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 A single-cell reference map for human blood and tissue T cell activation reveals functional states in health and disease

2019 ◽  
Author(s):  
Peter A. Szabo ◽  
Hanna Mendes Levitin ◽  
Michelle Miron ◽  
Mark E. Snyder ◽  
Takashi Senda ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interferon Response ◽  
Functional Responses ◽  
Human Lungs ◽  
Human T Cells ◽  
Reference Map ◽  
Response State

ABSTRACTHuman T cells coordinate adaptive immunity by localization in diverse tissue sites, though blood T cells are the most readily studied. Here, we used single-cell RNA-seq to define the functional responses of T cells isolated from human lungs, lymph nodes, bone marrow, and blood to TCR-stimulation. We reveal how human T cells in tissues relate to those in blood, and define activation states for CD4+ and CD8+T cells across all sites, including an interferon-response state for CD4+T cells and distinct effector states for CD8+T cells. We further show how profiles of individual tumor-associated T cells can be projected onto this healthy reference map, revealing their functional state.

scholarly journals Zinc Aspartate Induces IL-16 Secretion and Apoptosis in Human T Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 246
Author(s):  
Dirk Reinhold ◽  
Karina Guttek ◽  
Annika Reddig ◽  
Linda Voss ◽  
Claudia Schubert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
T Cell Activation ◽  
Cell Activation ◽  
Caspase 3 ◽  
Cell Function ◽  
Human T Cell ◽  
Human T Cells ◽  
Zinc Aspartate

T cell activation mediates immunity to pathogens. On the flipside, T cells are also involved in pathological immune responses during chronic autoimmune diseases. We recently reported that zinc aspartate, a registered drug with high bioavailability, dose-dependently inhibits T cell activation and Th1/Th2/Th17 cytokine production of stimulated human and mouse T cells. To understand the suppressive effect of zinc on T cell function, we here investigated the influence of zinc aspartate on human T cells focusing on the secretion of immunosuppressive cytokines, induction of apoptosis, and caspase 3/7 activity. To this end, we monitored either freshly stimulated or pre-activated human T cells in the presence of zinc aspartate from 40–140 µM over a period of 72 h. Under both experimental conditions, we observed a dose-dependent suppression of human T cell proliferation. While IL-1ra, latent TGF-β1, and IL-10 were dose-dependently reduced, we, unexpectedly, detected elevated levels of IL-16 upon zinc supplementation. In addition, the number of cells with active caspase 3/7 and, consecutively, the amount of cells undergoing apoptosis, steadily increased at zinc aspartate concentrations exceeding 100 µM. Taken together, our findings suggest that zinc aspartate impairs T cell fitness and might be beneficial for the treatment of T cell-mediated autoimmune diseases.

scholarly journals Induction of lysosomal and plasma membrane-bound sialidases in human T-cells via T-cell receptor

2004 ◽  
Vol 380 (2) ◽  
pp. 425-433 ◽  
Author(s):  
Peng WANG ◽  
Ji ZHANG ◽  
Hong BIAN ◽  
Ping WU ◽  
Reshma KUVELKAR ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Th2 Cytokines ◽  
Receptor Stimulation ◽  
Human T Cell ◽  
Human T Cells

Among the three isoenzymes of neuraminidase (Neu) or sialidase, Neu-1 has been suggested to be induced by cell activation and to be involved in IL (interleukin)-4 biosynthesis in murine T-cells. In the present study, we found that antigen-induced airway eosinophilia, a typical response dependent on Th2 (T-helper cell type 2) cytokines, as well as mRNA expression of Th2 cytokines, including IL-4, are suppressed in Neu-1-deficient mice, thereby demonstrating the in vivo role of murine Neu-1 in regulation of Th2 cytokines. To elucidate the roles of various sialidases in human T-cell activation, we investigated their tissue distribution, gene induction and function. Neu-1 is the predominant isoenzyme at the mRNA level in most tissues and cells in both mice and humans, including T-cells. T-cells also have significant levels of Neu-3 mRNAs, albeit much lower than those of Neu-1, whereas the levels of Neu-2 mRNAs are minimal. In human T-cells, both Neu-1 and Neu-3 mRNAs are significantly induced by T-cell-receptor stimulation, as is sialidase activity against 4-methylumbelliferyl-N-acetylneuramic acid (a substrate for both Neu-1 and Neu-3) and the ganglioside GD1a [NeuAcα2-3Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1-4Glcβ1-cer] (a substrate for Neu-3, but not for Neu-1). The expression of the two sialidase genes may be under differential regulation. Western blot analysis and enzymic comparison with recombinant sialidases have revealed that Neu-3 is induced as a major isoform in activated cells. The induction of Neu-1 and Neu-3 in T-cells is unique. In human monocytes and neutrophils stimulated with various agents, the only observation of sialidase induction has been by IL-1 in neutrophils. Functionally, a major difference has been observed in Jurkat T-cell lines over-expressing Neu-1- and Neu-3. Upon T-cell receptor stimulation, IL-2, interferon-γ, IL-4 and IL-13 are induced in the Neu-1 line, whereas in the Neu-3 line the same cytokines are induced, with the exception of IL-4. Taken together, these results suggest an important immunoregulatory role for both Neu-1 and Neu-3 in humans.

