bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒04‒11
twenty papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Nature. 2021 Apr 07.
      Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.
  2. Cold Spring Harb Perspect Biol. 2021 Apr 05. pii: a037770. [Epub ahead of print]
      The formation of long-lived memory T cells is a critical feature of the adaptive immune response. T cells undergo metabolic reprogramming to establish a functional memory population. While initial studies characterized key metabolic pathways necessary for memory T-cell development, recent findings highlight that metabolic regulation of memory T-cell subsets is diverse. Here we describe the different requirements for metabolic programs and metabolism-related signaling pathways in memory T-cell development. We further discuss the contribution of cellular metabolism to memory T-cell functional reprogramming and stemness within acute and chronic inflammatory environments. Last, we highlight knowledge gaps and propose approaches to determine the roles of metabolites and metabolic enzymes in memory T-cell fate. Understanding how cellular metabolism regulates a functionally diverse memory population will undoubtedly provide new therapeutic insights to modulate protective T-cell immunity in human disease.
  3. Nat Rev Nephrol. 2021 Apr 07.
      Insights into the relationship between immunometabolism and inflammation have enabled the targeting of several immunity-mediated inflammatory processes that underlie infectious diseases and cancer or drive transplant rejection, but this field remains largely unexplored in kidney diseases. The kidneys comprise heterogeneous cell populations, contain distinct microenvironments such as areas of hypoxia and hypersalinity, and are responsible for a functional triad of filtration, reabsorption and secretion. These distinctive features create myriad potential metabolic therapeutic targets in the kidney. Immune cells have crucial roles in the maintenance of kidney homeostasis and in the response to kidney injury, and their function is intricately connected to their metabolic properties. Changes in nutrient availability and biomolecules, such as cytokines, growth factors and hormones, initiate cellular signalling events that involve energy-sensing molecules and other metabolism-related proteins to coordinate immune cell differentiation, activation and function. Disruption of homeostasis promptly triggers the metabolic reorganization of kidney immune and non-immune cells, which can promote inflammation and tissue damage. The metabolic differences between kidney and immune cells offer an opportunity to specifically target immunometabolism in the kidney.
  4. Immunol Lett. 2021 Mar 31. pii: S0165-2478(21)00050-X. [Epub ahead of print]
      The human immune system is in continuous interaction with environmental factors (pathogens, exercise, stress, pollutants, diet, vaccines, and therapeutics) that condition its efficiency by promoting or moderating multiple immune mechanisms. While the deleterious impact of external factors can be avoided or limited, the immune system itself grows weaker with age. Immune cells persist in the elderly, and the observed decline of cellular immunity is related to cellular senescence. Immunosenescence, which affects both T and B cells, erodes lymphocyte-dependent responses to vaccines and pathogens. Germinal centers (GCs), the organized lymphoid structures where B cells engage in affinity maturation, are regulated by follicular helper (Tfh) and follicular regulatory (Tfr) T cells, the major T cell components of GCs. This review discusses how age-related changes affect Tfh and Tfr cells as key components of B cell immunity, and how they ultimately shape the response of the ageing immune system to vaccines and infectious challenges.
    Keywords:  Ageing; B cells; T cells
  5. Mol Cell. 2021 Mar 27. pii: S1097-2765(21)00213-6. [Epub ahead of print]
      Cellular senescence is a state of stable proliferative arrest triggered by damaging signals. Senescent cells persist during aging and promote age-related pathologies via the pro-inflammatory senescence-associated secretory phenotype (SASP), whose regulation depends on environmental factors. In vivo, a major environmental variable is oxygenation, which varies among and within tissues. Here, we demonstrate that senescent cells express lower levels of detrimental pro-inflammatory SASP factors in physiologically hypoxic environments, as measured in culture and in tissues. Mechanistically, exposure of senescent cells to low-oxygen conditions leads to AMPK activation and AMPK-mediated suppression of the mTOR-NF-κB signaling loop. Finally, we demonstrate that treatment with hypoxia-mimetic compounds reduces SASP in cells and tissues and improves strength in chemotherapy-treated and aged mice. Our findings highlight the importance of oxygen as a determinant for pro-inflammatory SASP expression and offer a potential new strategy to reduce detrimental paracrine effects of senescent cells.
