bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020‒08‒02
eleven papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Aging (Albany NY). 2020 Jul 26. 12
      Although aging in the liver contributes to the development of chronic liver diseases such as NAFLD and insulin resistance, little is known about the molecular and metabolic details of aging in hepatic cells. To examine these issues, we used sequential oxidative stress with hydrogen peroxide to induce premature senescence in AML12 hepatic cells. The senescent cells exhibited molecular and metabolic signatures, increased SA-βGal and γH2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled livers from aged mice. Metabolic phenotyping showed fuel switching towards glycolysis and mitochondrial glutamine oxidation as well as impaired energy production. The senescent AML12 cells also had increased mTOR signaling and decreased autophagy which likely contributed to the fuel switching from β-oxidation that occurred in normal AML12 cells. Additionally, senescence-associated secretory phenotype (SASP) proteins from conditioned media of senescent cells sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated senescent AML12 cells which displayed the molecular hallmarks of aging and also exhibited the aberrant metabolic phenotype, mitochondrial function, and cell signaling that occur in the aged liver.
    Keywords:  AML12 cells; aging; liver; metabolism; senescence
  2. Nat Immunol. 2020 Jul 27.
      The development of TCRαβ and TCRγδ T cells comprises a step-wise process in which regulatory events control differentiation and lineage outcome. To clarify these mechanisms, we employed RNA-sequencing, ATAC-sequencing and ChIPmentation on well-defined thymocyte subsets that represent the continuum of human T cell development. The chromatin accessibility dynamics show clear stage specificity and reveal that human T cell-lineage commitment is marked by GATA3- and BCL11B-dependent closing of PU.1 sites. A temporary increase in H3K27me3 without open chromatin modifications is unique for β-selection, whereas emerging γδ T cells, which originate from common precursors of β-selected cells, show large chromatin accessibility changes due to strong T cell receptor (TCR) signaling. Furthermore, we unravel distinct chromatin landscapes between CD4+ and CD8+ αβ-lineage cells that support their effector functions and reveal gene-specific mechanisms that define mature T cells. This resource provides a framework for studying gene regulatory mechanisms that drive normal and malignant human T cell development.
  3. Immunol Lett. 2020 Jul 24. pii: S0165-2478(20)30352-7. [Epub ahead of print]
      OBJECTIVE: An upward trend in life expectancy has been observed in a majority of developed countries and leading to increasing in aging-related diseases. Aging is a risk factor for the development of widespread clinical conditions such as cardiovascular and autoimmune diseases, cancer, infections. Although studies have been very active, the problem of aging still remains one of the most obscure aspects of human biology. Regulatory T (Treg) cells with immunosuppressive properties have a pivotal role in the maintenance of immune homeostasis. Alterations in Treg cell functionality appear to be of great importance in the development of immune senescence and contribute to increased susceptibility to immune-mediated diseases with age.DESIGN: This review highlights recent findings regarding the age-related changes in the numbers and functional activity of human Treg cells. Some of the mechanisms that maintain the balance of Treg cells during human aging are discussed. The possible roles of Treg lymphocytes in the pathogenesis of diseases associated with advanced age are also considered.
    RESULTS: Age-related systemic changes, such as thymic involution, hormonal status, and epigenetic modifications, may affect the state of the Treg cell population and trigger various diseases. These changes involve decline or amplification in the functional activity of Tregs, an increase in the memory Treg subset and shifting of a Th17/Treg balance.
    CONCLUSION: Taken together, the reviewed data suggest equal or even increased Treg functionality with age. Thus, age-mediated Treg expansion and higher Treg activity may contribute to elevated immune suppression and increased risk of infections and cancer.
    Keywords:  Aging; Autoimmunity; Cancer; FOXP3; Immune senescence; Immune suppression; Inflammaging; Regulatory T cells; T helper 17; Treg
  4. Int J Mol Sci. 2020 Jul 23. pii: E5236. [Epub ahead of print]21(15):
      Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.
