bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021‒09‒12
ten papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. T cells critically depend on pyruvate oxidation.
  2. PD-1+ Tcf1+ CD8+ T cells from established chronic infection can form memory while retaining a stableimprint of persistent antigen exposure.
  3. Influence of Exercise on Exhausted and Senescent T Cells: A Systematic Review.
  4. Distinct Immune Profiles of Exhausted Effector and Memory CD8+ T Cells in Individuals With Filarial Lymphedema.
  5. IL-6 enhances CD4 cell motility by sustaining mitochondrial Ca2+ through the noncanonical STAT3 pathway.
  6. Targeting Mitochondrial Oxidative Phosphorylation in Glioblastoma Therapy.
  7. Perspectives on the dynamic implications of cellular senescence and immunosenescence on macrophage aging biology.
  8. Deregulated Expression of Immune Checkpoints on Circulating CD4 T Cells May Complicate Clinical Outcome and Response to Treatment with Checkpoint Inhibitors in Multiple Myeloma Patients.
  9. Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells.
  10. Role of Copper on Mitochondrial Function and Metabolism.
  1. Cell Metab. 2021 Sep 07. pii: S1550-4131(21)00373-9. [Epub ahead of print]33(9): 1719-1720
    T cells critically depend on pyruvate oxidation.
    Christopher Schrecker, Andrew M Intlekofer.
      Supporting the notion that cell lineage is a key determinant of cancer cell metabolism, Jun et al. (2021) identify a selective requirement for pyruvate dehydrogenase (PDH) activity in T cells and T cell leukemia, but not hematopoietic stem cells (HSCs) or myeloid leukemia, in this issue of Cell Metabolism.
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.010
  2. Cell Rep. 2021 Sep 07. pii: S2211-1247(21)01116-5. [Epub ahead of print]36(10): 109672
    PD-1+ Tcf1+ CD8+ T cells from established chronic infection can form memory while retaining a stableimprint of persistent antigen exposure.
    Mélanie Charmoy, Tania Wyss, Mauro Delorenzi, Werner Held.
      Virus-specific PD1+ Tcf1+ memory-like CD8+ T cells (TMLs) maintain the CD8+ T cell response during chronic viral infection. However, the fate of these cells following cessation of persistent antigen exposure has been unclear. Here, we find that TMLs persist upon transfer into antigen-free hosts and form memory following recall stimulation. Phenotypic, functional, and transcriptome analyses show that TML-derived memory cells resemble those arising in response to acute, resolved infection, but they retain features of chronically stimulated cells, including elevated PD-1 and Tox and reduced cytokine expression. This chronic infection imprint is largely accounted for by constitutive Tox expression. Virus-specific Tcf1+ CD8+ T cells that persist after clearance of systemic infection also display a chronic infection imprint. Notwithstanding, renewed virus exposure induces a recall response, which controls virus infection in part. Thus, cessation of chronic antigen exposure yields a memory CD8+ T cell compartment that reflects prior stimulation.
    Keywords:  CD8(+) T cells; Tcf1; Tcf7; Tox; acute resolved LCMV infection; cell fate; chronic LCMV infection; chronic stimulation imprint; memory formation; memory-like; progenitor-exhausted
    DOI:  https://doi.org/10.1016/j.celrep.2021.109672
  3. Front Physiol. 2021 ;12 668327
    Influence of Exercise on Exhausted and Senescent T Cells: A Systematic Review.
    Thomasina Donovan, Amanda L Bain, Wenjuan Tu, David B Pyne, Sudha Rao.
      The impaired effector function of exhausted and senescent T cells is implicated in cancer progression and inadequate vaccine responses. Exercise has been shown to improve cancer therapy and vaccine efficacy, most likely by improving immune function. However, given inconsistent terminology and definitions, the interactions between exercise and exhausted and senescent T cells remain unclear. We therefore performed a systematic review to investigate the effect of exercise on senescent and exhausted CD8+ T cell populations clearly defined by protein surface markers. Thirty articles were included, with the majority (n = 24) reporting senescent T cell populations defined according to a variety of surface markers. Repeated exercise was shown to be beneficial through limiting the accumulation of senescent and exhausted CD8+ T cells. This outcome is likely related to exercise-induced preferential mobilization of senescent T cells promoting apoptosis in the peripheral blood compartment. Future studies need to determine the clinical relevance of this effect in cancer prevention and vaccine efficacy. Data regarding exercise and exhausted T cells are limited due to a lack of available high-quality studies. Future studies require the control of confounding variables such as sex and cytomegalovirus (CMV) status, and consistent definitions of exhausted and senescent T cell populations to improve comparisons between studies and interventions.
    Keywords:  T cells; exercise; exhausted; fitness; immune cells; senescent
    DOI:  https://doi.org/10.3389/fphys.2021.668327
  4. Front Cell Infect Microbiol. 2021 ;11 680832
    Distinct Immune Profiles of Exhausted Effector and Memory CD8+ T Cells in Individuals With Filarial Lymphedema.
