scholarly journals Induction of T Cell Senescence by Cytokine Induced Bystander Activation

2021 ◽  
Vol 2 ◽  
Author(s):  
Attiya A. Abbas ◽  
Arne N. Akbar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Critical Role ◽  
The Elderly ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Tcr Signaling ◽  
Bystander Activation

As people around the world continue to live longer, maintaining a good quality of life is of increasing importance. The COVID-19 pandemic revealed that the elderly are disproportionally vulnerable to infectious diseases and Immunosenescence plays a critical role in that. An ageing immune system influences the conventional activity of T cells which are at the forefront of eliminating harmful foreign antigens. With ageing, unconventional end-stage T cells, that exhibit a senescent phenotype, amass. These senescent T cells deviate from T cell receptor (TCR) signaling toward natural killer (NK) activity. The transition toward innate immune cell function from these adaptor T cells impacts antigen specificity, contributing to increased susceptibility of infection in the elderly. The mechanism by which senescent T cells arise remains largely unclear however in this review we investigate the part that bystander activation plays in driving the change in function of T cells with age. Cytokine-induced bystander activation may offer a plausible explanation for the induction of NK-like activity and senescence in T cells. Further understanding of these specific NK-like senescent T cells allows us to identify the benefits and detriments of these cells in health and disease which can be utilized or regulated, respectively. This review discusses the dynamic of senescent T cells in adopting NK-like T cells and the implications that has in an infectious disease context, predominately in the elderly.

scholarly journals Single-cell transcriptomics identifies multiple pathways underlying antitumor function of TCR- and CD8αβ-engineered human CD4+ T cells

2020 ◽  
Vol 6 (27) ◽  
pp. eaaz7809 ◽  
Author(s):  
Jan A. Rath ◽  
Gagan Bajwa ◽  
Benoit Carreres ◽  
Elisabeth Hoyer ◽  
Isabelle Gruber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cell Function ◽  
Xenograft Model ◽  
Cell Receptor ◽  
Target Cells ◽  
Antigen Specificity ◽  
Molecular Features ◽  
Mouse Xenograft Model

Transgenic coexpression of a class I–restricted tumor antigen–specific T cell receptor (TCR) and CD8αβ (TCR8) redirects antigen specificity of CD4+ T cells. Reinforcement of biophysical properties and early TCR signaling explain how redirected CD4+ T cells recognize target cells, but the transcriptional basis for their acquired antitumor function remains elusive. We, therefore, interrogated redirected human CD4+ and CD8+ T cells by single-cell RNA sequencing and characterized them experimentally in bulk and single-cell assays and a mouse xenograft model. TCR8 expression enhanced CD8+ T cell function and preserved less differentiated CD4+ and CD8+ T cells after tumor challenge. TCR8+CD4+ T cells were most potent by activating multiple transcriptional programs associated with enhanced antitumor function. We found sustained activation of cytotoxicity, costimulation, oxidative phosphorylation– and proliferation-related genes, and simultaneously reduced differentiation and exhaustion. Our study identifies molecular features of TCR8 expression that can guide the development of enhanced immunotherapies.

scholarly journals Conclusive Identification of Senescent T Cells Reveals Their Abundance in Aging Humans

2020 ◽  
Author(s):  
Ricardo Iván Martínez-Zamudio ◽  
Hannah K. Dewald ◽  
Themistoklis Vasilopoulos ◽  
Lisa Gittens-Williams ◽  
Patricia Fitzgerald-Bocarsly ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Function ◽  
Immune Cell ◽  
Functional Decline ◽  
The Elderly ◽  
Cd8 T Cell ◽  
Cell Senescence ◽  
Healthy Humans

