scholarly journals Dietary Intervention Impacts Immune Cell Functions and Dynamics by Inducing Metabolic Rewiring

2021 ◽  
Vol 11 ◽  
Author(s):  
Takuma Okawa ◽  
Motoyoshi Nagai ◽  
Koji Hase
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Dietary Intervention ◽  
Immune Cell ◽  
Aerobic Glycolysis ◽  
Acid Oxidation ◽  
Intermittent Fasting ◽  
Cell Trafficking ◽  
Cell Functions

Accumulating evidence has shown that nutrient metabolism is closely associated with the differentiation and functions of various immune cells. Cellular metabolism, including aerobic glycolysis, fatty acid oxidation, and oxidative phosphorylation, plays a key role in germinal center (GC) reaction, B-cell trafficking, and T-cell-fate decision. Furthermore, a quiescent metabolic status consolidates T-cell-dependent immunological memory. Therefore, dietary interventions such as calorie restriction, time-restricted feeding, and fasting potentially manipulate immune cell functions. For instance, intermittent fasting prevents the development of experimental autoimmune encephalomyelitis. Meanwhile, the fasting response diminishes the lymphocyte pool in gut-associated lymphoid tissue to minimize energy expenditure, leading to the attenuation of Immunoglobulin A (IgA) response. The nutritional status also influences the dynamics of several immune cell subsets. Here, we describe the current understanding of the significance of immunometabolism in the differentiation and functionality of lymphocytes and macrophages. The underlying molecular mechanisms also are discussed. These experimental observations could offer new therapeutic strategies for immunological disorders like autoimmunity.

scholarly journals Elevated expression of miR-146a correlates with high levels of immune cell exhaustion markers and suppresses cellular immune function in chronic HIV-1-infected patients

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ting Yu ◽  
Zhao Ju ◽  
Mingqi Luo ◽  
Ronghua Hu ◽  
Yan Teng ◽  
...  
Keyword(s):  
T Cell ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Inhibitory Receptors ◽  
Chronic Infections ◽  
Cell Exhaustion ◽  
Cell Functions ◽  
Cellular Immune ◽  
Hiv 1

AbstractFunctional exhaustion of immune cells is a defining characteristic of HIV-1 chronic infections, exhibiting dysregulation of cellular immune responses and expression of co-inhibitory receptors. Although the molecular mechanisms controlling immune-cell exhaustion retains largely unknown, immune checkpoint blockade strategy has shown inspiring potential to reinvigorate T cell functions in chronic infections. In this study, we investigated peripheral blood mononuclear cells (PBMCs) exhaustion markers from 109 chronic HIV-1-infected patients and found they correlated positively with microRNA-146a, which was inversely correlated with CD4+ T cell count. Intriguingly, ex vivo neutralization of miR-146a in PBMCs from chronic HIV-1 infection exhibited an elevated antiviral cytokines production as well as the expression of GZMB and perforin, while simultaneously, decreased the inhibitory receptors expression such as PD-1, CTLA-4, TIM-3 and LAG-3. These results highlight the importance of miR-146a to HIV-1 induced immune cell exhaustion, and uncover a novel layer of HIV/AIDS pathogenesis and provide potential targets for improved immune intervention.

scholarly journals Regulation of Immune Cell Functions by Metabolic Reprogramming

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Jaehong Kim
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Aerobic Glycolysis ◽  
Metabolic Changes ◽  
Metabolic Reprogramming ◽  
Functional Plasticity ◽  
Inflammatory Reactions ◽  
Cell Functions

Recent findings show that the metabolic status of immune cells can determine immune responses. Metabolic reprogramming between aerobic glycolysis and oxidative phosphorylation, previously speculated as exclusively observable in cancer cells, exists in various types of immune and stromal cells in many different pathological conditions other than cancer. The microenvironments of cancer, obese adipose, and wound-repairing tissues share common features of inflammatory reactions. In addition, the metabolic changes in macrophages and T cells are now regarded as crucial for the functional plasticity of the immune cells and responsible for the progression and regression of many pathological processes, notably cancer. It is possible that metabolic changes in the microenvironment induced by other cellular components are responsible for the functional plasticity of immune cells. This review explores the molecular mechanisms responsible for metabolic reprogramming in macrophages and T cells and also provides a summary of recent updates with regard to the functional modulation of the immune cells by metabolic changes in the microenvironment, notably the tumor microenvironment.

