The Importance of Metabolism for Immune Homeostasis in Allergic Diseases

There is increasing evidence that the metabolic status of T cells and macrophages is associated with severe phenotypes of chronic inflammation, including allergic inflammation. Metabolic changes in immune cells have a crucial role in their inflammatory or regulatory responses. This notion is reinforced by metabolic diseases influencing global energy metabolism, such as diabetes or obesity, which are known risk factors of severity in inflammatory conditions, due to the metabolic-associated inflammation present in these patients. Since several metabolic pathways are closely tied to T cell and macrophage differentiation, a better understanding of metabolic alterations in immune disorders could help to restore and modulate immune cell functions. This link between energy metabolism and inflammation can be studied employing animal, human or cellular models. Analytical approaches rank from classic immunological studies to integrated analysis of metabolomics, transcriptomics, and proteomics. This review summarizes the main metabolic pathways of the cells involved in the allergic reaction with a focus on T cells and macrophages and describes different models and platforms of analysis used to study the immune system and its relationship with metabolism.

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Targeting T cell metabolism in the tumor microenvironment: an anti-cancer therapeutic strategy

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1409-3 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 18

Author(s):

Zhongping Yin ◽

Ling Bai ◽

Wei Li ◽

Tanlun Zeng ◽

Huimin Tian ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Metabolic Pathways ◽

Cell Metabolism ◽

Basic Research ◽

Metabolic Reprogramming ◽

Activated T Cells ◽

Cell Functions ◽

Anti Cancer

Abstract T cells play important roles in anti-tumor immunity. Emerging evidence has revealed that distinct metabolic changes impact the activation and differentiation of T cells. Tailoring immune responses by manipulating cellular metabolic pathways and the identification of new targets may provide new options for cancer immunotherapy. In this review, we focus on recent advances in the metabolic reprogramming of different subtypes of T cells and T cell functions. We summarize how metabolic pathways accurately regulate T cell development, differentiation, and function in the tumor microenvironment. Because of the similar metabolism in activated T cells and tumor cells, we also describe the effect of the tumor microenvironment on T cell metabolism reprogramming, which may provide strategies for maximal anti-cancer effects and enhancing the immunity of T cells. Thus, studies of T lymphocyte metabolism can not only facilitate the basic research of immune metabolism, but also provide potential targets for drug development and new strategies for clinical treatment of cancer.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21207507 ◽

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.

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Metabolite releasing polymers control dendritic cell function by modulating their energy metabolism

Journal of Materials Chemistry B ◽

10.1039/d0tb00790k ◽

2020 ◽

Vol 8 (24) ◽

pp. 5195-5203

Author(s):

Joslyn L. Mangal ◽

Sahil Inamdar ◽

Yi Yang ◽

Subhadeep Dutta ◽

Mamta Wankhede ◽

...

Keyword(s):

Energy Metabolism ◽

Dendritic Cell ◽

Immune Cells ◽

Cell Function ◽

Immune Cell ◽

Dendritic Cell Function ◽

Cell Functions

Metabolites control immune cell functions, and delivery of these metabolites in a sustained manner modulate the function of the immune cells.

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In Vitro Responsiveness of γδ T Cells fromMycobacterium bovis-Infected Cattle to Mycobacterial Antigens: Predominant Involvement of WC1+Cells

Infection and Immunity ◽

10.1128/iai.69.1.89-96.2001 ◽

2001 ◽

Vol 69 (1) ◽

pp. 89-96 ◽

Cited By ~ 56

Author(s):

Allister J. Smyth ◽

Michael D. Welsh ◽

R. Martyn Girvin ◽

John M. Pollock

Keyword(s):