    Keywords:  SASP; aging; hypoxia; hypoxia mimetics; oxygen; p16; senescence
  6. Nat Metab. 2021 Apr 08.
      Nicotinamide adenine dinucleotide phosphate (NADP+) is vital to produce NADPH, a principal supplier of reducing power for biosynthesis of macromolecules and protection against oxidative stress. NADPH exists in separate pools, in both the cytosol and mitochondria; however, the cellular functions of mitochondrial NADPH are incompletely described. Here, we find that decreasing mitochondrial NADP(H) levels through depletion of NAD kinase 2 (NADK2), an enzyme responsible for production of mitochondrial NADP+, renders cells uniquely proline auxotrophic. Cells with NADK2 deletion fail to synthesize proline, due to mitochondrial NADPH deficiency. We uncover the requirement of mitochondrial NADPH and NADK2 activity for the generation of the pyrroline-5-carboxylate metabolite intermediate as the bottleneck step in the proline biosynthesis pathway. Notably, after NADK2 deletion, proline is required to support nucleotide and protein synthesis, making proline essential for the growth and proliferation of NADK2-deficient cells. Thus, we highlight proline auxotrophy in mammalian cells and discover that mitochondrial NADPH is essential to enable proline biosynthesis.
  7. Curr Mol Biol Rep. 2020 Dec;6(4): 173-182
      Purpose of review: Mesenchymal stem cells (MSCs) have been extensively studied for therapeutic application in tissue engineering and regenerative medicine. Despite their promise, recent findings suggest that MSC replication during repair process may lead to replicative senescence and stem cell exhaustion. Here, we review the basic mechanisms of MSC senescence, how it leads to degenerative diseases, and potential treatments for such diseases.Recent findings: Emerging evidence has shown a link between senescent MSCs and degenerative diseases, especially age-related diseases such as osteoarthritis and idiopathic pulmonary fibrosis. During these disease processes, MSCs undergo cell senescence and mediate Senescence Associated Secretory Phenotypes (SASP) to affect the surrounding microenvironment. Thus, senescent MSCs can accelerate tissue aging by increasing the number of senescent cells and spreading inflammation to neighboring cells.
    Summary: Senescent MSCs not only hamper tissue repair through cell senescence associated stem cell exhaustion, but also mediate tissue degeneration by initiating and spreading senescence-associated inflammation. It suggests new strategies of MSC-based cell therapy to remove, rejuvenate, or replace (3Rs) the senescent MSCs.
    Keywords:  Age-associated diseases; Cell senescence; Mesenchymal stem cells; Osteoarthritis; Replication stress; Senolytics
  8. Nature. 2021 Apr 07.
      Bile acids are lipid-emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine1. As detergents, bile acids can cause toxicity and inflammation in enterohepatic tissues2. Nuclear receptors maintain bile acid homeostasis in hepatocytes and enterocytes3, but it is unclear how mucosal immune cells tolerate high concentrations of bile acids in the small intestine lamina propria (siLP). CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1 (encoded by Abcb1a) in the siLP to prevent bile acid toxicity and suppress Crohn's disease-like small bowel inflammation4. Here we identify the nuclear xenobiotic receptor CAR (encoded by Nr1i3) as a regulator of MDR1 expression in T cells that can safeguard against bile acid toxicity and inflammation in the mouse small intestine. Activation of CAR induced large-scale transcriptional reprogramming in Teff cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine IL-10. Accordingly, CAR deficiency in T cells exacerbated bile acid-driven ileitis in T cell-reconstituted Rag1-/- or Rag2-/- mice, whereas pharmacological activation of CAR suppressed it. These data suggest that CAR acts locally in T cells that infiltrate the small intestine to detoxify bile acids and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohn's disease and defines lymphocyte sub-specialization in the small intestine.
  9. Cell Metab. 2021 Mar 31. pii: S1550-4131(21)00115-7. [Epub ahead of print]
      Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation, and many age-related pathologies. By contrast, lipid components of the SASP are understudied. We show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. These data identify an important aspect of cellular senescence and a method to detect senolysis.
    Keywords:  15d-PGJ2; RAS; SASP; aging; biomarker; cellular senescence; dihomo-prostaglandin; eicosanoid; lipids; mass spectrometry; metabolomics; oxylipin; prostaglandin; senescence
  10. Nat Rev Drug Discov. 2021 Apr 08.
      Cell therapy is one of the fastest growing areas in the pharmaceutical industry, with considerable therapeutic potential. However, substantial challenges regarding the utility of these therapies will need to be addressed before they can become mainstream medicines with applicability similar to that of small molecules or monoclonal antibodies. Engineered T cells have achieved success in the treatment of blood cancers, with four chimeric antigen receptor (CAR)-T cell therapies now approved for the treatment of B cell malignancies based on their unprecedented efficacy in clinical trials. However, similar results have not yet been achieved in the treatment of the much larger patient population with solid tumours. For cell therapies to become mainstream medicines, they may need to offer transformational clinical effects for patients and be applicable in disease settings that remain unaddressed by simpler approaches. This Perspective provides an industry perspective on the progress achieved by engineered T cell therapies to date and the opportunities and current barriers for accessing broader patient populations, and discusses the solutions and new development strategies required to fully industrialize the therapeutic potential of engineered T cells as medicines.