scholarly journals Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells

Science ◽  
2018 ◽  
Vol 361 (6407) ◽  
pp. eaao2933 ◽  
Author(s):  
Daniel DiToro ◽  
Colleen J. Winstead ◽  
Duy Pham ◽  
Steven Witte ◽  
Rakieb Andargachew ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
Immune Cell ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Immune Functions ◽  
Fate Determination ◽  
Cell Functions ◽  
Tcr Signals

In response to infection, naïve CD4+ T cells differentiate into two subpopulations: T follicular helper (TFH) cells, which support B cell antibody production, and non-TFH cells, which enhance innate immune cell functions. Interleukin-2 (IL-2), the major cytokine produced by naïve T cells, plays an important role in the developmental divergence of these populations. However, the relationship between IL-2 production and fate determination remains unclear. Using reporter mice, we found that differential production of IL-2 by naïve CD4+ T cells defined precursors fated for different immune functions. IL-2 producers, which were fated to become TFH cells, delivered IL-2 to nonproducers destined to become non-TFH cells. Because IL-2 production was limited to cells receiving the strongest T cell receptor (TCR) signals, a direct link between TCR-signal strength, IL-2 production, and T cell fate determination has been established.

scholarly journals Enhanced B7-H4 Expression in Gliomas With Low PD-L1 Expression Identifies Cold Tumors

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Di Chen ◽  
Gaopeng Li ◽  
Chunxia Ji ◽  
Qiqi Lu ◽  
Ying Qi ◽  
...  
Keyword(s):  
T Cell ◽  
Mrna Expression ◽  
Immune Cell ◽  
Expression Profiles ◽  
Tumor Infiltrating Lymphocytes ◽  
Expression Level ◽  
Cell Trafficking ◽  
Mrna Expression Level ◽  
Cell Functions ◽  
Genes Expression

Abstract INTRODUCTION The expression profiles of different immune checkpoint molecules are promising for triaging personalized targeted immunotherapy. Our study was performed to determine co-expression levels of 2 major B7 immune molecules, PD-L1 and B7-H4, in gliomas where both have demonstrated to inhibit antitumor host immunity. METHODS We assessed tumor issues from primary gliomas stage II to IV (n = 505) by immunohistochemistry (IHC) for protein levels of both PD-L1 and B7-H4. Gene co-expression analysis assessing clusters based on extent of PD-L1/B7-H4 classifier genes expression were investigated in 2 transcriptome datasets (TCGA and CGGA) to validate IHC expression profiles and explore properties of the glioma immune microenvironment among specific co-expression PD-L1/B7-H4 cluster groups. RESULTS PD-L1 was detected in 61% of patients whereby 23% expressed high levels. B7-H4 was expressed in 54% whereby 20% were identified as high expression. Co-expression of PD-L1 and B7-H4 in high levels was limited to 2% cases. Comparable results were seen in RNA-sequencing datasets when PD-L1 mRNA expression level corelated negatively with B7-H4. Gene co-expression modules clustered in each grade gliomas without double-high modules (gliomas cluster with high mRNA expression of both PD-L1 and B7-H4 classifier genes) also verified restricted coexpression pattern. B7-H4 mRNA expression level had negative correlation with extent of immune cell infiltration, including tumor-infiltrating lymphocytes (TILs), and high-B7-H4 module gliomas (high B7-H4 but low PD-L1 classifier genes expression) was related to a cold tumor with less TILs. CONCLUSION The majority of gliomas express PD-L1 or B7-H4, however, co-expression of both at high levels is minimal. The high-B7-H4 module was significantly lacking in TILs, suggesting that B7-H4 might inhibit T cell trafficking into the central nervous system (CNS). This study demonstrates that PD-L1 expression alone is not fully informative in gliomas for immune targeted or active-specific immunotherapy, and PD-L1 and B7-H4 probably inhibit different aspects of the T cell functions.

