bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒04‒25
twelve papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

  1. Front Immunol. 2021 ;12 638010
      Background: Immune non-responders (INR) are HIV+, ART-controlled (>2 yrs) people who fail to reconstitute their CD4 T cell numbers. Systemic inflammation and markers of T cell senescence and exhaustion are observed in INR. This study aims to investigate T cell senescence and exhaustion and their possible association with soluble immune mediators and to understand the immune profile of HIV-infected INR. Selected participants were <50 years old to control for the confounder of older age. Methods: Plasma levels of IL-6, IP10, sCD14, sCD163, and TGF-β and markers of T cell exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were measured in ART-treated, HIV+ participants grouped by CD4 T cell counts (n = 63). Immune parameters were also measured in HIV-uninfected, age distribution-matched controls (HC; n = 30). Associations between T cell markers of exhaustion and senescence and plasma levels of immune mediators were examined by Spearman rank order statistics. Results: Proportions of CD4 T cell subsets expressing markers of exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were elevated in HIV+ participants. When comparing proportions between INR and IR, INR had higher proportions of CD4 memory PD-1+, EM CD57+, TEM TIGIT+ and CD8 EM and TEM TIGIT+ cells. Plasma levels of IL-6, IP10, and sCD14 were elevated during HIV infection. IP10 was higher in INR. Plasma TGF-β levels and CD4 cycling proportions of T regulatory cells were lower in INR. Proportions of CD4 T cells expressing TIGIT, PD-1, and CD57 positively correlated with plasma levels of IL-6. Plasma levels of TGF-β negatively correlated with proportions of TIGIT+ and PD-1+ T cell subsets. Conclusions: INR have lower levels of TGF-β and decreased proportions of cycling CD4 T regulatory cells and may have difficulty controlling inflammation. IP10 is elevated in INR and is linked to higher proportions of T cell exhaustion and senescence seen in INR.
    Keywords:  HIV+ immune non-responders; IL-6; T regulatory cells; TGF-β; age; exhaustion; inflammation; senescence
  2. Nat Rev Immunol. 2021 Apr 20.
      The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term persistence. In patients with cancer, the presence of endogenous or adoptively transferred T cells with stem-like memory or precursor phenotype correlates with improved therapeutic outcomes. Advances in our understanding of T cell differentiation states at the epigenetic and transcriptional levels have led to the development of novel methods to generate tumour-specific T cells - namely, chimeric antigen receptor T cells - that are more persistent and resistant to the development of dysfunction. These include the use of novel culture methods before infusion, modulation of transcriptional, metabolic and/or epigenetic programming, and strategies that fine-tune antigen receptor signalling. This Review discusses existing barriers and strategies to overcome them for successful T cell expansion and persistence in the context of adoptive T cell immunotherapy for solid cancers.
  3. Trends Immunol. 2021 Apr 15. pii: S1471-4906(21)00054-5. [Epub ahead of print]
      In the direct competition for metabolic resources between cancer cells and tumor-infiltrating CD8+ T cells, the latter are bound to lose out. These effector lymphocytes are therefore rendered exhausted or dysfunctional. Emerging insights into the mechanisms of T cell unresponsiveness in the tumor microenvironment (TME) point towards epigenetic mechanisms as crucial regulatory factors. In this review, we discuss the effects of characteristic components of the TME, i.e. glucose/amino acid dearth with elevated levels of reactive oxygen species (ROS), on DNA methylation and histone modifications in CD8+ T cells. We then take a closer look at the translational potential of epigenetic interventions that aim to improve current immunotherapeutic strategies, including the adoptive transfer of T cell receptor (TCR) or chimeric antigen receptor (CAR) engineered T cells.
  4. Front Immunol. 2021 ;12 652687
      T cells undergo metabolic reprogramming and multiple biological processes to satisfy their energetic and biosynthetic demands throughout their lifespan. Several of these metabolic pathways result in the generation of reactive oxygen species (ROS). The imbalance between ROS generation and scavenging could result in severe damage to the cells and potential cell death, ultimately leading to T cell-related diseases. Interestingly, ROS play an essential role in T cell immunity. Here, we introduce the important connectivity between T cell lifespan and the metabolic reprogramming among distinct T cell subsets. We also discuss the generation and sources of ROS production within T cell immunity as well as highlight recent research concerning the effects of ROS on T cell activities.
    Keywords:  T cells; cell metabolism; disease; immunity; reactive oxygen species
  5. Nat Med. 2021 Apr 22.
      While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19- disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials ( NCT02588456 and NCT02650414 ) of T cells bearing a 4-1BB-based, CD22-targeting CAR in patients with relapsed or refractory ALL. The primary end point of these studies was to assess safety, and the secondary end point was antileukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homodimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 4-1BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs and, on the basis of these observations, designed a new short-linker CD22 single-chain variable fragment for clinical evaluation. Our findings both suggest that tonic 4-1BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.