  11. Front Immunol. 2021 ;12 645242
      Emerging reports show that metabolic pathways can be targeted to enhance T cell-mediated immunity to tumors. Yet, tumors consume key metabolites in the host to survive, thus robbing T cells of these nutrients to function and thrive. T cells are often deprived of basic building blocks for energy in the tumor, including glucose and amino acids needed to proliferate or produce cytotoxic molecules against tumors. Immunosuppressive molecules in the host further compromise the lytic capacity of T cells. Moreover, checkpoint receptors inhibit T cell responses by impairing their bioenergetic potential within tumors. In this review, we discuss the fundamental metabolic pathways involved in T cell activation, differentiation and response against tumors. We then address ways to target metabolic pathways to improve the next generation of immunotherapies for cancer patients.
    Keywords:  T cell metabolism; adoptive T cell transfer; immune checkpoint therapy; tumor infiltrating lymphocytes; tumor metabolism; tumor microenvironment
  12. Nat Immunol. 2021 Apr 08.
      FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (Treg) cells. CD4+ T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous Treg-like cells, some very similar to normal Treg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4+ T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal Treg cells exerted dominant suppression, quenching the disease signature and revealing in mutant Treg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes Treg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering Treg cell dysfunction. Accordingly, interleukin-2 treatment improved the Treg-like compartment and survival.
  13. JCI Insight. 2021 Apr 06. pii: 137761. [Epub ahead of print]
      T cell receptor (TCR) triggering by antigen results in metabolic reprogramming that, in turn, facilitates T cells' exit from quiescence. The increased nutrient requirements of activated lymphocytes are met in part by upregulation of cell surface transporters and enhanced uptake of amino acids, fatty acids and glucose from the environment. However, the role of intracellular pathways of amino acid biosynthesis in T cell activation is relatively unexplored. Asparagine (Asn) is a non-essential amino acid that can be synthesized intracellularly through the glutamine-hydrolyzing enzyme asparagine synthetase (ASNS). We set out to define the requirements for uptake of extracellular Asn and ASNS activity in CD8+ T cell activation. At early timepoints of activation in vitro, CD8+ T cells expressed little or no ASNS and, as a consequence, viability and TCR-stimulated growth, activation and metabolic reprogramming were substantially impaired under conditions of Asn deprivation. At later timepoints (>24h of activation), TCR-induced mTOR-dependent signals resulted in upregulation of ASNS, that endowed CD8+ T cells with the capacity to function independently of extracellular Asn. Thus, our data suggest that the coordinated upregulation of ASNS expression and uptake of extracellular Asn is involved in optimal T cell effector responses.
    Keywords:  Amino acid metabolism; Immunology; T cells
  14. Cell Rep. 2021 Apr 06. pii: S2211-1247(21)00258-8. [Epub ahead of print]35(1): 108944
      Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.
    Keywords:  CCL5; CDK4/6 inhibitors; ROS; adoptive cell transfer; anti-tumor immunity; cancer metabolism; chemokines; metabolic stress; palbociclib
  15. Mol Ther Methods Clin Dev. 2021 Jun 11. 21 133-143
      In solid malignancies, including head and neck squamous cell carcinoma (HNSCC), the immunosuppressive molecule adenosine, which accumulates in the tumor, suppresses cytotoxic CD8+ T cell functions including chemotaxis and tumor infiltration. Adenosine functions through binding to the adenosine A2A receptor (A2AR) present on T cells. In order to increase T cell migration into the tumor, the negative effect of adenosine must be abrogated. Systemic drug treatments targeting A2AR are available; however, they could lead to negative toxicities due to the broad expression of this receptor. Herein, we developed a lipid nanoparticle (NP)-based targeted delivery approach to knock down A2AR in T cells in order to increase their chemotaxis in the presence of adenosine. By using flow cytometry, immunofluorescence, qRT-PCR, and 3D-chemotaxis, we demonstrated that CD45RO-labeled nanoparticles delivering ADORA2A gene-silencing-RNAs decreased ADORA2A mRNA expression and rescued the chemotaxis of HNSCC CD8+ memory T cells. Overall, the data indicate that targeting the adenosine signaling pathway with lipid NPs is successful at suppressing the inhibitory effect of adenosine on the chemotaxis of HNSCC memory T cells, which could ultimately help increase T cell infiltration into the tumor.