Abstract 14: An Anti-inflammatory Proton Sensing-receptor Contributes To Cardiovascular Protection Of Gut Microbiota-derived Metabolites

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Liang Xie ◽  
Rikeish R Muralitharan ◽  
Evany Dinakis ◽  
Michael E Nakai ◽  
Hamdi Jama ◽  
...  
Keyword(s):  
T Cell ◽  
Gut Microbiota ◽  
Dietary Fibre ◽  
Dietary Intervention ◽  
Immune Cell ◽  
Ang Ii ◽  
Direct Role ◽  
Cardiovascular Protection ◽  
Anti Inflammatory ◽  
The Impact

High fibre (HF) diet protects against hypertension via the production of acidic metabolites, e.g. short-chain fatty acids, by the gut microbiota. While these metabolites have a direct role in blood pressure (BP) regulation, their acidic nature may activate proton-sensing receptors, which have anti-inflammatory functions. G-protein coupled receptor 65 (GPR65) is a proton-sensing receptor activated around pH 6.5 and is critical for gut homeostasis. We hypothesized that GPR65 is involved in the cardiovascular protection by dietary fibre. We first measured cecal pH of C57BL/6 (WT) mice after a 7-day dietary intervention with either HF or low fibre (LF) diets (n=6/group). HF diet lowered cecal pH to a level where GPR65 is highly activated, compared to the LF diet (6.5±0.1 vs 7.6±0.1, P<0.001). The impact of pH and GPR65 on T cell production of IFNγ, a pro-inflammatory cytokine, in vitro was measured by flow cytometry. Acidic pH inhibited the production of IFNγ by CD8+ T cells (pH 6.5 vs pH 7.5, P<0.001). Cells lacking GPR65 had higher IFNγ at both pH (P<0.001). To determine if GPR65 is involved in BP regulation by dietary fibre, WT and GPR65 knockout ( Gpr65 -/- ) mice were implanted with minipumps containing angiotensin II (Ang II, 0.5mg/kg/day, 28 days, n=8-9/group) and fed with HF diet. BP, cardiorenal function and immune cell infiltration were measured. Gpr65 -/- mice had higher BP compared to WT mice after 2 weeks (mean arterial pressure ± SEM; WT 79.8±2.4 vs Gpr65 -/- 95.8±1.6mmHg, P<0.001) and 4 weeks of Ang II infusion (WT 92.3±2.4 vs Gpr65 -/- 99.5±1.3, P=0.062). Gpr65 -/- mice developed cardiac (P=0.035) and renal (P=0.025) hypertrophy, and impaired renal natriuretic (P=0.054) and diuretic (P=0.056) function compared to WT mice. This was accompanied by higher macrophage (P=0.009) and γδ T cell (P=0.014) infiltration in the kidneys. In conclusion, our data suggest that pH-sensing by GPR65 contributes to the protection against hypertension by dietary fibre via inflammatory mechanisms. This is a novel mechanism that contributes to BP regulation via the gut microbiota.

scholarly journals 641 Spatially organized multicellular immune hubs in MMRd and MMRp colorectal cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A670-A670
Author(s):  
Jonathan Chen ◽  
Karin Pelka ◽  
Matan Hofree ◽  
Marios Giannakis ◽  
Genevieve Boland ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Mismatch Repair ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Single Cells ◽  
Large Set ◽  
Colon Tissue

BackgroundImmune responses to cancer are highly variable, with DNA mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. Almost all tumors are infiltrated with immune cells, but the types of immune responses and their effects on tumor growth, metastasis and death, vary greatly between different cancers and individual tumors. Which of the numerous cell subsets in a tumor contribute to the response, how their interactions are regulated, and how they are spatially organized within tumors remains poorly understood.MethodsTo understand the rules governing these varied responses, we transcriptionally profiled 371,223 single cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd treatment-naive patients. We developed a systematic approach to discover cell types, their underlying gene programs, and cellular communities based on single cell RNA-seq (scRNAseq) profiles and applied it to study the distinguishing features of human MMRd and MMRp colorectal cancer. Cellular communities discovered from this analysis were spatially mapped in tissue sections using multiplex RNA in situ hybridization microscopy.ResultsTo understand the basis for differential immune responses in CRC, we first determined and compared the immune cell composition of MMRd and MMRp CRC and normal colon tissue, finding dramatic remodeling between tumor and normal tissue and between MMRd and MMRp tumors, particularly within the myeloid, T cell, and stromal compartments. Among the clusters enriched in MMRd tumors were activated CXCL13+ CD8 T cells. Importantly, gene program co-variation analysis revealed multicellular networks. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage, and an MMRd-enriched immune hub within the tumor, with activated IFNG+ and CXCL13+ T cells together with malignant and myeloid cells expressing T-cell-attracting chemokines (figure 1).ConclusionsOur study provides a rich dataset of cellular states, gene programs and their transformations in tumors across a relatively large cohort of patients with colorectal cancer. Our predictions of several multicellular hubs based on co-variation of gene expression programs, and subsequent spatial localization of two major immune-malignant hubs, organizes a large set of cell states and programs into a smaller number of coordinated networks of cells and processes. Understanding the molecular mechanisms underlying these hubs, and studying their temporal and spatial regulation upon treatment will be critical for advancing cancer therapy.Ethics ApprovalThis study was approved by the DF-HCC institutional review board (protocols 03-189 and 02-240).Abstract 641 Figure 1A coordinated network of CXCL13+ T cells with myeloid and malignant cells expressing ISGs. Image shows a portion of formalin-fixed paraffin-embedded tissue from an MMRd CRC specimen stained with multiplex RNA ISH / IF for PanCK-IF, CD3E-ISH, CXCL10/CXCL11-ISH, CXCL13-ISH, and IFNG-ISH. Note IFNG+ and CXCL13+ cells in proximity to cells expressing the chemokines CXCL10/CXCL11

