bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022‒01‒30
eight papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Blood Adv. 2022 Jan 24. pii: bloodadvances.2021005103. [Epub ahead of print]
      Chronic graft-versus-host disease (cGVHD) remains a major obstacle impeding successful allogeneic hematopoietic cell transplantation (allo-HCT). MicroRNAs (miRs) play key roles in immune regulation during acute GVHD development. Preclinical studies to identify miRs that impact cGVHD pathogenesis are required to develop these as potential life-saving interventions. Using oligonucleotide array, we identified miR-31 that was significantly elevated in allogeneic T cells following HCT in mice. Using genetic and pharmacological approaches, we demonstrated a key role for miR-31 in mediating donor T-cell pathogenicity in cGVHD. Recipients of miR-31-deficient T cells displayed improved cutaneous and pulmonary cGVHD. Deficiency of miR-31 reduced T-cell expansion and Th17 differentiation, but increased generation and function of Tregs. MiR-31 facilitated Neuropilin-1 down-regulation, Foxp3 loss and IFNγ production in alloantigen-induced Tregs. Mechanistically, miR-31 was required for Hypoxia-inducible Factor 1α (HIF1α) upregulation in allogeneic T cells. Hence, miR-31-deficient CD4 T cells displayed impaired activation, survival, Th17 differentiation and glycolytic metabolism under hypoxia. Upregulation of Factor Inhibiting HIF1 (FIH1), a direct target of miR-31, in miR-31-deficient T cells was essential for attenuating T-cell pathogenicity. However, miR-31-deficienty CD8 T cells maintained intact glucose metabolism, cytolytic activity and graft-versus-leukemia response. Importantly, systemic administration of a specific inhibitor of miR-31 effectively reduced donor T-cell expansion, improved Treg generation, and attenuated cGVHD. Taken together, miR-31 is a key driver for T-cell pathogenicity in cGVHD but not for the anti-leukemia activity. Taken together, miR-31 is essential to drive cGVHD pathogenesis and represents a novel potential therapeutic target for controlling cGVHD.
  2. Ageing Res Rev. 2022 Jan 24. pii: S1568-1637(22)00015-0. [Epub ahead of print] 101573
      Indoleamine 2,3-dioxygenase 1 (IDO1) is activated in chronic inflammatory states, e.g., in the aging process and age-related diseases. IDO1 enzyme catabolizes L-tryptophan (L-Trp) into kynurenine (KYN) thus stimulating the KYN pathway. The depletion of L-Trp inhibits the proliferation of immune cells in inflamed tissues and it also reduces serotonin synthesis predisposing to psychiatric disorders. Interestingly, IDO1 protein contains two immunoreceptor tyrosine-based inhibitory motifs (ITIM) which trigger suppressive signaling through the binding of PI3K p110 and SHP-1 proteins. This immunosuppressive activity is not dependent on the catalytic activity of IDO1. KYN and its metabolite, kynurenic acid (KYNA), are potent activators of the aryl hydrocarbon receptor (AhR) which can enhance immunosuppression. IDO1-KYN-AhR signaling counteracts excessive pro-inflammatory responses in acute inflammation but in chronic inflammatory states it has many harmful effects. A chronic low-grade inflammation is associated with the aging process, a state called inflammaging. There is substantial evidence that the activation of the IDO1-KYN-AhR pathway robustly increases with the aging process. The activation of IDO1-KYN-AhR signaling does not only suppress the functions of effector immune cells, probably promoting immunosenescence, but it also impairs autophagy, induces cellular senescence, and remodels the extracellular matrix as well as enhancing the development of osteoporosis and vascular diseases. I will review the function of IDO1-KYN-AhR signaling and discuss its activation with aging as an enhancer of the aging process.
