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Calcium signalling in T cells.
Trebak, M, Kinet, JP
Nature reviews. Immunology. 2019;(3):154-169
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Abstract
Calcium (Ca2+) signalling is of paramount importance to immunity. Regulated increases in cytosolic and organellar Ca2+ concentrations in lymphocytes control complex and crucial effector functions such as metabolism, proliferation, differentiation, antibody and cytokine secretion and cytotoxicity. Altered Ca2+ regulation in lymphocytes leads to various autoimmune, inflammatory and immunodeficiency syndromes. Several types of plasma membrane and organellar Ca2+-permeable channels are functional in T cells. They contribute highly localized spatial and temporal Ca2+ microdomains that are required for achieving functional specificity. While the mechanistic details of these Ca2+ microdomains are only beginning to emerge, it is evident that through crosstalk, synergy and feedback mechanisms, they fine-tune T cell signalling to match complex immune responses. In this article, we review the expression and function of various Ca2+-permeable channels in the plasma membrane, endoplasmic reticulum, mitochondria and endolysosomes of T cells and their role in shaping immunity and the pathogenesis of immune-mediated diseases.
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Coeliac Disease and Mast Cells.
Frossi, B, De Carli, M, Calabrò, A
International journal of molecular sciences. 2019;(14)
Abstract
Over the last decades, there has been an impressive progress in our understanding of coeliac disease pathogenesis and it has become clear that the disorder is the final result of complex interactions of environmental, genetic, and immunological factors. Coeliac disease is now considered a prototype of T-cell-mediated disease characterized by loss of tolerance to dietary gluten and the targeted killing of enterocytes by T-cell receptor αβ intraepithelial lymphocytes. Accumulating evidence, however, indicates that the induction of a gluten-specific T helper-1 response must be preceded by the activation of the innate immune system. Mast cells are key players of the innate immune response and contribute to the pathogenesis of a multitude of diseases. Here, we review the results of studies aimed at investigating the role of mast cells in the pathogenesis of coeliac disease, showing that these cells increase in number during the progression of the disease and contribute to define a pro-inflammatory microenvironment.
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3.
Universal CARs, universal T cells, and universal CAR T cells.
Zhao, J, Lin, Q, Song, Y, Liu, D
Journal of hematology & oncology. 2018;(1):132
Abstract
Currently, the two approved T cell products with chimeric antigen receptors (CAR) are from autologous T cells. These CAR T cells approved for clinical use must be generated on a custom-made basis. This case-by-case autologous T cell production platform remains a significant limiting factor for large-scale clinical application due to the costly and lengthy production process. There is also an inherent risk of production failure. The individualized, custom-made autologous CAR T cell production process also posts constriction on the wide application on diverse tumor types. Therefore, universal allogeneic T cells are needed for the preparation of universal CAR T cells that can serve as the "off-the-shelf" ready-to-use therapeutic agents for large-scale clinical applications. Genome-editing technologies including ZFN (zinc finger nuclease), TALEN (transcription activator-like effector nuclease), and CRISPR-Cas9 are being used to generate the universal third-party T cells. In addition, split, universal, and programmable (SUPRA) CARs are being developed to enhance the flexibility and controllability of CAR T cells. The engineered universal T cells and universal CARs are paving the road for a totally new generation of CAR T cells capable of targeting multiple antigens and/ or being delivered to multiple recipients without re-editing of T cells. This may escalate to a new wave of revolution in cancer immunotherapy. This review summarized the latest advances on designs and development of universal CARs, universal T cells, and clinical application of universal CAR T cells.
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Survival of the fittest: Cancer challenges T cell metabolism.
Franchina, DG, He, F, Brenner, D
Cancer letters. 2018;:216-223
Abstract
T cells represent the major contributors to antitumor-specific immunity among the tumor-infiltrating lymphocytes. However, tumors acquire ways to evade immunosurveillance and anti-tumor responses are too weak to eradicate the disease. T cells are often functionally impaired as a result of interaction with, or signals from, transformed cells and the tumor microenvironment, including stromal cells. Among these, nutrients use and consumption is critically important for the control of differentiation and effector mechanisms of T cells. Moreover, Treg cells-skewing conditions often coexist within the cancer milieu, which sustains the notion of immune privileged tumors. Additionally, cancer cells contend with tumor infiltrating lymphocytes for nutrients and can outcompete the immune response. PD1- and CTLA-based immunotherapies partially remodel cell metabolism leading the way to clinical approaches of metabolic reprogramming for therapeutic purposes. Here we shortly discuss T cell fates during anti-tumor immune responses and how signals within tumor microenvironment influence T cell metabolism, altering functions and longevity of the cell.
