scholarly journals Integrated Metabolomic and Transcriptomic Profiling Reveals Novel Activation-Induced Metabolic Networks in Human T cells

2019 ◽  
Author(s):  
S. Hiemer ◽  
S. Jatav ◽  
J. Jussif ◽  
J. Alley ◽  
S. Lathwal ◽  
...  
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
Metabolic Pathways ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Cell Function ◽  
Immune Cell ◽  
Transcriptomic Profiling ◽  
Human T Cell

AbstractThe targeting of metabolic pathways is emerging as an exciting new approach for modulating immune cell function and polarization states. In this study, carbon tracing and systems biology approaches integrating metabolomic and transcriptomic profiling data were used to identify adaptations in human T cell metabolism important for fueling pro-inflammatory T cell function. Results of this study demonstrate that T cell receptor (TCR) stimulation leads to a significant increase in glucose and amino acid metabolism that trigger downstream biosynthetic processes. Specifically, increased expression of several enzymes such as CTPS1, IL4I1, and ASL results in the reprogramming of amino acid metabolism. Additionally, the strength of TCR signaling resulted in different metabolic enzymes utilized by T cells to facilitate similar biochemical endpoints. Furthermore, this study shows that cyclosporine represses the pathways involved in amino acid and glucose metabolism, providing novel insights on the immunosuppressive mechanisms of this drug. To explore the implications of the findings of this study in clinical settings, conventional immunosuppressants were tested in combination with drugs that target metabolic pathways. Results showed that such combinations increased efficacy of conventional immunosuppressants. Overall, the results of this study provide a comprehensive resource for identifying metabolic targets for novel combinatorial regimens in the treatment of intractable immune diseases.

scholarly journals Amino Acid Metabolism in Lupus

2021 ◽  
Vol 12 ◽  
Author(s):  
Michihito Kono ◽  
Nobuya Yoshida ◽  
George C. Tsokos
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
T Cell Activation ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Cell Metabolism ◽  
Cell Subset ◽  
Metabolic Reprogramming ◽  
Acid Oxidation

T cell metabolism is central to cell proliferation, survival, differentiation, and aberrations have been linked to the pathophysiology of systemic autoimmune diseases. Besides glycolysis and fatty acid oxidation/synthesis, amino acid metabolism is also crucial in T cell metabolism. It appears that each T cell subset favors a unique metabolic process and that metabolic reprogramming changes cell fate. Here, we review the mechanisms whereby amino acid transport and metabolism affects T cell activation, differentiation and function in T cells in the prototype systemic autoimmune disease systemic lupus erythematosus. New insights in amino acid handling by T cells should guide approaches to correct T cell abnormalities and disease pathology.

scholarly journals Comprehensive transcriptome and metabolome profiling reveal metabolic mechanisms of Nitraria sibirica Pall. to salt stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Huanyong Li ◽  
Xiaoqian Tang ◽  
Xiuyan Yang ◽  
Huaxin Zhang
Keyword(s):  
Salt Stress ◽  
Amino Acid ◽  
Salt Tolerance ◽  
Metabolic Pathways ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Sulfur Metabolism ◽  
Enrichment Analysis ◽  
Extracellular Region ◽  
Nitraria Sibirica