    Keywords:  Ageing; MDSC; NAD; RelB; Tolerance
  3. Dev Cell. 2022 Jan 25. pii: S1534-5807(22)00002-8. [Epub ahead of print]
      Tumor-derived extracellular vesicles (TEVs) suppress the proliferation and cytotoxicity of CD8+ T cells, thereby contributing to tumor immune evasion. Here, we report that the adhesion molecule intercellular adhesion molecule 1 (ICAM-1) co-localizes with programmed death ligand 1 (PD-L1) on the exosomes; both ICAM-1 and PD-L1 are upregulated by interferon-γ. Exosomal ICAM-1 interacts with LFA-1, which is upregulated in activated T cells. Blocking ICAM-1 on TEVs reduces the interaction of TEVs with CD8+ T cells and attenuates PD-L1-mediated suppressive effects of TEVs. During this study, we have established an extracellular vesicle-target cell interaction detection through SorTagging (ETIDS) system to assess the interaction between a TEV ligand and its target cell receptor. Using this system, we demonstrate that the interaction of TEV PD-L1 with programmed cell death 1 (PD-1) on T cells is significantly reduced in the absence of ICAM-1. Our study demonstrates that ICAM-1-LFA-1-mediated adhesion between TEVs and T cells is a prerequisite for exosomal PD-L1-mediated immune suppression.
    Keywords:  CD8(+) T cells; ICAM-1; PD-L1; exosome; extracellular vesicles; immune suppression
  4. Cell Stem Cell. 2022 Jan 13. pii: S1934-5909(21)00519-1. [Epub ahead of print]
      Host microbiota crosstalk is essential for the production and functional modulation of blood-cell lineages. Whether, and if so how, the microbiota influences hematopoietic stem cells (HSCs) is unclear. Here, we show that the microbiota regulates HSC self-renewal and differentiation under stress conditions by modulating local iron availability in the bone marrow (BM). In microbiota-depleted mice, HSC self-renewal was enhanced during regeneration, while the commitment toward differentiation was dramatically compromised. Mechanistically, microbiota depletion selectively impaired the recycling of red blood cells (RBCs) by BM macrophages, resulting in reduced local iron levels without affecting systemic iron homeostasis. Limiting iron availability in food (in vivo) or in culture (ex vivo), or by CD169+ macrophage depletion, enhanced HSC self-renewal and expansion. These results reveal an intricate interplay between the microbiota, macrophages, and iron, and their essential roles in regulating critical HSC fate decisions under stress.
    Keywords:  erythrophagocytosis; fate decision; hematopoietic regeneration; hematopoietic stem cell; iron; macrophage; microbiota; self-renewal
  5. J Immunol Res. 2022 ;2022 6284124
      Iron plays an important role in macrophage polarization by altering metabolic and redox status. However, the impact of iron on the immune status of macrophages is still controversial. In this study, we report that ferric ammonium citrate (FAC) upregulates PD-L1 expression in macrophages. FAC not only altered the phenotype of macrophages but also led to enriching immune-modulatory T cell subsets. Since iron is known to be a constituent of coenzymes facilitating metabolic processes in mitochondria, we examined the metabolic status of FAC-overloaded macrophages by measuring the oxygen consumption rate (OCR) and the represented coenzyme, aconitase. In addition to enhancement of metabolic processes, FAC accelerated the Fenton reaction in macrophages, which also contributed to the facilitation of oxygen consumption. We reasoned that the enhancement of the OCR leads to the production of reactive oxygen species (ROS), which are directly linked to PD-L1 induction. Using ferrostatin, rotenone, and N-acetyl-L-cysteine, we confirmed that metabolic and redox regulation is responsible for FAC-mediated PD-L1 expression. Furthermore, we suggested that FAC-induced ROS production may explain FAC-mediated pro- and anti-inflammatory responses in macrophages. These findings may extend our understanding of regulating iron concentration during immune checkpoint therapy in cancer patients.