ABSTRACTAging leads to a progressive functional decline of the immune system, which renders the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this functional decline, however, remains unclear since methods to accurately identify and isolate senescent immune cells are missing. By measuring senescence-associated ß-galactosidase activity, a hallmark of senescent cells, we demonstrate here that healthy humans develop senescent T lymphocytes in peripheral blood with advancing age. Particularly senescent CD8+ T cells increased in abundance with age, ranging from 30% of the total CD8+ T cell population in donors in their 20s and reaching levels of 64% in donors in their 60s. Senescent CD8+ T cell populations displayed features of telomere dysfunction-induced senescence as well as p16-mediated senescence, developed in various T cell differentiation states and established gene expression signatures consistent with the senescence state observed in other cell types. On the basis of our results we propose that cellular senescence of T lymphocytes is a major contributing factor to the observed decline of immune cell function with advancing age and that immune cell senescence, therefore, plays a significant role in the increased susceptibility of the elderly to age-associated diseases and infection.

scholarly journals Exhausted CD8+ T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ioana Sandu ◽  
Dario Cerletti ◽  
Manfred Claassen ◽  
Annette Oxenius
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Viral Infections ◽  
Cell Receptor ◽  
Target Cells ◽  
Tcr Signaling ◽  
And Function

Abstract Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+ T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8+ T cell signaling and function in vivo.

scholarly journals The transcriptional repressor HIC1 regulates intestinal immune homeostasis

2016 ◽  
Author(s):  
Kyle Burrows ◽  
Frann Antignano ◽  
Michael Bramhall ◽  
Alistair Chenery ◽  
Sebastian Scheer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vitamin A ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Central Component ◽  
Food Antigens

ABSTRACTThe intestine is a unique immune environment that must respond to infectious organisms but remain tolerant to commensal microbes and food antigens. However, the molecular mechanisms that regulate immune cell function in the intestine remain unclear. Here we identify the POK/ZBTB family transcription factor Hypermethylated in cancer 1 (HIC1, ZBTB29) as a central component of immunity and inflammation in the intestine. HIC1 is specifically expressed in immune cells in the intestinal lamina propria (LP) in the steady state and mice with a T cell-specific deletion of HIC1 have reduced numbers of T cells in the LP. HIC1 expression is regulated by the Vitamin A metabolite retinoic acid, as mice raised on a Vitamin A-deficient diet lack HIC1-positive cells in the intestine. HIC1-deficient T cells overproduce IL-17A in vitro and in vivo, and fail to induce intestinal inflammation, identifying a critical role for HIC1 in the regulation of T cell function in the intestinal microenvironment under both homeostatic and inflammatory conditions.

scholarly journals Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8+ T Cells

Vaccines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1294
Author(s):  
Richard M. Powell ◽  
Marlies J. W. Peeters ◽  
Anne Rahbech ◽  
Pia Aehnlich ◽  
Tina Seremet ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tyrosine Kinases ◽  
Cell Function ◽  
Immune Cell ◽  
Ex Vivo ◽  
Cell Receptor ◽  
Induce Cell Cycle Arrest

There is an increasing interest in the development of Receptor Tyrosine Kinases inhibitors (RTKIs) for cancer treatment, as dysregulation of RTK expression can govern oncogenesis. Among the newer generations of RTKIs, many target Mer Tyrosine Kinase (MERTK) and Fms related RTK 3 (FLT3). Next to being overexpressed in many cancers, MERTK and FLT3 have important roles in immune cell development and function. In this study, we address how the new generation and potent RTKIs of MERTK/FLT3 affect human primary CD8+ T cell function. Using ex vivo T cell receptor (TCR)-activated CD8+ T cells, we demonstrate that use of dual MERTK/FLT3 inhibitor UNC2025 restricts CD8+ T proliferation at the G2 phase, at least in part by modulation of mTOR signaling. Cytokine production and activation remain largely unaffected. Finally, we show that activated CD8+ T cells express FLT3 from day two post activation, and FLT3 inhibition with AC220 (quizartinib) or siRNA-mediated knockdown affects cell cycle kinetics. These results signify that caution is needed when using potent RTKIs in the context of antitumor immune responses.