T Cells ◽

Diagnostic Tests ◽

Protective Immunity ◽

Cellular Proliferation ◽

Mononuclear Cells ◽

Immune Cell ◽

Γδ T Cells ◽

Peripheral Blood Mononuclear ◽

Cell Functions

ABSTRACT It is generally accepted that protective immunity against tuberculosis is generated through the cell-mediated immune (CMI) system, and a greater understanding of such responses is required if better vaccines and diagnostic tests are to be developed. γδ T cells form a major proportion of the peripheral blood mononuclear cells (PBMC) in the ruminant system and, considering data from other species, may have a significant role in CMI responses in bovine tuberculosis. This study compared the in vitro responses of αβ and γδ T cells from Mycobacterium bovis-infected and uninfected cattle. The results showed that, following 24 h of culture of PBMC withM. bovis-derived antigens, the majority of γδ T cells from infected animals became highly activated (upregulation of interleukin-2R), while a lower proportion of the αβ T-cell population showed activation. Similar responses were evident to a lesser degree in uninfected animals. Study of the kinetics of this response showed that γδ T cells remained significantly activated for at least 7 days in culture, while activation of αβ T cells declined during that period. Subsequent analysis revealed that the majority of activated γδ T cells expressed WC1, a 215-kDa surface molecule which is not expressed on human or murine γδ T cells. Furthermore, in comparison with what was found for CD4+ T cells, M. bovis antigen was found to induce strong cellular proliferation but relatively little gamma interferon release by purified WC1+ γδ T cells. Overall, while the role of these cells in protective immunity remains unclear, their highly activated status in response to M. bovis suggests an important role in antimycobacterial immunity, and the ability of γδ T cells to influence other immune cell functions remains to be elucidated, particularly in relation to CMI-based diagnostic tests.

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Surfactant protein D decreases pollen-induced IgE-dependent mast cell degranulation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00009.2005 ◽

2005 ◽

Vol 289 (5) ◽

pp. L856-L866 ◽

Cited By ~ 26

Author(s):

Delphine C. Malherbe ◽

Veit J. Erpenbeck ◽

Soman N. Abraham ◽

Erika C. Crouch ◽

Jens M. Hohlfeld ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Immune Cell ◽

Allergic Inflammation ◽

Surfactant Protein ◽

Mast Cell Degranulation ◽

Surfactant Protein D ◽

Dependent Manner ◽

Cell Functions ◽

Pulmonary Surfactant Proteins

Mast cells play a key role in allergy and asthma. They reside at the host-environment interface and are among the first cells to make contact with inhaled microorganisms and particulate antigens. Pulmonary surfactant proteins A and D (SP-A and SP-D) function in lung host defense by enhancing microbe phagocytosis and mediating other immune cell functions, but little is known about their effects on mast cells. We hypothesized that SP-A and/or SP-D modulate IgE-dependent mast cell functions. Pollen starch granules (PSG) extracted from Dactylis glomerata and coated with trinitrophenol (TNP) were used as a model of an inhaled organic particulate allergen. Our data revealed that SP-D inhibited by 50% the release of β-hexosaminidase by peritoneal mast cells sensitized with IgE anti-TNP and stimulated with TNP-PSG. In contrast, SP-A had no effect. Furthermore, SP-D aggregated PSG in a dose-dependent manner, and this aggregation was mediated by SP-D's carbohydrate recognition domain. A single arm SP-D mutant (RrSP-Dser15,20) neither aggregated PSG nor inhibited degranulation, suggesting that multimerization of SP-D is required for maximal PSG aggregation and inhibition of PSG-induced mast cell degranulation. This study is the first to demonstrate that SP-D modulates IgE-mediated mast cell functions, which are important in asthma and allergic inflammation.

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Regulation of Immune Functions by Non-Neuronal Acetylcholine (ACh) via Muscarinic and Nicotinic ACh Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms22136818 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6818

Author(s):

Masato Mashimo ◽

Yasuhiro Moriwaki ◽

Hidemi Misawa ◽

Koichiro Kawashima ◽

Takeshi Fujii

Keyword(s):

T Cells ◽

B Cells ◽

Immune Cells ◽

Immune Cell ◽

Immune Functions ◽

Cell Functions ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Cellular And Humoral Immunity ◽

