bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒06‒27
ten papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Front Immunol. 2021 ;12 666231
      Although cancer immunotherapy is effective against hematological malignancies, it is less effective against solid tumors due in part to significant metabolic challenges present in the tumor microenvironment (TME), where infiltrated CD8+ T cells face fierce competition with cancer cells for limited nutrients. Strong metabolic suppression in the TME is often associated with impaired T cell recruitment to the tumor site and hyporesponsive effector function via T cell exhaustion. Increasing evidence suggests that mitochondria play a key role in CD8+ T cell activation, effector function, and persistence in tumors. In this study, we showed that there was an increase in overall mitochondrial function, including mitochondrial mass and membrane potential, during both mouse and human CD8+ T cell activation. CD8+ T cell mitochondrial membrane potential was closely correlated with granzyme B and IFN-γ production, demonstrating the significance of mitochondria in effector T cell function. Additionally, activated CD8+ T cells that migrate on ICAM-1 and CXCL12 consumed significantly more oxygen than stationary CD8+ T cells. Inhibition of mitochondrial respiration decreased the velocity of CD8+ T cell migration, indicating the importance of mitochondrial metabolism in CD8+ T cell migration. Remote optical stimulation of CD8+ T cells that express our newly developed "OptoMito-On" successfully enhanced mitochondrial ATP production and improved overall CD8+ T cell migration and effector function. Our study provides new insight into the effect of the mitochondrial membrane potential on CD8+ T cell effector function and demonstrates the development of a novel optogenetic technique to remotely control T cell metabolism and effector function at the target tumor site with outstanding specificity and temporospatial resolution.
    Keywords:  T cell migration; cancer immunotherapy; effector T cell; metabolism; optogenetics
  2. Proc Natl Acad Sci U S A. 2021 Jun 22. pii: e2023752118. [Epub ahead of print]118(25):
      Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8+ T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8+ T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.
    Keywords:  T cell; fever; immunology; metabolism; mitochondria
  3. Front Immunol. 2021 ;12 669456
      In Type 1 Diabetes (T1D), CD4+ T cells initiate autoimmune attack of pancreatic islet β cells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4+ T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, a competitive inhibitor of the rate limiting glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3 (PFKFB3). Our results confirmed PFK15 inhibited glycolysis utilization by diabetogenic CD4+ T cells and reduced T cell responses to β cell antigen in vitro. In an adoptive transfer model of T1D, PFK15 treatment delayed diabetes onset, with 57% of animals remaining euglycemic at the end of the study period. Protection was due to induction of a hyporesponsive T cell phenotype, characterized by increased and sustained expression of the checkpoint molecules PD-1 and LAG-3 and downstream functional and metabolic exhaustion. Glycolysis inhibition terminally exhausted diabetogenic CD4+ T cells, which was irreversible through restimulation or checkpoint blockade in vitro and in vivo. In sum, our results demonstrate a novel therapeutic strategy to control aberrant T cell responses by exploiting the metabolic reprogramming of these cells during T1D. Moreover, the data presented here highlight a key role for nutrient availability in fueling T cell function and has implications in our understanding of T cell biology in chronic infection, cancer, and autoimmunity.
    Keywords:   LAG-3; PD-1; T cell exhaustion; autoimmunity; glycolysis; immunometabolism; type 1 diabetes
  4. Tissue Cell. 2021 Jun 04. pii: S0040-8166(21)00085-9. [Epub ahead of print]71 101569
      γδ T cell is one of the most important pathogenic immune cells in autoimmunity, especially in mucosal and epithelial diseases. Metabolism is essential for the maintenance of immune homeostasis. However, unlike αβ T cells, the metabolic regulation of γδ T cell activation still remain unclear. Here, we identified glutamine metabolism as a critical regulator for the generation of IL-17-producing γδ T cells. Metabolic screening uncovered that amino acids related to glutamine metabolism increased most obviously during γδ T cell activation. Pharmaceutical blocking of glutamine impaired IL-17 production in γδ T cells both in vitro and in vivo. Mechanism studies further revealed that genes downregulated upon glutamine deprivation enriched in IL-17 and IL-23/STAT3 signaling pathways. Consistent with this, the activation of STAT3 was suppressed after glutamine blocking. More importantly, application of glutamine antagonist in vivo alleviated the progression of IL-23 induced psoriatic mice model. In addition, both the glutamine level and the expression of glutamine related enzymes were found higher in psoriasis patients when compared with healthy controls. Therefore, our work identified an important metabolic regulatory pathway in γδ T cell activation and suggested that glutamine metabolism could be used as a target for the treatment of γδ T cell related diseases.
    Keywords:  Autoimmune disease; Glutamine metabolism; γδ T cell
  5. Nutr Diabetes. 2021 Jun 23. 11(1): 22
      Various nutrients can change cell structure, cellular metabolism, and cell function which is particularly important for cells of the immune system as nutrient availability is associated with the activation and function of diverse immune subsets. The most important nutrients for immune cell function and fate appear to be glucose, amino acids, fatty acids, and vitamin D. This perspective will describe recently published information describing the mechanism of action of prominent nutritional intervention agents where evidence exists as to their action and potency.