scholarly journals MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function

2020 ◽  
Vol 21 (17) ◽  
pp. 6200
Author(s):  
Zoe Grewers ◽  
Andreas Krueger
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Signal Strength ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Cell Repertoire ◽  
T Cell Function ◽  
Complex Process ◽  
Peripheral T Cells

The selection of T cells during intra-thymic d evelopment is crucial to obtain a functional and simultaneously not self-reactive peripheral T cell repertoire. However, selection is a complex process dependent on T cell receptor (TCR) thresholds that remain incompletely understood. In peripheral T cells, activation, clonal expansion, and contraction of the active T cell pool, as well as other processes depend on TCR signal strength. Members of the microRNA (miRNA) miR-181 family have been shown to be dynamically regulated during T cell development as well as dependent on the activation stage of T cells. Indeed, it has been shown that expression of miR-181a leads to the downregulation of multiple phosphatases, implicating miR-181a as ‘‘rheostat’’ of TCR signaling. Consistently, genetic models have revealed an essential role of miR-181a/b-1 for the generation of unconventional T cells as well as a function in tuning TCR sensitivity in peripheral T cells during aging. Here, we review these broad roles of miR-181 family members in T cell function via modulating TCR signal strength.

scholarly journals 166. TGF-β Restricts T-cell IFNg Production in Pulmonary Tuberculous Granulomas

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S16-S16
Author(s):  
Benjamin Gern ◽  
Kristin Adams ◽  
Courtney Plumlee ◽  
Michael Gerner ◽  
Kevin Urdahl
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Conditional Knockout ◽  
Antigen Specificity ◽  
Tcr Signaling ◽  
Infected Cells ◽  
Ifng Production

Abstract Background IFNg production by CD4 T cells has been thought to be critical for immunity against Mycobacterium tuberculosis (Mtb); however, recent studies show that IFNg-producing CD4 T cells are more effective at preventing dissemination than controlling Mtb in the lung. Because optimal control of Mtb infection requires direct interactions between CD4 T cells and Mtb-infected cells presenting cognate antigen on MHCII, we sought to determine the location of CD4 T-cell antigen recognition and IFNg production in the Mtb-infected lung. Methods We infected mice with an ultra-low dose (ULD) of Mtb (1–3 CFU), a model developed in our laboratory which results in well-circumscribed granulomas that recapitulate many features of human Mtb granulomas. Using immunohistochemistry and quantitative imaging, we examined their lungs 35 days later for phenotypic and spatial analysis of T-cell receptor (TCR) signaling (using IRF4) and IFNγ production. We tested the antigen specificity of these responses with an adoptive transfer of both Mtb-specific and OVA-specific control CD4 T cells into ULD Mtb-infected mice. To assess the role of TGFβ signaling on T-cell localization and function, we performed the same analysis in mice lacking the TGFβ receptor (TGFβR) on T cells. Results Within Mtb-infected lungs, many T cells localize near Mtb cells and undergo TCR signaling. Despite this, we found very few cells producing IFNγ within the granuloma (Figure 1). In our adoptive transfer experiment, both cell types infiltrated the granuloma. The Mtb-specific, but not OVA-specific, T cells had active TCR engagement though only a small fraction of these cells produced IFNγ, and this IFNγ was diminished near Mtb (Figure 2). Conversely, in the TGFβR conditional knockout, we found increased IFNγ production that was highest within the granuloma (Figure 3). Conclusion Despite ongoing TCR stimulation in T cells, IFNγ production is restricted in areas where cognate interactions are most likely to occur. TGFβ plays a critical role in mediating this effect, as T cells lacking the receptor can produce more IFNγ near infected cells. These findings help explain why IFNγ-producing T cells have limited capacity to control pulmonary Mtb infection and could guide new strategies for vaccine and immunotherapeutic development. Disclosures All authors: No reported disclosures.

