bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒02‒28
thirteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Exp Mol Med. 2021 Feb 24.
      Chronic infection with persistent antigenic stimulation results in the generation of exhausted CD8+ T cells, which are considered defective effector CD8+ T cells, and thus compromises effective immune responses. However, recent studies have illustrated that exhausted CD8+ T cells may be purposely generated and maintained to provide mild immune responses against chronic infection or cancer, which can be safer over a long period of time than strong immune responses. Indeed, a specific population of exhausted CD8+ T cells that behaves similarly to self-renewing stem cells and provides a continuous supply of exhausted CD8+ T cells has been identified, indicating that this population can be considered progenitors of exhausted CD8+ T cells. Furthermore, several ground-breaking studies in the last few years have shed new light on the transcriptional regulatory network governing the generation and propagation of exhausted CD8+ T cells, which involves T cell receptor (TCR) signaling that leads to NFAT-TCF1 (nuclear factor of activated T cells-T cell factor 1) activity followed by activation of the TOX/NR4A axis. Elucidation of the intracellular signaling pathways will help to define the definitive developmental stages leading to exhausted CD8+ T cells, which can be exploited to advance our never-ending battle against cancer. This review will summarize the recent discoveries that have deepened our understanding of the exhaustion program of cytotoxic CD8+ T cells.
  2. Front Immunol. 2020 ;11 623989
      Accumulating evidence has shown that nutrient metabolism is closely associated with the differentiation and functions of various immune cells. Cellular metabolism, including aerobic glycolysis, fatty acid oxidation, and oxidative phosphorylation, plays a key role in germinal center (GC) reaction, B-cell trafficking, and T-cell-fate decision. Furthermore, a quiescent metabolic status consolidates T-cell-dependent immunological memory. Therefore, dietary interventions such as calorie restriction, time-restricted feeding, and fasting potentially manipulate immune cell functions. For instance, intermittent fasting prevents the development of experimental autoimmune encephalomyelitis. Meanwhile, the fasting response diminishes the lymphocyte pool in gut-associated lymphoid tissue to minimize energy expenditure, leading to the attenuation of Immunoglobulin A (IgA) response. The nutritional status also influences the dynamics of several immune cell subsets. Here, we describe the current understanding of the significance of immunometabolism in the differentiation and functionality of lymphocytes and macrophages. The underlying molecular mechanisms also are discussed. These experimental observations could offer new therapeutic strategies for immunological disorders like autoimmunity.
    Keywords:  AMPK; GCN2; calorie restriction; dietary intervention; fasting; mTOR; metabolic rewiring
  3. Immunol Rev. 2020 Dec 07.
      Once alerted to the presence of a pathogen, activated CD4+ T cells initiate distinct gene expression programs that produce multiple functionally specialized T helper (Th) subsets. The cytokine milieu present at the time of antigen encounter instructs CD4+ T cells to differentiate into interferon-(IFN)-γ-producing Th1 cells, interleukin-(IL)-4-producing Th2 cells, IL-17-producing Th17 cells, follicular T helper (Tfh) cells, or regulatory T (Treg) cells. In each of these Th cell subsets, a single transcription factor has been identified as a critical regulator of its specialized differentiation program. In this context, the expression of the "master regulator" is necessary and sufficient to activate lineage-specific genes while restricting the gene expression program of alternative Th fates. Thus, the transcription factor T-bet controls Th1 differentiation program, while the development of Th2, Th17, Tfh, and Treg cells is dependent on transcription factors GATA3, RORγt, Bcl6, and Foxp3, respectively. Nevertheless, master regulators or, more precisely, lineage-defining transcription factors do not function in isolation. In fact, they interact with a complex network of transcription factors, orchestrating cell lineage specification programs. In this review, we discuss the concept of the combinatorial interactions of key transcription factors in determining helper T cell identity. Additionally, lineage-defining transcription factors have well-established functions beyond their role in CD4+ Th subsets. They play critically important functions at distinct stages during T cell development in the thymus and they control the development of innate lymphoid cells (ILCs) in the bone marrow. In tracking the journey of T cells traversing from the thymus to the periphery and during the immune response, we discuss in broad terms developmental stage and context-dependent functions of lineage-defining transcription factors in regulating specification programs of innate and adaptive lymphocytes.
    Keywords:  T cells; Th1/Th2/Th17 cells; cell lineages and subsets; molecules; transcription factors
  4. Front Immunol. 2020 ;11 592328
      Chronic hepatotropic viral infections are characterized by exhausted CD8+ T cells in the presence of cognate antigen in the liver. The impairment of T cell response limits the control of chronic hepatotropic viruses. Immune-modulatory strategies are attractive options to re-invigorate exhausted T cells. However, in hepatotropic viral infections, the knowledge about immune-modulatory effects on the in-situ regulation of exhausted intrahepatic CD8+ T cells is limited. In this study, we elucidated the functional heterogeneity in the pool of exhausted CD8+ T cells in the liver of mice expressing the model antigen Ova in a fraction of hepatocytes. We found a subpopulation of intrahepatic CXCR5+ Ova-specific CD8+ T cells, which are profoundly cytotoxic, exhibiting efficient metabolic functions as well as improved memory recall and self-maintenance. The intrahepatic Ova-specific CXCR5+ CD8+ T cells are possibly tissue resident cells, which may rely largely on OXPHOS and glycolysis to fuel their cellular processes. Importantly, host conditioning with CpG oligonucleotide reinvigorates and promotes exhausted T cell expansion, facilitating complete antigen eradication. The CpG oligonucleotide-mediated reinvigoration may support resident memory T cell formation and the maintenance of CXCR5+ Ova-specific CD8+ T cells in the liver. These findings suggest that CpG oligodinucleotide may preferentially target CXCR5+ CD8+ T cells for expansion to facilitate the revival of exhausted T cells. Thus, therapeutic strategies aiming to expand CXCR5+ CD8+ T cells might provide a novel approach against chronic liver infection.