    Keywords:  mitochondria; mitochondrial dysfunction; muscle aging; sarcopenia; skeletal muscle
  5. Curr Opin Genet Dev. 2020 Jul 25. pii: S0959-437X(20)30099-X. [Epub ahead of print]64 94-100
      Cellular senescence has recently become causally implicated in pathological ageing. Hence, a great deal of research is currently dedicated towards developing senolytic agents to selectively kill senescent cells. However, senescence also plays important roles in a range of physiological processes including during organismal development, providing a barrier to tumorigenesis and in limiting fibrosis. Recent evidence also suggests a role for senescence in coordinating tissue remodelling and in the regeneration of complex structures. Through its non-cell-autonomous effects, a transient induction of senescence may create a permissive environment for remodelling or regeneration through promoting local proliferation, cell plasticity, tissue patterning, balancing growth, or indirectly through finely tuned interactions with infiltrating immune mediators. A careful analysis of the beneficial roles of cellular senescence may provide insights into important physiological processes as well as informing strategies to counteract its detrimental consequences in ageing and disease.
  6. Am J Pathol. 2020 Jul 28. pii: S0002-9440(20)30345-X. [Epub ahead of print]
      RORγt, a retinoid orphan nuclear receptor and the master transcription factor of the Th17 subset of CD4+T helper cells, is one of the most promising targets to treat a host of autoimmune diseases. This includes the inflammatory bowel diseases (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-caused by untoward reactivity of the immune system to the components of the intestinal microbiome. The mammalian intestinal tract is a highly complex and compartmentalized organ with specialized functions, and is a privileged site for the generation of both peripherally induced regulatory CD4+ T cells (Treg) and effector T helper 17 (Th17) cells. As Th17 cells can be proinflammatory in nature, the equilibrium between effector Th17 and Treg cells is critical for balancing intestinal homeostasis and inflammation. Recent findings suggest that RORγt, besides Th17 cells, is also expressed in peripherally induced, colonic regulatory CD4+T cells. Therefore, RORγt is expressed in both effector and regulatory subsets of CD4+T cells in the intestine. The present review discusses the role of RORγt in cellular and molecular differentiation of Th17 and Treg, and examines how targeting RORγt in IBD therapy could influence the development of these two diverse subsets of immune cells with opposing functions.
  7. Mech Ageing Dev. 2020 Jul 28. pii: S0047-6374(20)30117-2. [Epub ahead of print] 111321
      Decline in immune system function (immunosenescence) has been implicated in several age-related disorders. However, little is known about whether alteration in T-cell senescence, a process underlying immunological ageing, is related to muscle health in very old adults (aged ≥85 years). Utilising data from the Newcastle 85+ Study, we aimed to (a) derive and characterise immunosenescence profiles by clustering 13 baseline immunosenescence-related biomarkers of lymphocyte compartments in 657 participants; (b) explore the association between the profiles and 5-year change in muscle strength (grip strength) and physical performance (Timed Up-and-Go test), and (c) determine whether immunosenescence profiles predict 3-year incident sarcopenia. Two distinct clusters were identified; Cluster 1 ('Senescent-like phenotype', n = 421), and Cluster 2 ('Less senescent-like phenotype', n = 236) in individuals with complete biomarker data. Although Cluster 1 was characterised by T-cell senescence (e.g., higher frequency of CD4 and CD8 senescence-like effector memory cells), and elements of the immune risk profile (lower CD4/CD8 ratio, CMV+), it was not associated with change in muscle function over time, or with prevalent or incident sarcopenia. Future studies will determine whether more in-depth characterisation or change in T-cell phenotypes predict the decline in muscle health in late adulthood.
    Keywords:  immunosenescence; lymphocyte compartments; physical performance; sarcopenia; very old adults
  8. J Anat. 2020 Jul 31.
      Once regarded merely as a bland lipid storage disease consequence of aging, atherosclerosis is currently considered a slow and continuous inflammatory process (partially controllable by treatment) with complex etiology involving a multitude of genetic and environmental risk factors which ultimately result in the formation of the plaque. The vascular endothelium, a monolayer of endothelial cells (ECs), is an important regulatory "organ" critical for cardiovascular homeostasis in health which also contributes significantly to the pathomechanisms of several disease states, including atherosclerosis. Over the years, there has been evidence highlighting the central role of endoplasmic reticulum (ER) in the maintenance of endothelial function and perturbations in ER biology have been proposed to adversely affect a diverse range of endothelial functions. Of particular interest is the evidence that under certain pathophysiological circumstances, abnormal ER ultrastructure correlates with altered ER function and signaling and can contribute to cell injury and apoptosis. Therefore, the ultrastructural traits of ER membranes can have important implications not only for their functional bearings but also for the etiology and pathophysiology of diverse human disorders. With regard to atherosclerosis, the focus of ER research has been centered on the molecular signals originated from the ER to manage conditions of stress, leaving the fine structure of this organelle an almost unexplored (but promising) area of studies. There is, also, increasing evidence that mitochondrial dysfunction plays a critical role in promoting cell apoptosis, inflammation, and oxidative stress, thereby contributing to atheroma growth. It is within this context that the present study has been undertaken to investigate the microscopic architecture of ECs in human atherosclerosis and to determine whether the potential structural abnormalities of ER and mitochondria may play a central pathogenic role in atherogenesis or may merely reflect the condition of a tissue whose integrity has already been disturbed or destroyed. For this purpose, transmission electron microscopy (TEM) remains a powerful technique that can not only provide information about the ultrastructural state of cell organelles but also allow the correlation between different subcellular alterations indicative of a certain pathophysiological condition and cellular response. The present study expands the spectrum of ultrastructural defects known to exist in human atherosclerosis and suggests that ER alterations may be of great importance in the pathogenesis of the disease. The architectural changes of ER may be considered early pathological events that precede any overt histologic abnormalities in the vascular endothelium and its subcellular organelles, primarily the mitochondrial pool.