scholarly journals The multi-faceted functioning portrait of LRF/ZBTB7A

2019 ◽  
Vol 13 (1) ◽  
Author(s):  
Caterina Constantinou ◽  
Magda Spella ◽  
Vasiliki Chondrou ◽  
George P. Patrinos ◽  
Adamantia Papachatzopoulou ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Aerobic Glycolysis ◽  
Specific Cell ◽  
Regulation Of Transcription ◽  
Cancer Type ◽  
Cellular Effects ◽  
Physiological Processes ◽  
Signaling Axis

AbstractTranscription factors (TFs) consisting of zinc fingers combined with BTB (for broad-complex, tram-track, and bric-a-brac) domain (ZBTB) are a highly conserved protein family that comprises a multifunctional and heterogeneous group of TFs, mainly modulating cell developmental events and cell fate. LRF/ZBTB7A, in particular, is reported to be implicated in a wide variety of physiological and cancer-related cell events. These physiological processes include regulation of erythrocyte maturation, B/T cell differentiation, adipogenesis, and thymic insulin expression affecting consequently insulin self-tolerance. In cancer, LRF/ZBTB7A has been reported to act either as oncogenic or as oncosuppressive factor by affecting specific cell processes (proliferation, apoptosis, invasion, migration, metastasis, etc) in opposed ways, depending on cancer type and molecular interactions. The molecular mechanisms via which LRF/ZBTB7A is known to exert either physiological or cancer-related cellular effects include chromatin organization and remodeling, regulation of the Notch signaling axis, cellular response to DNA damage stimulus, epigenetic-dependent regulation of transcription, regulation of the expression and activity of NF-κB and p53, and regulation of aerobic glycolysis and oxidative phosphorylation (Warburg effect). It is a pleiotropic TF, and thus, alterations to its expression status become detrimental for cell survival. This review summarizes its implication in different cellular activities and the commonly invoked molecular mechanisms triggered by LRF/ZBTB7A’s orchestrated action.

scholarly journals Plant-derived oleanolic acid ameliorates markers of subclinical inflammation and innate immunity activation in diet-induced pre-diabetic rats

2020 ◽  
Vol 11 ◽  
pp. 204201882093577
Author(s):  
Mlindeli Gamede ◽  
Lindokuhle Mabuza ◽  
Phikelelani Ngubane ◽  
Andile Khathi
Keyword(s):  
Cell Count ◽  
Oleanolic Acid ◽  
Proinflammatory Cytokines ◽  
Immune Activation ◽  
Molecular Mechanisms ◽  
Dietary Intervention ◽  
Immune Cell ◽  
Diabetic Rats ◽  
Sprague Dawley ◽  
Cell Counts