    Keywords:  CXCR5+ T cells; CpG oligonucleotide; T cell exhaustion; T cell reinvigoration; exhausted stem-like T cells; follicular helper-like T cells; liver; liver resident T cells
  5. Inflammation. 2021 Feb 24.
      PD-1 is a critical therapeutic target in cancer immunotherapy and antibodies blocking PD-1 are approved for multiple types of malignancies. The phosphatase SHP2 is the main effector mediating PD-1 downstream signaling and accordingly attempts have been made to target this enzyme as an alternative approach to treat immunogenic tumors. Unfortunately, small molecule inhibitors of SHP2 do not work as expected, suggesting that the role of SHP2 in T cells is more complex than initially hypothesized. To better understand the perplexing role of SHP2 in T cells, we performed interactome mapping of SAP, an adapter protein that is associated with SHP2 downstream signaling. Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions. This study suggests that ITK is a unique target in this pathway, and since ITK is a SHP2-dependent specific mediator of PD-1 signaling, the combination of ITK inhibitors with PD-1 blockade may improve upon PD-1 monotherapy in the treatment of cancer.
    Keywords:  ITK; PD-1; SHP2; T cell receptor
  6. Cell. 2021 Feb 22. pii: S0092-8674(21)00171-9. [Epub ahead of print]
      How early events in effector T cell (TEFF) subsets tune memory T cell (TMEM) responses remains incompletely understood. Here, we systematically investigated metabolic factors in fate determination of TEFF and TMEM cells using in vivo pooled CRISPR screening, focusing on negative regulators of TMEM responses. We found that amino acid transporters Slc7a1 and Slc38a2 dampened the magnitude of TMEM differentiation, in part through modulating mTORC1 signaling. By integrating genetic and systems approaches, we identified cellular and metabolic heterogeneity among TEFF cells, with terminal effector differentiation associated with establishment of metabolic quiescence and exit from the cell cycle. Importantly, Pofut1 (protein-O-fucosyltransferase-1) linked GDP-fucose availability to downstream Notch-Rbpj signaling, and perturbation of this nutrient signaling axis blocked terminal effector differentiation but drove context-dependent TEFF proliferation and TMEM development. Our study establishes that nutrient uptake and signaling are key determinants of T cell fate and shape the quantity and quality of TMEM responses.
    Keywords:  GDP-fucose; Notch; T cell memory; cell cycle exit; immunometabolism; in vivo pooled CRISPR screening; metabolic heterogeneity; nutrient signaling; systems immunology; terminal effector cell
  7. Cell Death Dis. 2021 Feb 26. 12(2): 215
      Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.
  8. Nat Commun. 2021 02 22. 12(1): 1209
      Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.
  9. Cell. 2021 Feb 25. pii: S0092-8674(21)00169-0. [Epub ahead of print]
      Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.
    Keywords:  CD8; CRISPR; Fli1; cancer; chronic infection; effector CD8 T cell; exhausted CD8 T cell; exhaustion; immunotherapy; protective immunity
  10. Oxid Med Cell Longev. 2021 ;2021 8865791
      Leukocytes, including macrophages and T cells, represent key players in the human immune system, which plays a considerable role in the development and progression of tumors by immune surveillance or immune escape. Boosting the recruitment of leukocytes into the tumor microenvironment and promoting their antitumor responses have been hot areas of research in recent years. Although immunotherapy has manifested a certain level of success in some malignancies, the overall effectiveness is far from satisfactory. Iron is an essential trace element required in multiple, normal cellular processes, such as DNA synthesis and repair, cellular respiration, metabolism, and signaling, while dysregulated iron metabolism has been declared one of the metabolic hallmarks of malignant cancer cells. Furthermore, iron is implicated in the modulation of innate and adaptive immune responses, and elucidating the targeted regulation of iron metabolism may have the potential to benefit antitumor immunity and cancer treatment. In the present review, we briefly summarize the roles of leukocytes and iron metabolism in tumorigenesis, as well as their crosstalk in the tumor microenvironment. The combination of immunotherapy with targeted regulation of iron and iron-dependent regulated cell death (ferroptosis) may be a focus of future research.
  11. Nat Rev Immunol. 2021 Feb 24.
      Effector T cells leave the lymph nodes armed with specialized functional attributes. Their antigenic targets may be located anywhere in the body, posing the ultimate challenge: how to efficiently identify the target tissue, navigate through a complex tissue matrix and, ultimately, locate the immunological insult. Recent advances in real-time in situ imaging of effector T cell migratory behaviour have revealed a great degree of mechanistic plasticity that enables effector T cells to push and squeeze their way through inflamed tissues. This process is shaped by an array of 'stop' and 'go' guidance signals including target antigens, chemokines, integrin ligands and the mechanical cues of the inflamed microenvironment. Effector T cells must sense and interpret these competing signals to correctly position themselves to mediate their effector functions for complete and durable responses in infectious disease and malignancy. Tuning T cell migration therapeutically will require a new understanding of this complex decision-making process.
  12. Front Immunol. 2020 ;11 622509
      Tumor-specific CD8+T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called "exhaustion." Though functioning to limit damage caused by immune response, T cell exhaustion leads to attenuated effector function whereby cytotoxic CD8+T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to "progenitor exhaustion" through to "terminally exhaustion" with distinct properties. With the rapid development of immunotherapy via enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8+T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.
    Keywords:  CD8+ T cell activation; CD8+ T cell exhaustion; differentiation; immunotherapy; tumor microenvironment