scholarly journals The GSK3β-β-catenin-TCF1 pathway improves naive T cell activation in old adults by upregulating miR-181a

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhongde Ye ◽  
Timothy M. Gould ◽  
Huimin Zhang ◽  
Jun Jin ◽  
Cornelia M. Weyand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
The Elderly ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers ◽  
Old Adults ◽  
Tcr Activation

AbstractMicroRNAs play an important role in the regulation of T cell development, activation, and differentiation. One of the most abundant microRNAs in lymphocytes is miR-181a, which controls T cell receptor (TCR) activation thresholds in thymic selection as well as in peripheral T cell responses. We previously found that miR-181a levels decline in T cells in the elderly. In this study, we identified TCF1 as a transcriptional regulator of pri-miR-181a. A decline in TCF1 levels in old individuals accounted for the reduced miR-181a expression impairing TCR signaling. Inhibition of GSK3ß restored expression of miR-181a by inducing TCF1 in T cells from old adults. GSK3ß inhibition enhanced TCR signaling to increase downstream expression of activation markers and production of IL-2. The effect involved the upregulation of miR-181a and the inhibition of DUSP6 expression. Thus, inhibition of GSK3ß can restore responses of old T cells by inducing miR-181a expression through TCF1.

scholarly journals N6-adenosine methylation of mRNAs requires Wtap expression and controls T cell receptor signaling and survival

2021 ◽  
Author(s):  
Vigo Heissmeyer ◽  
Taku Ito-Kureha ◽  
Cristina Leoni ◽  
Kayla Borland ◽  
Marian Bataclan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transcriptional Repression ◽  
Cell Function ◽  
Complex Function ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
T Cell Receptor Signaling ◽  
Tcr Signal Transduction ◽  
Store Operated Calcium Entry

Abstract T cell antigen receptor (TCR) signaling controls the development, activation and survival of T cells by involving several layers and numerous mechanisms of gene regulation. N6-methyladenosine (m6A) is the most prevalent mRNA modification affecting splicing, translation and stability of transcripts. Here, we describe the Wtap protein as essential for m6A methyltransferase complex function and reveal its crucial role in TCR signaling. Wtap and m6A methyltransferase functions were required for the differentiation of thymocytes, control of activation-induced death of peripheral T cells and prevention of colitis by enabling gut RORγt+ regulatory T cell function. Transcriptome and epitranscriptomic analyses reveal that m6A modification destabilizes Orai1 and Ripk1 mRNAs. Lack of post-transcriptional repression of the encoded proteins correlated with increased store-operated calcium entry (SOCE) activity and diminished survival of T cells. These findings uncover how m6A modification impacts on TCR signal transduction and determines activation and survival of T cells.

scholarly journals Naturally Occurring Genetic Alterations in Proximal TCR Signaling and Implications for Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrew Kent ◽  
Natalie V. Longino ◽  
Allison Christians ◽  
Eduardo Davila
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cell Activity ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Tcr Signaling

T cell-based immunotherapies including genetically engineered T cells, adoptive transfer of tumor-infiltrating lymphocytes, and immune checkpoint blockade highlight the impressive anti-tumor effects of T cells. These successes have provided new hope to many cancer patients with otherwise poor prognoses. However, only a fraction of patients demonstrates durable responses to these forms of therapies and many develop significant immune-mediated toxicity. These heterogeneous clinical responses suggest that underlying nuances in T cell genetics, phenotypes, and activation states likely modulate the therapeutic impact of these approaches. To better characterize known genetic variations that may impact T cell function, we 1) review the function of early T cell receptor-specific signaling mediators, 2) offer a synopsis of known mutations and genetic alterations within the associated molecules, 3) discuss the link between these mutations and human disease and 4) review therapeutic strategies under development or in clinical testing that target each of these molecules for enhancing anti-tumor T cell activity. Finally, we discuss novel engineering approaches that could be designed based on our understanding of the function of these molecules in health and disease.

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