Ach Receptors

Acetylcholine (ACh) is the classical neurotransmitter in the cholinergic nervous system. However, ACh is now known to regulate various immune cell functions. In fact, T cells, B cells, and macrophages all express components of the cholinergic system, including ACh, muscarinic, and nicotinic ACh receptors (mAChRs and nAChRs), choline acetyltransferase, acetylcholinesterase, and choline transporters. In this review, we will discuss the actions of ACh in the immune system. We will first briefly describe the mechanisms by which ACh is stored in and released from immune cells. We will then address Ca2+ signaling pathways activated via mAChRs and nAChRs on T cells and B cells, highlighting the importance of ACh for the function of T cells, B cells, and macrophages, as well as its impact on innate and acquired (cellular and humoral) immunity. Lastly, we will discuss the effects of two peptide ligands, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) and hippocampal cholinergic neurostimulating peptide (HCNP), on cholinergic activity in T cells. Overall, we stress the fact that ACh does not function only as a neurotransmitter; it impacts immunity by exerting diverse effects on immune cells via mAChRs and nAChRs.

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Metabolic substrate utilization in stress-induced immune cells

Intensive Care Medicine Experimental ◽

10.1186/s40635-020-00316-0 ◽

2020 ◽

Vol 8 (S1) ◽

Author(s):

Xiaomin Zhang ◽

Fabian Zink ◽

Felix Hezel ◽

Josef Vogt ◽

Ulrich Wachter ◽

...

Keyword(s):

Immune Cells ◽

Metabolic Pathways ◽

Cell Activation ◽

Immune Cell ◽

Tca Cycle ◽

Therapeutic Interventions ◽

Functional Changes ◽

Cell Functions ◽

Immune Cell Activation ◽

Metabolic Functions

AbstractImmune cell activation leads to the acquisition of new functions, such as proliferation, chemotaxis, and cytokine production. These functional changes require continuous metabolic adaption in order to sustain ATP homeostasis for sufficient host defense. The bioenergetic demands are usually met by the interconnected metabolic pathways glycolysis, TCA cycle, and oxidative phosphorylation. Apart from glucose, other sources, such as fatty acids and glutamine, are able to fuel the TCA cycle.Rising evidence has shown that cellular metabolism has a direct effect on the regulation of immune cell functions. Thus, quiescent immune cells maintain a basal metabolic state, which shifts to an accelerated metabolic level upon immune cell activation in order to promote key effector functions.This review article summarizes distinct metabolic signatures of key immune cell subsets from quiescence to activation and demonstrates a methodical concept of how to assess cellular metabolic pathways. It further discusses why metabolic functions are of rising interest for translational research and how they can be affected by the underlying pathophysiological condition and/or therapeutic interventions.

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Recent thymic emigrants produce antimicrobial IL-8, express complement receptors and are precursors of a tissue-homing Th8 lineage of memory cells

10.1101/059535 ◽

2016 ◽

Cited By ~ 1

Author(s):

Marcin L Pekalski ◽

Arcadio Rubio García ◽

Ricardo C Ferreira ◽

Daniel B Rainbow ◽

Deborah J Smyth ◽

...

Keyword(s):

T Cells ◽

Immune Cell ◽

Bacterial Pathogen ◽

Adaptive Immune System ◽

Complement Receptors ◽

Memory Cells ◽

Recent Thymic Emigrants ◽

Naive T Cells ◽

Naïve T Cells ◽

Cell Functions

ABSTRACTThe adaptive immune system utilizes multiple mechanisms linked to innate immune cell functions to respond appropriately to pathogens and commensals. Here we discover further aspects of this connectivity by demonstrating that naïve T cells as they emerge from the thymus (recent thymic emigrants, RTEs) express complement receptors (CR1 and CR2), the bacterial pathogen recognition receptor TLR1 and an enzyme that deactivates bacterial lipopolysaccharide (AOAH) and following activation secrete the anti-microbial cytokine IL-8. CR2+ naïve T cells also express a selection of genes associated with tissue migration, consistent with the hypothesis that following emigration from the thymus RTEs seed peripheral compartments where some pursue their anti-microbial potential by becoming IL-8-producing CR2+ memory cells while others undergo homeostatic expansion. CR2+ naïve and memory cells are abundant in children but decrease with age, coinciding with the involution of the thymus. The ability of CR2, which is also a receptor for Epstein-Barr Virus (EBV), to identify recent thymic emigrants will facilitate assessment of thymic function during aging and aid investigations of multiple clinical areas including the occurrence of T cell lymphomas caused by EBV.