  16. Front Immunol. 2020 ;11 624199
      Resident memory CD8+ T (TRM) cells are a lymphocyte lineage distinct from circulating memory CD8+ T cells. TRM lodge within peripheral tissues and secondary lymphoid organs where they provide rapid, local protection from pathogens and control tumor growth. However, dysregulation of CD8+ TRM formation and/or activation may contribute to the pathogenesis of autoimmune diseases. Intrinsic mechanisms, including transcriptional networks and inhibitory checkpoint receptors control TRM differentiation and response. Additionally, extrinsic stimuli such as cytokines, cognate antigen, fatty acids, and damage signals regulate TRM formation, maintenance, and expansion. In this review, we will summarize knowledge of CD8+ TRM generation and highlight mechanisms that regulate the persistence and responses of heterogeneous TRM populations in different tissues and distinct microenvironments.
    Keywords:  T cell differentiation; microenvironment; recall response; tissue resident memory T cell; transcriptional regulation
  17. Front Cell Dev Biol. 2021 ;9 634003
      Lymphocyte homeostasis, activation and differentiation crucially rely on basal autophagy. The fine-tuning of this process depends on autophagy-related (ATG) proteins and their interaction with the trafficking machinery that orchestrates the membrane rearrangements leading to autophagosome biogenesis. The underlying mechanisms are as yet not fully understood. The intraflagellar transport (IFT) system, known for its role in cargo transport along the axonemal microtubules of the primary cilium, has emerged as a regulator of autophagy in ciliated cells. Growing evidence indicates that ciliogenesis proteins participate in cilia-independent processes, including autophagy, in the non-ciliated T cell. Here we investigate the mechanism by which IFT20, an integral component of the IFT system, regulates basal T cell autophagy. We show that IFT20 interacts with the core autophagy protein ATG16L1 and that its CC domain is essential for its pro-autophagic activity. We demonstrate that IFT20 is required for the association of ATG16L1 with the Golgi complex and early endosomes, both of which have been identified as membrane sources for phagophore elongation. This involves the ability of IFT20 to interact with proteins that are resident at these subcellular localizations, namely the golgin GMAP210 at the Golgi apparatus and Rab5 at early endosomes. GMAP210 depletion, while leading to a dispersion of ATG16L1 from the Golgi, did not affect basal autophagy. Conversely, IFT20 was found to recruit ATG16L1 to early endosomes tagged for autophagosome formation by the BECLIN 1/VPS34/Rab5 complex, which resulted in the local accumulation of LC3. Hence IFT20 participates in autophagosome biogenesis under basal conditions by regulating the localization of ATG16L1 at early endosomes to promote autophagosome biogenesis. These data identify IFT20 as a new regulator of an early step of basal autophagy in T cells.
    Keywords:  ATG16L1; T cell; autophagy; early endosomes; intraflagellar transport; vesicular trafficking
  18. J Clin Invest. 2021 Apr 06. pii: 147683. [Epub ahead of print]
      Inhibitors of calcineurin phosphatase activity (CNIs) such as cyclosporin A (CsA) are widely used to treat tissue transplant rejection and acute graft-versus-host disease (aGVHD), for which inhibition of NFAT-dependent gene expression is the mechanistic paradigm. We recently reported that CNIs inhibit TCR-proximal signaling by preventing calcineurin-mediated dephosphorylation of LckS59, an inhibitory modification, raising the possibility of another mechanism by which CNIs suppress immune responses. Here we utilized T cells from mice that express LckS59A, which cannot accept a phosphate at residue 59, to initiate aGVHD. Although CsA inhibited NFAT-dependent gene upregulation in allo-aggressive T cells expressing either LckWT or LckS59A, it was ineffective in treating disease when the T cells expressed LckS59A. Two important NFAT-independent T cell functions were found to be CsA-resistant in LckS59A T cells: upregulation of the cytolytic protein perforin in tissue-infiltrating CD8+ T cells and antigen-specific T:DC (dendritic cell) adhesion and clustering in lymph nodes. These results demonstrate that effective treatment of aGVHD by CsA requires NFAT-independent inhibition of TCR signaling. Given that NFATs are widely expressed and off-target effects are a major limitation in CNI use, it is possible that targeting TCR-associated calcineurin directly may provide effective therapies with less toxicity.
    Keywords:  Immunology; Organ transplantation; Signal transduction