  6. J Physiol. 2021 Jun 23.
      KEY POINTS: Increased large artery stiffness and impaired endothelium dependent dilation occur with advanced age. We sought to determine whether T cells mechanistically contribute to age-related arterial dysfunction. We found that old mice exhibited greater proinflammatory T cell accumulation around both the aorta and mesenteric arteries. Pharmacologic depletion or genetic deletion of T cells in old mice resulted in ameliorated large artery stiffness and greater endothelium dependent dilation compared to mice with T cells intact.ABSTRACT: Aging of the arteries is characterized by increased large artery stiffness and impaired endothelium dependent dilation. T cells contribute to hypertension in acute rodent models but whether they contribute to chronic age-related arterial dysfunction is unknown. To determine whether T cells directly mediate age-related arterial dysfunction, we examined large elastic artery and resistance artery function in young (4-6 months) and old (22-24 months) wild type mice treated with anti-CD3 F(ab'2) fragments to deplete T cells (150μg, i.p. every 7 days for 28 days) or isotype control fragments. Old mice exhibited greater numbers of T cells in both aorta and mesenteric vasculature when compared to young mice. Old mice treated with anti-CD3 fragments exhibited depletion of T cells in blood, spleen, aorta and mesenteric vasculature. Old mice also exhibited greater numbers of aortic and mesenteric IFN-γ and TNF-α producing T cells when compared to young. Old control mice exhibited greater large artery stiffness and impaired resistance artery endothelium dependent dilation in comparison to young mice. In old mice, large artery stiffness was ameliorated with anti-CD3 treatment. Anti-CD3 treated old mice also exhibited greater endothelium dependent dilation compared to age-matched controls. We also examined arterial function in young and old Rag-1-/- mice, which lack lymphocytes. Rag-1-/- mice exhibited blunted increases in large artery stiffness with age compared to wild type mice. Old Rag-1-/- mice also exhibited greater endothelium dependent dilation compared to old wild type mice. Collectively, these results demonstrate that T cells play an important role in age-related arterial dysfunction. This article is protected by copyright. All rights reserved.
    Keywords:  aorta; endothelium; immune system; lymphocytes; mesentery; vascular
  7. Nat Biomed Eng. 2021 Jun 24.
      The performance of immune-checkpoint inhibitors, which benefit only a subset of patients and can cause serious immune-related adverse events, underscores the need for strategies that induce T-cell immunity with minimal toxicity. The gut microbiota has been implicated in the outcomes of patients following cancer immunotherapy, yet manipulating the gut microbiome to achieve systemic antitumour immunity is challenging. Here we show in multiple murine tumour models that inulin-a widely consumed dietary fibre-formulated as a 'colon-retentive' orally administered gel can effectively modulate the gut microbiome in situ, induce systemic memory-T-cell responses and amplify the antitumour activity of the checkpoint inhibitor anti-programmed cell death protein-1 (α-PD-1). Orally delivered inulin-gel treatments increased the relative abundances of key commensal microorganisms and their short-chain-fatty-acid metabolites, and led to enhanced recall responses for interferon-γ+CD8+ T cells as well as to the establishment of stem-like T-cell factor-1+PD-1+CD8+ T cells within the tumour microenvironment. Gels for the in situ modulation of the gut microbiome may be applicable more broadly to treat pathologies associated with a dysregulated gut microbiome.
  8. EMBO Mol Med. 2021 Jun 21. e14323
      Very-low-carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno-nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T-cell responses. CD4+ , CD8+ , and regulatory T-cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very-low-carbohydrate diet as a clinical tool to improve human T-cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required.
    Keywords:  T-cell immunity; immunometabolism; ketogenic diet; metabolic therapy; nutritional intervention
  9. J Biol Chem. 2021 Jun 19. pii: S0021-9258(21)00704-3. [Epub ahead of print] 100904
      Mitochondria are critical for regulation of the activation, differentiation, and survival of macrophages and other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes to mitochondrial metabolism and physiology could underlie the corresponding state of macrophage activation. These changes include alterations of oxidative metabolism, mitochondrial membrane potential, and tricarboxylic acid (TCA) cycling, as well as the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) and transformation of the mitochondrial ultrastructure. Here, we provide an updated review of how changes in mitochondrial metabolism and various metabolites such as fumarate, succinate, and itaconate coordinate to guide macrophage activation to distinct cellular states, thus clarifying the vital link between mitochondria metabolism and immunity. We also discuss how in disease settings, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response. Therefore, mitochondria are a vital source of dynamic signals that regulate macrophage biology to fine-tune immune responses.
    Keywords:  macrophage activation; macrophage biology; mitochondrial dysfunction; mitochondrial metabolism; oxidative stress
  10. Cell. 2021 Jun 24. pii: S0092-8674(21)00699-1. [Epub ahead of print]184(13): 3356-3357
      Education of the human immune system begins in utero via T cell activation and memory development. However, whether part of the education is provided by exposure to microbes in utero remains controversial and unclear. In this issue of Cell, Mishra et al. provide new evidence that the fetal gut may be colonized by bacteria that prime T cell memories.