  6. JBMR Plus. 2022 Jan;6(1): e10572
      The relationship between the active form of vitamin D3 (1,25-dihydroxyvitamin D, 1,25(OH)2D) and reactive oxygen species (ROS), two integral signaling molecules of the cell, is poorly understood. This is striking, given that both factors are involved in cancer cell regulation and metabolism. Mitochondria (mt) dysfunction is one of the main drivers of cancer, producing more mitochondria, higher cellular energy, and ROS that can enhance oxidative stress and stress tolerance responses. To study the effects of 1,25(OH)2D on metabolic and mt dysfunction, we used the vitamin D receptor (VDR)-sensitive MG-63 osteosarcoma cell model. Using biochemical approaches, 1,25(OH)2D decreased mt ROS levels, membrane potential (ΔΨmt), biogenesis, and translation, while enforcing endoplasmic reticulum/mitohormetic stress adaptive responses. Using a mitochondria-focused transcriptomic approach, gene set enrichment and pathway analyses show that 1,25(OH)2D lowered mt fusion/fission and oxidative phosphorylation (OXPHOS). By contrast, mitophagy, ROS defense, and epigenetic gene regulation were enhanced after 1,25(OH)2D treatment, as well as key metabolic enzymes that regulate fluxes of substrates for cellular architecture and a shift toward non-oxidative energy metabolism. ATACseq revealed putative oxi-sensitive and tumor-suppressing transcription factors that may regulate important mt functional genes such as the mTORC1 inhibitor, DDIT4/REDD1. DDIT4/REDD1 was predominantly localized to the outer mt membrane in untreated MG-63 cells yet sequestered in the cytoplasm after 1,25(OH)2D and rotenone treatments, suggesting a level of control by membrane depolarization to facilitate its cytoplasmic mTORC1 inhibitory function. The results show that 1,25(OH)2D activates distinct adaptive metabolic responses involving mitochondria to regain redox balance and control the growth of osteosarcoma cells. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
  7. STAR Protoc. 2022 Mar 18. 3(1): 101084
      The elevation of glycolysis in autoreactive T cells is a key target for the prevention and treatment of T cell-related autoimmune diseases, such as type 1 diabetes (T1D). Here, we describe a simple and efficient protocol for isolating human peripheral blood mononuclear cells (PBMCs) and T cells, and the subsequent assessment of T cell glycolysis using Seahorse analyzer. This protocol is useful to analyze different subsets of T cells and applicable to different autoimmune disease models (i.e., T1D, multiple sclerosis). For complete details on the use and execution of this profile, please refer to Kong et al. (2021).
    Keywords:  Cell isolation; Cell-based Assays; Classification Description: Cell Biology; Immunology; Metabolism
  8. Scand J Immunol. 2022 Jan 24. e13146
      1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ), the active metabolite of vitamin D3 has a strong impact on the differentiation and function of immune cells. Here we analyzed the influence of its precursor 25-hydroxyvitamin D3 (25(OH)D3 ) on the differentiation of human CD4+ T cells applying physiological concentrations in vitro. Our data show that 25(OH)D3 is converted to its active form 1,25(OH)2 D3 by T cells, which in turn supports FOXP3, CD25 and CTLA-4 expression and inhibits IFN-γ production. These changes were not reflected in the demethylation of the respective promoters. Furthermore, we investigated the impact of vitamin D3 metabolites under induced Treg polarization conditions using TGF-β. Surprisingly, no additive effect but a decreased percentage of FOXP3 expressing cells was observed. However, the combination of 25(OH)D3 or 1,25(OH)2 D3 together with TGF-β further upregulated CD25 and CTLA-4 and significantly increased soluble CTLA-4 and IL-10 secretion whereas IFN-γ expression of iTreg was decreased. Our data suggest that physiological levels of 25(OH)D3 act as potent modulator of human CD4+ T cells and autocrine or paracrine production of 1,25(OH)2 D3 by T cells might be crucial for the local regulation of an adaptive immune response. However, since no epigenetic changes are detected by 25(OH)D3 a rather transient phenotype is induced.
    Keywords:  1,25(OH)2D3; 25(OH)D3; CD4; CTLA-4; CYP27B1; FOXP3; IFN-γ; IL-10; TGF-β; Treg; VDR; Vitamin D3