-cultured T cells revealed that a high-density matrix induces downregulation of cytotoxic activity markers and upregulation of regulatory T cell markers. These transcriptional changes were predicted to involve autocrine TGF-B signaling and they were accompanied by an impaired ability of tumor-infiltrating T cells to kill autologous cancer cells.ConclusionsOur study identifies a new immune modulatory mechanism, which could be essential for suppression of T cell activity in the tumor microenvironment.

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