scholarly journals Functional expression of the murine Thy-1.2 gene in transfected human T cells.

1986 ◽  
Vol 163 (2) ◽  
pp. 285-300 ◽  
Author(s):  
K C Gunter ◽  
R A Kroczek ◽  
E M Shevach ◽  
R N Germain
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Signal Transmission ◽  
Functional Expression ◽  
Jurkat Cells ◽  
Human T Cell ◽  
Human T Cells ◽  
Regulatory Defect

The interaction of certain mAbs with the Thy-1 molecules of murine T lymphocytes leads to cell activation and proliferation. To examine the signal transduction mechanism underlying this process and to determine what, if any, relationship exists between Thy-1-dependent triggering and T cell activation mediated through the T3-antigen receptor (T3-Ti) complex, a genomic clone of murine Thy-1.2 was isolated and transfected into the human T cell tumor, Jurkat. The transfected gene was actively transcribed in these human cells and high levels of Thy-1.2 glycoprotein were found on the cell membrane. Although certain mAbs to Thy-1.2 failed to bind to the Thy-1 transfected Jurkat cells, several known mitogenic anti-Thy-1 mAbs did react, and in the presence of phorbol ester, induced IL-2 secretion. One Thy-1+ transfectant out of five failed to produce IL-2 in response to anti-T3/Ti antibodies even though it retained the ability to increase intracytoplasmic calcium concentration [( Ca2+]i) in response to these ligands. A Thy-1 negative revertant of this cell regained anti-T3/Ti reactivity, suggesting a regulatory defect in signal transmission via T3/Ti in the original transfectant. These data confirm the ability of Thy-1 to act as an activation receptor for T cells. They reveal a potential role for changes in [Ca2+]i in this process, in common with other pathways of T cell activation, but also indicate a more complex series of events is involved.

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.

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 Human T cell activation. IV. T cell activation and proliferation via the early activation antigen EA 1.

1989 ◽  
Vol 169 (3) ◽  
pp. 677-689 ◽  
Author(s):  
S Nakamura ◽  
S S Sung ◽  
J M Bjorndahl ◽  
S M Fu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Early Activation ◽  
Human T Cell ◽  
Accessory Cells ◽  
Activation Antigen

A new mAb G38 was generated against purified EA 1, an early activation antigen. In immunoprecipitation, it was reactive with the same complex precipitated by the initial anti-EA 1 mAb P8. mAb G38 augmented PMA-induced proliferation of PBMC. It was shown to be mitogenic for purified T cells in collaboration with PMA in a dose-dependent manner. This effect was independent of monocytes and other accessory cells. mAb G38 augmented PMA-induced IL-2-R expression. In conjunction with PMA, it induced IL-2 synthesis and secretion. Its effects on IL-2-R and IL-2 expression were documented at both protein and mRNA levels. Both anti-EA 1 mAbs did not induce Ca2+ influx by themselves in PMA-treated T cells. However, the addition of second anti-mouse Ig antibodies induced readily detectable increases in [Ca2+]i. Ca2+-mediated pathways may be utilized as the transduction signal mechanisms. mAb Leu-23 was shown to be reactive with EA 1. mAb Leu-23 was also mitogenic for T cells in the presence of PMA. These findings provide evidence for a functional role for EA 1 in T cell activation and proliferation.

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