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5.
Gene-knocked out chimeric antigen receptor (CAR) T cells: Tuning up for the next generation cancer immunotherapy.
Mirzaei, HR, Pourghadamyari, H, Rahmati, M, Mohammadi, A, Nahand, JS, Rezaei, A, Mirzaei, H, Hadjati, J
Cancer letters. 2018;:95-104
Abstract
Recently clinical trials utilizing genetically engineered T cells expressing a chimeric antigen receptor (CAR) that is half monoclonal antibody and half T-cell receptor have demonstrated remarkable response in patients with advanced cancers like relapsed or refractory acute lymphoblastic leukemia (ALL) and lymphoma. Moreover, emerging chimeric genome editing tools such as zinc-finger nucleases (ZNFs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas composed of sequence-specific DNA binding module(s) linked to a non-specific DNA cleavage domain have made possible to dramatically expand the ability to manipulate cells aim to treat and/or study a wide range of diseases including cancer. Here, we will discuss how joint application of these two chimeras will help us to manipulate CAR T cells aiming to enhance the efficacy of CAR T cell therapy in preclinical and clinical settings.
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6.
DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system.
Li, Y, Goronzy, JJ, Weyand, CM
Experimental gerontology. 2018;:118-127
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Abstract
The aging process is the major driver of morbidity and mortality, steeply increasing the risk to succumb to cancer, cardiovascular disease, infection and neurodegeneration. Inflammation is a common denominator in age-related pathologies, identifying the immune system as a gatekeeper in aging overall. Among immune cells, T cells are long-lived and exposed to intense replication pressure, making them sensitive to aging-related abnormalities. In successful T cell aging, numbers of naïve cells, repertoire diversity and activation thresholds are preserved as long as possible; in maladaptive T cell aging, protective T cell functions decline and pro-inflammatory effector cells are enriched. Here, we review in the model system of rheumatoid arthritis (RA) how maladaptive T cell aging renders the host susceptible to chronic, tissue-damaging inflammation. In T cells from RA patients, known to be about 20years pre-aged, three interconnected functional domains are altered: DNA damage repair, metabolic activity generating energy and biosynthetic precursor molecules, and shaping of plasma membranes to promote T cell motility. In each of these domains, key molecules and pathways have now been identified, including the glycolytic enzymes PFKFB3 and G6PD; the DNA repair molecules ATM, DNA-PKcs and MRE11A; and the podosome marker protein TKS5. Some of these molecules may help in defining targetable pathways to slow the T cell aging process.
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T-cells and their cytokine production: The anti-inflammatory and immunosuppressive effects of strenuous exercise.
Shaw, DM, Merien, F, Braakhuis, A, Dulson, D
Cytokine. 2018;:136-142
Abstract
Strenuous exercise bouts and heavy training are associated with a heightened anti-inflammatory state and a transient suppression of several immune components. In turn, many athletes are susceptible to illness, particularly upper respiratory symptoms (e.g. cough, sore throat, running nose). T-lymphocytes (T-cells) are important for orchestrating the immune response and can be categorised into subsets according to their phenotypical characteristics resulting from polarisation (i.e. type-1, type-2 and regulatory T-cells). Each T-cell subset has a unique functional role, including their capacity to produce pro- and anti-inflammatory cytokines in response to an immune challenge. Prolonged and exhaustive exercise typically reduces peripheral blood type-1 T-cell number and their capacity to produce the pro-inflammatory cytokine, interferon-γ. Moreover, heavy training loads are associated with elevated numbers of resting peripheral blood type-2 and regulatory T-cells, which characteristically produce the anti-inflammatory cytokines, interleukin-4 and interleukin-10, respectively. This appears to increase the risk of upper respiratory symptoms, potentially due to the cross-regulatory effect of interleukin-4 on interferon-γ production and immunosuppressive action of IL-10. Catecholamines significantly influence the number of peripheral blood T-cells in response to exercise. Whereas, glucocorticoids and prostaglandin E2 promote the production of anti-inflammatory cytokines by T-cells. In summary, strenuous exercise bouts and heavy training shifts T-cell immunity towards an anti-inflammatory state. This impairs the ability of the immune system to mount an inflammatory response to an immune challenge, which may weaken defences against intracellular pathogens (e.g. viruses), and increase the risk of infection and viral reactivation.