Aims: Sub-clinical inflammation during pre-diabetes is one of the predisposing factors that facilitates the progression of pre-diabetes to type 2 diabetes. The administration of oleanolic acid (OA) with or without dietary intervention ameliorates the metabolic and cardiovascular complications in diet-induced pre-diabetes animal models of pre-diabetes. This study aimed to investigate whether OA can also suppress immune activation and ameliorate pro-inflammatory markers. Methods: Pre-diabetes was induced by feeding Sprague Dawley rats a high-fat high carbohydrate diet for 20 weeks. The pre-diabetic rats were then treated with OA (80 mg/kg) or metformin (500 mg/kg) in the presence or absence of dietary interventions for a period of 12 weeks. At the end of the treatment period, the animals were euthanised and whole blood was used for platelet and immune cell count while plasma was used for fibrinogen, cluster differentiation 40 ligand and pro-inflammatory cytokine evaluation. Results: The results of this study revealed that OA, with or without dietary intervention, improved lipid metabolism by restoring high-density lipoprotein (HDL) and low-density lipoproteins (LDLs) as well as reducing platelets and immune cell counts. Furthermore, OA also decreased plasma proinflammatory cytokines, including tumour necrosis factor-α and -1β. Markers of immune activation such as C-reactive protein, fibrinogen, and CD40L were also decreased upon administration of OA with or without dietary intervention. Conclusion: The findings of this study suggest that OA may provide an alternative to prevent the progression of pre-diabetes to overt diabetes. This was evident by the reduction of differential white blood cell count and proinflammatory cytokines that exercebate insulin resistance. However, more studies are needed to elucidate the molecular mechanisms and to improve efficacy.

scholarly journals Platelet Induced Functional Alteration of CD4+ and CD8+ T Cells in HNSCC

2020 ◽  
Vol 21 (20) ◽  
pp. 7507
Author(s):  
Christina Polasky ◽  
Franziska Wendt ◽  
Ralph Pries ◽  
Barbara Wollenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Spatial Separation ◽  
Cell Regulation ◽  
Activation Markers ◽  
Indirect Contact ◽  
Cell Functions ◽  
T Cell Regulation ◽  
Regulatory Functions

Platelets (PLT) are the second most abundant cell type in human blood and exert various immune-regulatory functions under both physiological and pathological conditions. In fact, immune cell regulation via platelets has been demonstrated in several studies within the past decade. However, the exact mechanisms behind T cell regulation remain poorly understood. We questioned whether the formation of aggregates of platelets and T cells has an impact on T-cell functions. In the present study, we stimulated PBMC cultures with anti-CD3 and anti-CD28 mABs and cultured them at a PLT: PBMC ratio of 1:1 or 100:1. After 24, 48, and 72 h, PD-1, PD-L1 expression, and proliferation were analyzed on T cells using flow cytometry. Cytokine production was measured in PHA stimulated CD4 cells after 6 h. We found a significant platelet-mediated decrease in PD-1 and PD-L1 expression, proliferation, as well as IFN-γ and TNF-α production. Perturbations also at least partially remained after spatial separation of PLTs from PBMCs in Transwell-assays. T cell-platelet aggregates showed similar levels of activation markers, proliferation, and secreted cytokines as their non-complexed counterparts. Results indicate a platelet mediated regulation of T cells via direct and indirect contact, but only mediocre effects of the complex formation itself.

MicroRNAs in the regulation of immune cell functions – implications for atherosclerotic vascular disease

2012 ◽  
Vol 107 (04) ◽  
pp. 626-633 ◽  
Author(s):  
Alma Zernecke
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Chronic Inflammatory Disease ◽  
Vascular Pathology ◽  
Lipid Uptake ◽  
T Helper ◽  
Atherosclerotic Vascular Disease ◽  
Cell Functions

SummaryRegarded as a chronic inflammatory disease of the vessel wall, the development of atherosclerotic lesions is shaped by immune responses and their regulation. Macrophages and dendritic cells are positioned at the crossroad of innate and adaptive immune responses by sensing atherogenic danger signals and by taking up and presenting antigens. T helper cells and auto-antibodies produced by B cells, together with their cytokine responses in turn modulate atheroprogression. In addition, platelets contribute to atherosclerosis by multiple pathways. microRNAs (miRNAs) that post-transcriptionally regulate gene expression may thus critically control immune cell differentiation and functions during plaque evolution. This review summarises the role of miRNAs in regulating lipid uptake and expression of inflammatory mediators in monocytes/macrophages and dendritic cells, in lymphocyte functions with a focus on T helper cell responses, as well as in platelet biology, and the implications of altering these functions in vascular pathology and atherosclerosis. T systematically survey miRNA functions in controlling molecular mechanisms and immune responses in atherosclerosis holds potential for the development of novel miRNA-based strategies for therapies targeting inflammation and immunity in atherosclerosis.

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