AbstractNitraria sibirica Pall., a typical halophyte that can survive under extreme drought conditions and in saline-alkali environments, exhibits strong salt tolerance and environmental adaptability. Understanding the mechanism of molecular and physiological metabolic response to salt stress of plant will better promote the cultivation and use of halophytes. To explore the mechanism of molecular and physiological metabolic of N. sibirica response to salt stress, two-month-old seedlings were treated with 0, 100, and 400 mM NaCl. The results showed that the differentially expressed genes between 100 and 400 mmol L−1 NaCl and unsalted treatment showed significant enrichment in GO terms such as binding, cell wall, extemal encapsulating structure, extracellular region and nucleotide binding. KEGG enrichment analysis found that NaCl treatment had a significant effect on the metabolic pathways in N. sibirica leaves, which mainly including plant-pathogen interaction, amino acid metabolism of the beta alanine, arginine, proline and glycine metabolism, carbon metabolism of glycolysis, gluconeogenesis, galactose, starch and sucrose metabolism, plant hormone signal transduction and spliceosome. Metabolomics analysis found that the differential metabolites between the unsalted treatment and the NaCl treatment are mainly amino acids (proline, aspartic acid, methionine, etc.), organic acids (oxaloacetic acid, fumaric acid, nicotinic acid, etc.) and polyhydric alcohols (inositol, ribitol, etc.), etc. KEGG annotation and enrichment analysis showed that 100 mmol L−1 NaCl treatment had a greater effect on the sulfur metabolism, cysteine and methionine metabolism in N. sibirica leaves, while various amino acid metabolism, TCA cycle, photosynthetic carbon fixation and sulfur metabolism and other metabolic pathways have been significantly affected by 400 mmol L−1 NaCl treatment. Correlation analysis of differential genes in transcriptome and differential metabolites in metabolome have found that the genes of AMY2, BAM1, GPAT3, ASP1, CML38 and RPL4 and the metabolites of L-cysteine, proline, 4-aminobutyric acid and oxaloacetate played an important role in N. sibirica salt tolerance control. This is a further improvement of the salt tolerance mechanism of N. sibirica, and it will provide a theoretical basis and technical support for treatment of saline-alkali soil and the cultivation of halophytes.

scholarly journals The Diverse Functions of Non-Essential Amino Acids in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 675 ◽  
Author(s):  
Bo-Hyun Choi ◽  
Jonathan L. Coloff
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Therapy ◽  
Metabolic Pathways ◽  
Essential Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Essential Amino Acids ◽  
Redox Status ◽  
Antioxidant Systems

Far beyond simply being 11 of the 20 amino acids needed for protein synthesis, non-essential amino acids play numerous important roles in tumor metabolism. These diverse functions include providing precursors for the biosynthesis of macromolecules, controlling redox status and antioxidant systems, and serving as substrates for post-translational and epigenetic modifications. This functional diversity has sparked great interest in targeting non-essential amino acid metabolism for cancer therapy and has motivated the development of several therapies that are either already used in the clinic or are currently in clinical trials. In this review, we will discuss the important roles that each of the 11 non-essential amino acids play in cancer, how their metabolic pathways are linked, and how researchers are working to overcome the unique challenges of targeting non-essential amino acid metabolism for cancer therapy.

Xuebijing Injection Affects the Dynamic Change of Metabolism in CLP-Induced Septic Rats

2021 ◽  
Author(s):  
Yanjuan Liu ◽  
Qi Zeng ◽  
Wen Xiao ◽  
Fang Chen ◽  
Lianhong Zou ◽  
...  
Keyword(s):  
Amino Acid ◽  
Metabolic Pathways ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Dynamic Change ◽  
Sepsis Group ◽  
Control Group ◽  
Multivariate Statistical ◽  
Xuebijing Injection ◽  
Kegg Pathway Analysis

Abstract Xuebijing injection has been widely applied to treat sepsis. However, its roles in the dynamic change of metabolism in sepsis are still unknown. In our study, Gas chromatography-mass spectrometer (GC-MS) combined with multivariate statistical techniques was used to detect the metabolic change in septic rats with or without XBJ injection treatment. The KEGG pathway analysis was used to further analyze the related metabolic pathways in which the identified metabolites were involved. Based on the fold change, variable important in projection, and P value, we found 11, 33 and 26 differential metabolites in the sepsis group at 2, 6 and 12 hours post CLP, compared with the control group. Besides, we also found 32, 23 and 28 differential metabolites in the XBJ group at 2, 6 and 12 hours post CLP. The related pathways of differential metabolites were glycometabolism at 2h, glycometabolism and amino acid metabolism at 6h and amino acid metabolism at 12h post CLP in the sepsis group compared with the control group. Besides, glycometabolism, amino acid metabolism and lipid metabolism changed markedly after XBJ injection for 2 hours; while only amino acid metabolism changed significantly with the treatment of XBJ injection for 6 and 12 hours, compared with the sepsis group. Further analysis showed 3, 6 and 6 differential metabolites were overlapped in the sepsis group and XBJ group at 2, 6 and 12 hours post CLP. These identified differential metabolites were majorly involved in arginine and proline metabolism, suggesting that XBJ injection is capable of improving metabolic disorders in CLP-induced septic rat to a certain extent.