  6. Immun Ageing. 2021 Apr 19. 18(1): 19
      BACKGROUND: The impact of aging on the immune system is unequivocal and results in an altered immune status termed immunosenescence. In humans, the mechanisms of immunosenescence have been examined almost exclusively in blood. However, most immune cells are present in tissue compartments and exhibit differential cell (e.g., memory T cells -TM) subset distributions. Thus, it is crucial to understand immunosenescence in tissues, especially those that are exposed to pathogens (e.g., intestine). Using a human model of oral live attenuated typhoid vaccine, Ty21a, we investigated the effect of aging on terminal ileum (TI) tissue resident memory T (TRM) cells. TRM provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts TRM S. Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI S. Typhi-responsive TRM subsets elicited by Ty21a immunization.RESULTS: We observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) TM and TRM in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ TRM displayed a positive correlation with age whilst the CD4/CD8 ratio in LPMC displayed a negative correlation with age. We observed that elderly volunteers have weaker S. Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ TRM showed reduced IL-17A production, while CD103- CD4+ TRM exhibited lower levels of IL-17A and IL-2 in the elderly than in adults following Ty21a immunization. Similar results were observed in LPMC CD8+ TRM and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ TRM subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses.
    CONCLUSIONS: Aging influences tissue resident TM S. Typhi-specific responses in the terminal ileum following oral Ty21a-immunization. This study is the first to provide insights in the generation of local vaccine-specific responses in the elderly population and highlights the importance of evaluating tissue immune responses in the context of infection and aging.
    TRIAL REGISTRATION: This study was approved by the Institutional Review Board and registered on (identifier NCT03970304 , Registered 29 May 2019 - Retrospectively registered).
    Keywords:  Aging; Oral vaccine; Terminal ileum LPMC; Tissue resident memory T cells; Ty21a; Vaccine-induced responses
  7. Front Immunol. 2021 ;12 637960
      Regulatory T cells (Tregs) are essential for mitigating inflammation. Tregs are found in nearly every tissue and play either beneficial or harmful roles in the host. The availability of various nutrients can either enhance or impair Treg function. Mitochondrial oxidative metabolism plays a major role in supporting Treg differentiation and fitness. While Tregs rely heavily on oxidation of fatty acids to support mitochondrial activity, they have found ways to adapt to different tissue types, such as tumors, to survive in competitive environments. In addition, metabolic by-products from commensal organisms in the gut also have a profound impact on Treg differentiation. In this review, we will focus on the core metabolic pathways engaged in Tregs, especially in the context of tissue nutrient environments, and how they can affect Treg function, stability and differentiation.
    Keywords:  metabolic adaptation; metabolism; nutrients; regulatory T cells; tissues
  8. FEBS J. 2021 Apr 18.
      The mammalian sirtuin family consists of seven proteins, three of which (SIRT3, SIRT4, and SIRT5) localise specifically within mitochondria and preserve mitochondrial function and homeostasis. Mitochondrial sirtuins are involved in diverse functions such as deacetylation, ADP-ribosylation, demalonylation and desuccinylation, thus affecting various aspect of cell fate. Intriguingly, mitochondrial sirtuins are able to manage these delicate processes with accuracy mediated by cross-talk between the nucleus and mitochondria. Previous studies have provided ample information about their substrates and targets, whereas less is known about their role in cancer and stem cells. Here, we review and discuss recent advances in our understanding of the structural and functional properties of mitochondrial sirtuins, including their targets in cancer and stem cells. These advances could help to improve the understanding of their interplay with signalling cascades and pathways, leading to new avenues for developing novel drugs for sirtuin-related disease treatments. We also highlight the complex network of mitochondrial sirtuins in cancer and stem cells, which may be important in deciphering the molecular mechanism for their activation and inhibition.
    Keywords:   SIRT3 ; SIRT4 ; SIRT5 ; Cancer; Mitochondria; Sirtuins; Stem cells
  9. Geroscience. 2021 Apr 24.
      Both glucose tolerance and adaptive immune function exhibit significant age-related alterations. The influence of the immune system on obesity-associated glucose intolerance is well characterized; however, whether the immune system contributes to age-related glucose intolerance is not as well understood. Here, we report that advancing age results in an increase in T cell infiltration in the epididymal white adipose tissue (eWAT), liver, and skeletal muscle. Subtype analyses show that both CD4+, CD8+ T cells are greater with advancing age in each of these tissues and that aging results in a blunted CD4 to CD8 ratio. Anti-CD3 F(ab')2 fragments depleted CD4+ and CD8+ cells in eWAT, CD4+ cells only in the liver, and did not deplete quadriceps T cells. In old mice, T cells producing both interferon-γ and tumor necrosis factor-α are accumulated in the eWAT and liver, and a greater proportion of skeletal muscle T cells produced interferon-γ. Aging resulted in increased proportion and numbers of T regulatory cells in eWAT, but not in the liver or muscle. Aging also resulted in greater numbers of eWAT and quadriceps CD206- macrophages and eWAT, liver and quadriceps B cells; neither cell type was altered by anti-CD3 treatment. Anti-CD3 treatment improved glucose tolerance in old mice and was accompanied by improved signaling related to liver and skeletal muscle insulin utilization and decreased gluconeogenesis-related gene expression in the liver. Our findings indicate a critical role of the adaptive immune system in the age-related metabolic dysfunction.