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Molecular profiles and immunomodulatory activities of glioblastoma-derived exosomes

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa056 ◽

2020 ◽

Vol 2 (1) ◽

Cited By ~ 3

Author(s):

Juliana Hofstatter Azambuja ◽

Nils Ludwig ◽

Saigopalakrishna Yerneni ◽

Aparna Rao ◽

Elizandra Braganhol ◽

...

Keyword(s):

T Cells ◽

T Cell Activation ◽

Cd8 T Cells ◽

Immune Cells ◽

Cell Activation ◽

Immune Cell ◽

Size Exclusion ◽

Cell Functions

Abstract Background Glioblastoma is one of the most immunosuppressive human tumors. Emerging data suggest that glioblastoma-derived exosomes (GBex) reprogram the tumor microenvironment into a tumor-promoting milieu by mechanisms that not yet understood. Methods Exosomes were isolated from supernatants of glioblastoma cell lines by size exclusion chromatography. The GBex endosomal origin, size, protein cargos, and ex vivo effects on immune cell functions were determined. GBex were injected intravenously into mice to evaluate their ability to in vivo modulate normal immune cell subsets. Results GBex carried immunosuppressive proteins, including FasL, TRAIL, CTLA-4, CD39, and CD73, but contained few immunostimulatory proteins. GBex co-incubated with primary human immune cells induced simultaneous activation of multiple molecular pathways. In CD8+ T cells, GBex suppressed TNF-α and INF-γ release and mediated apoptosis. GBex suppressed natural killer (NK) and CD4+ T-cell activation. GBex activated the NF-κB pathway in macrophages and promoted their differentiation into M2 cells. Inhibition of the NF-κB pathway in macrophages reversed the GBex-mediated effects. GBex-driven reprogramming of macrophages involved the release of soluble factors that promoted tumor proliferation in vitro. In mice injected with GBex, the frequency of splenic CD8+ T cells, NK cells, and M1-like macrophages was reduced, while that of naïve and M2-like macrophages increased (P < .05). Conclusions GBex reprogrammed functions of all types of immune cells in vitro and altered their frequency in vivo. By creating and sustaining a highly immunosuppressive environment, GBex play a key role in promoting tumor progression.

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Comprehensive genomic and immunophenotypic analysis of CD4 T cell infiltrating human triple-negative breast cancer

Cancer Immunology Immunotherapy ◽

10.1007/s00262-020-02807-1 ◽

2020 ◽

Author(s):

He Zhang ◽

Guohui Qin ◽

Hui Yu ◽

Xu Han ◽

Sha Zhu

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

T Cells ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Immune Cell ◽

Differential Expression Analysis ◽

Effector Memory ◽

Activated T Cells ◽

Cell Functions

AbstractThe aim of this study is to investigate the gene expression module of tumor-infiltrating CD4+T cells and its potential roles in modulating immune cell functions in triple-negative breast cancer. Differentially expressed genes were identified by comparison of the expression profile in CD4+T cells isolated from tumor tissues and peripheral blood of TNBC patients respectively. The differential expression analysis was conducted using R, and then the functional and pathway enrichment of the DEGs were analyzed using GSEA, followed by integrated regulatory network construction and genetic analysis of tumor-infiltrating immune cells based on a scientific deconvolution algorithm. As a result, abundant Treg and exhausted lymphocytes were detected, accompanied by largely decreased of effector/memory and cytotoxic T cells. Immune-related gene correlation analysis showed that the extent of follicular helper T cells gene expression signatures were inversely associated with those of CD4+ naive T cells and CD4+ memory resting T cells, but positively correlated with that of CD4+ memory activated T cells. In addition, we found five core genes including IFNG, CTLA4, FAS, CXCR6, and JUN were significantly over expressed in CD4+ TILs which may contribute to exhaustion of lymphocytes and participate in biological processes associated with regulation of chemotaxis. Study provides a comprehensive understanding of the roles of DEGs associated with the chemotactic and exhausted immunophenotypes of CD4+ TILs that are a valuable resource from which future investigation may be carried out to better understand the mechanisms that promote TNBC progression.

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