    Keywords:  atherosclerosis; electron microscopy; endoplasmic reticulum; endothelial cells; mitochondria
  9. Nat Biomed Eng. 2020 Jul 27.
      The function of a T cell depends on its subtype and activation state. Here, we show that imaging of the autofluorescence lifetime signals of quiescent and activated T cells can be used to classify the cells. T cells isolated from human peripheral blood and activated in culture using tetrameric antibodies against the surface ligands CD2, CD3 and CD28 showed specific activation-state-dependent patterns of autofluorescence lifetime. Logistic regression models and random forest models classified T cells according to activation state with 97-99% accuracy, and according to activation state (quiescent or activated) and subtype (CD3+CD8+ or CD3+CD4+) with 97% accuracy. Autofluorescence lifetime imaging can be used to non-destructively determine T-cell function.
  10. Exp Hematol. 2020 Jul 28. pii: S0301-472X(20)30301-5. [Epub ahead of print]
      The coordinated differentiation of hematopoietic stem and progenitor cells (HSPCs) into the various mature blood cell types is responsible for sustaining blood and immune system homeostasis. The cell fate decisions underlying this important biological process are made at the level of single cells. Methods to trace the fate of single cells are therefore essential for understanding the hematopoietic system activity in health and disease, and have made a major impact in how we understand and represent hematopoiesis. Here, we discuss the basic methodologies and technical considerations for three important clonal assays: single cell transplantation, lentiviral barcoding, and sleeping beauty barcoding. This Perspective is a synthesis of presentations and discussions from the 2019 International Society for Experimental Hematology (ISEH) Annual Meeting New Investigator Technology Session and the 2019 ISEH Winter Webinar.
    Keywords:  HSC transplantation; Hematopoiesis; hematopoietic progenitor cell; hematopoietic stem cell; lentiviral barcoding; lineage tracing; single cell biology; sleeping beauty
  11. Front Cell Dev Biol. 2020 ;8 591
      Regulation of stem cell fate is best understood at the level of gene and protein regulatory networks, though it is now clear that multiple cellular organelles also have critical impacts. A growing appreciation for the functional interconnectedness of organelles suggests that an orchestration of integrated biological networks functions to drive stem cell fate decisions and regulate metabolism. Metabolic signaling itself has emerged as an integral regulator of cell fate including the determination of identity, activation state, survival, and differentiation potential of many developmental, adult, disease, and cancer-associated stem cell populations and their progeny. As the primary adenosine triphosphate-generating organelles, mitochondria are well-known regulators of stem cell fate decisions, yet it is now becoming apparent that additional organelles such as the lysosome are important players in mediating these dynamic decisions. In this review, we will focus on the emerging role of organelles, in particular lysosomes, in the reprogramming of both metabolic networks and stem cell fate decisions, especially those that impact the determination of cell identity. We will discuss the inter-organelle interactions, cell signaling pathways, and transcriptional regulatory mechanisms with which lysosomes engage and how these activities impact metabolic signaling. We will further review recent data that position lysosomes as critical regulators of cell identity determination programs and discuss the known or putative biological mechanisms. Finally, we will briefly highlight the potential impact of elucidating mechanisms by which lysosomes regulate stem cell identity on our understanding of disease pathogenesis, as well as the development of refined regenerative medicine, biomarker, and therapeutic strategies.
    Keywords:  cancer stem cell (CSC); lysosomes; metabolism; neural crest (NC); neural stem cell (NSC); pluripotent stem cell (PSC); stem cell identity and fate