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.

scholarly journals Neuroblastoma formation requires unconventional CD4 T cells and myeloid amino acid metabolism

2021 ◽  
Author(s):  
Lee-Ann Van de Velde ◽  
E. Kaitlynn Allen ◽  
Jeremy Chase Crawford ◽  
Taylor L. Wilson ◽  
Clifford S. Guy ◽  
...  
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
B Cells ◽  
Tumor Growth ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Myeloid Cells ◽  
Tumor Formation ◽  
Arginase 1 ◽  
Longitudinal Imaging

SummaryBy mirroring their function as tissue repair organizers in normal tissues, immune cells regulate tumor growth. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunological manipulation with non-invasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Using spatial transcriptomic analysis, we co-localized CD4+ and myeloid populations within the tumor parenchyma, while CD8+ T cells and B cells were peripherally dispersed. Depletion of CD4+ T cells or CCR2+ macrophages, but not B cells, CD8+, or NK cells, prevented tumor formation. Tumor CD4+ T cells displayed unconventional phenotypes, were clonotypically diverse, and antigen-independent. Within the myeloid fraction, tumor growth required myeloid cells expressing Arginase-1. Overall, our results suggest that arginine-metabolizing myeloid cells conspire with pathogenic CD4+ T cells to create permissive conditions for tumor formation, and therefore suggest that these pro-tumorigenic pathways can be disabled by targeting myeloid amino acid metabolism.

scholarly journals Tumors induce de novo steroid biosynthesis in T cells to evade immunity

2018 ◽  
Author(s):  
Bidesh Mahata ◽  
Jhuma Pramanik ◽  
Louise van der Weyden ◽  
Krzysztof Polanski ◽  
Gozde Kar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Immunity ◽  
Cell Function ◽  
Immune Cell ◽  
De Novo ◽  
Steroid Biosynthesis ◽  
Genetic Ablation ◽  
Tumor Immunosuppression

ABSTRACTTumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a novel transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway was sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

scholarly journals A multivariate, quantitative assay that disentangles key kinetic parameters of primary human T cell function in vitro

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241421
Author(s):  
Grace L. Huang ◽  
Daniel P. Nampe ◽  
Jason Yi ◽  
Grant B. Gabrelow ◽  
Kathleen R. Negri ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Limiting Factor ◽  
Preclinical Development ◽  
Effector Cells ◽  
Recent Success ◽  
Natural Ligand ◽  
Human T Cell

Cell therapy is poised to play a larger role in medicine, most notably for immuno-oncology. Despite the recent success of CAR-T therapeutics in the treatment of blood tumors and the rapid progress toward improved versions of both CAR- and TCR-Ts, important analytical aspects of preclinical development and manufacturing of engineered T cells remain immature. One limiting factor is the absence of robust multivariate assays to disentangle key parameters related to function of engineered effector cells, especially in the peptide-MHC (pMHC) target realm, the natural ligand for TCRs. Here we describe an imaging-based primary T cell assay that addresses several of these limitations. To our knowledge, this assay is the first quantitative, high-content assay that separates the key functional parameters of time- and antigen-dependent T cell proliferation from cytotoxicity. We show that the assay sheds light on relevant biology of CAR- and TCR-T cells, including response kinetics and the influence of effector:target ratio.

scholarly journals Sprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases

PLoS Biology ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. e3001063
Author(s):  
Anand Sripada ◽  
Kapil Sirohi ◽  
Lidia Michalec ◽  
Lei Guo ◽  
Jerome T. McKay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Airway Hyperreactivity ◽  
Mouse Strains ◽  
Caveolin 1 ◽  
T Cell Function ◽  
Human T Cell ◽  
Extracellular Signal

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell–targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2−/− CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4+ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1–bound CSK restored ERK1/2 activation in Spry2−/− T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.

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.

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