    Keywords:  Adipose tissue; Glucose intolerance; Liver; Macrophages; Skeletal muscle; T lymphocyte
  10. Clin Exp Immunol. 2021 Apr 18.
      Ageing dramatically affects number and function of both innate and adaptive arms of immune system, particularly T cell subsets, contributing to reduced vaccination efficacy, decreased resistance to infections and increased prevalence of cancer in the older people. In the present paper, we analysed the age-related changes in the absolute number of lymphocytes in 214 Sicilian subjects, and in the percentages of T and NK cells in a sub-cohort of donors. We compared these results with the immunophenotype of the oldest living Italian supercentenarian (111 years old). The results were also sorted by gender. The correlation between number/percentage of cells and age in all individuals and, separately, in males and females, was examined using a simple linear regression analysis. We did not record the increase in the rate of inversion of the CD4/CD8 ratio frequently reported as associated with ageing in literature. Our observation was the direct consequence of a flat average trend of CD4+ and CD8+ T cell percentages in ageing donors, even when gender differences were included. Our results also suggest that CD4+ and CD8+ subsets are not affected equally by age comparing females with males, and we speculated that gender may affect the response to CMV infection. The supercentenarian showed a unique immunophenotypic signature as regards the relative percentages of her T cell subsets, with CD4+ and CD8+ T cell percentages and CD4+ naïve T cell values in line with those recorded for the octogenarian subjects. This suggests that the supercentenarian has a naïve "younger" T cell profile comparable to that of a >80 year old female.
    Keywords:  CMV; Gender; Supercentenarian; T Lymphocyte subsets
  11. Nat Commun. 2021 Apr 23. 12(1): 2398
      Arginine plays diverse roles in cellular physiology. As a semi-essential amino acid, arginine deprivation has been used to target cancers with arginine synthesis deficiency. Arginine-deprived cancer cells exhibit mitochondrial dysfunction, transcriptional reprogramming and eventual cell death. In this study, we show in prostate cancer cells that arginine acts as an epigenetic regulator to modulate histone acetylation, leading to global upregulation of nuclear-encoded oxidative phosphorylation (OXPHOS) genes. TEAD4 is retained in the nucleus by arginine, enhancing its recruitment to the promoter/enhancer regions of OXPHOS genes and mediating coordinated upregulation in a YAP1-independent but mTOR-dependent manner. Arginine also activates the expression of lysine acetyl-transferases and increases overall levels of acetylated histones and acetyl-CoA, facilitating TEAD4 recruitment. Silencing of TEAD4 suppresses OXPHOS functions and prostate cancer cell growth in vitro and in vivo. Given the strong correlation of TEAD4 expression and prostate carcinogenesis, targeting TEAD4 may be beneficially used to enhance arginine-deprivation therapy and prostate cancer therapy.
  12. Proc Natl Acad Sci U S A. 2021 Apr 27. pii: e2023172118. [Epub ahead of print]118(17):
      The production of proinflammatory cytokines, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF), by pathogenic CD4+ T cells is central for mediating tissue injury in inflammatory and autoimmune diseases. However, the factors regulating the T cell pathogenic gene expression program remain unclear. Here, we investigated how the Ikaros transcription factor regulates the global gene expression and chromatin accessibility changes in murine T cells during Th17 polarization and after activation via the T cell receptor (TCR) and CD28. We found that, in both conditions, Ikaros represses the expression of genes from the pathogenic signature, particularly Csf2, which encodes GM-CSF. We show that, in TCR/CD28-activated T cells, Ikaros binds a critical enhancer downstream of Csf2 and is required to regulate chromatin accessibility at multiple regions across this locus. Genome-wide Ikaros binding is associated with more compact chromatin, notably at multiple sites containing NFκB or STAT5 target motifs, and STAT5 or NFκB inhibition prevents GM-CSF production in Ikaros-deficient cells. Importantly, Ikaros also limits GM-CSF production in TCR/CD28-activated human T cells. Our data therefore highlight a critical conserved transcriptional mechanism that antagonizes GM-CSF expression in T cells.
    Keywords:  GM-CSF; IL-17; Ikaros; pathogenicity; proinflammatory cytokines