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8.
Genome-Editing Technologies in Adoptive T Cell Immunotherapy for Cancer.
Singh, N, Shi, J, June, CH, Ruella, M
Current hematologic malignancy reports. 2017;(6):522-529
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Abstract
PURPOSE OF REVIEW In this review, we discuss the most recent developments in gene-editing technology and discuss their application to adoptive T cell immunotherapy. RECENT FINDINGS Engineered T cell therapies targeting cancer antigens have demonstrated significant efficacy in specific patient populations. Most impressively, CD19-directed chimeric antigen receptor T cells (CART19) have led to impressive responses in patients with B-cell leukemia and lymphoma. CTL019, or KYMRIAH™ (tisagenlecleucel), a CD19 CAR T cell product developed by Novartis and the University of Pennsylvania, was recently approved for clinical use by the Food and Drug Administration, representing a landmark in the application of adoptive T cell therapies. As CART19 enters routine clinical use, improving the efficacy of this exciting platform is the next step in broader application. Novel gene-editing technologies like CRISPR-Cas9 allow facile editing of specific genes within the genome, generating a powerful platform to further optimize the activity of engineered T cells.
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Update of syncytiotrophoblast derived extracellular vesicles in normal pregnancy and preeclampsia.
Tannetta, D, Masliukaite, I, Vatish, M, Redman, C, Sargent, I
Journal of reproductive immunology. 2017;:98-106
Abstract
The release of extracellular vesicles (EV) by the syncytiotrophoblast (STB) may be an important mechanism by which the placenta signals to the mother. STB derived EV (STBEV) are comprised predominantly of exosomes (50-150nm) and microvesicles (100-1000nm) that contain bioactive mediators such as proteins, nucleic acids and lipids. They, along with larger syncytial nuclear aggregates are released by the STB into the maternal circulation throughout gestation in normal pregnancy where they appear to have an immunoregulatory role, inhibiting T cell and NK cell responses. In pre-eclampsia (PE) STBEV are released in significantly increased numbers and have pro-inflammatory, anti-angiogenic and procoagulant activity, implicating them in the maternal systemic inflammation, endothelial dysfunction and activation of the clotting system which typifies the disorder. Research has focused on understanding the biological significance of STBEV by measuring their size and repertoire of molecules carried and how they differ in normal pregnancy and PE, using techniques such as Nanoparticle Tracking Analysis, flow cytometry and mass spectrometry. We have also found alterations in STBEV surface glycans associated with PE. The goal is to better understand the role STBEV play in normal pregnancy and PE and whether they are potential biomarkers of placental pathology and therapeutic targets in PE.
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T Cell Populations and Functions Are Altered in Human Obesity and Type 2 Diabetes.
Touch, S, Clément, K, André, S
Current diabetes reports. 2017;(9):81
Abstract
PURPOSE OF THE REVIEW Obesity and type 2 diabetes (T2D) are considered chronic inflammatory diseases. While early publications have reported the implication of innate immune cells such as macrophages to promote systemic inflammation and metabolic dysfunctions, recent publications underline the alterations of the T cell compartment in human obesity and type 2 diabetes. These recent findings are the focus of this review. RECENT FINDINGS In humans, obesity and T2D induce the expansion of proinflammatory T cells such as CD4 Th1, Th17, and CD8 populations, whereas innate T cells such as MAIT and iNKT cells are decreased. These alterations reflect a loss of total T cell homeostasis that may contribute to tissue and systemic inflammation. Whether these changes are adaptive to nutritional variations and/or contribute to the progression of metabolic diseases remains to be clarified. T cell phenotyping may improve obese and/or T2D patient stratification with therapeutic and prognostic implications.