    Sacha Horn, Dennis Borrero-Wolff, Manuel Ritter, Kathrin Arndts, Anna Wiszniewsky, Linda Batsa Debrah, Alexander Y Debrah, Jubin Osei-Mensah, Mkunde Chachage, Achim Hoerauf, Inge Kroidl, Laura E Layland.
      CD8+ T cells are crucial for the clearance of viral infections, and current research begins to highlight their importance in parasitic diseases too. In-depth research about characteristics of CD8+ T-cell subsets and exhaustion remains uncertain, especially during filariasis, a chronic helminth infection. Lymphatic filariasis, elicited by Wuchereria bancrofti, remains a serious health problem in endemic areas in Ghana, especially in those suffering from morbidity due to lymphedema (LE). In this observational study, the characteristics and profiles of CD8+ T cells were compared between asymptomatic Wuchereria bancrofti-infected individuals, uninfected endemic normals, and those with LE (grades 2-6). Focusing on exhausted memory (CD8+exmem: CD8+ T-betdimEomeshi) and effector (CD8+exeff: CD8+T-bethiEomesdim) CD8+ T-cell subsets, advanced flow cytometry revealed that LE individuals presented reduced frequencies of IFN-γ+CD8+exmem T cells expressing Tim-3 or LAG-3 which negatively correlated to the presence of LE. Moreover, the LE cohort further showed significantly higher frequencies of IL-10+CD8+exeff T cells expressing either Tim-3, LAG-3, CD39, KLRG-1, or PD-1, all associated markers of exhaustion, and that these frequencies positively correlated with the presence of LE. In summary, this study shows that distinct exhausted CD8+ T-cell subsets are prominent in individuals suffering from LE, suggesting that enhanced inflammation and constant immune activation might drive exhaustion of CD8+ T cells. Since T-cell exhaustion is known to be associated with insufficient control of persisting antigen, the data presented here reveals that these CD8+ T-cell exhaustion patterns in filarial LE should be taken into consideration for prevention and control management of LE.
    Keywords:  CD8+ T cell exhaustion; Filariae; Wuchereria bancrofti infection; immune modulation; lymphatic filariasis; lymphedema; memory and effector T cell subsets
    DOI:  https://doi.org/10.3389/fcimb.2021.680832
  5. Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2103444118. [Epub ahead of print]118(37):
    IL-6 enhances CD4 cell motility by sustaining mitochondrial Ca2+ through the noncanonical STAT3 pathway.
    Felipe Valença-Pereira, Qian Fang, Isabelle J Marié, Emily L Giddings, Karen A Fortner, Rui Yang, Alejandro V Villarino, Yina H Huang, David A Frank, Haitao Wen, David E Levy, Mercedes Rincon.
      Interleukin 6 (IL-6) is known to regulate the CD4 T cell function by inducing gene expression of a number of cytokines through activation of Stat3 transcription factor. Here, we reveal that IL-6 strengthens the mechanics of CD4 T cells. The presence of IL-6 during activation of mouse and human CD4 T cells enhances their motility (random walk and exploratory spread), resulting in an increase in travel distance and higher velocity. This is an intrinsic effect of IL-6 on CD4 T-cell fitness that involves an increase in mitochondrial Ca2+ Although Stat3 transcriptional activity is dispensable for this process, IL-6 uses mitochondrial Stat3 to enhance mitochondrial Ca2+-mediated motility of CD4 T cells. Thus, through a noncanonical pathway, IL-6 can improve competitive fitness of CD4 T cells by facilitating cell motility. These results could lead to alternative therapeutic strategies for inflammatory diseases in which IL-6 plays a pathogenic role.
    Keywords:  CD4 T cells; STAT3; interleukin-6; mitochondrial calcium; motility
    DOI:  https://doi.org/10.1073/pnas.2103444118
  6. Neuromolecular Med. 2021 Sep 06.
    Targeting Mitochondrial Oxidative Phosphorylation in Glioblastoma Therapy.
    Zhihao Wu, Winson S Ho, Rongze Lu.
      As a multi-functional cellular organelle, mitochondrial metabolic reprogramming is well recognized as a hallmark of cancer. The center of mitochondrial metabolism is oxidative phosphorylation (OXPHOS), in which cells use enzymes to oxidize nutrients, thereby converting the chemical energy to the biological energy currency ATPs. OXPHOS also creates the mitochondrial membrane potential and serve as the driving force of other mitochondrial metabolic pathways and experiences significant reshape in the different stages of tumor progression. In this minireview, we reviewed the major mitochondrial pathways that are connected to OXPHOS and are affected in cancer cells. In addition, we summarized the function of novel bio-active molecules targeting mitochondrial metabolic processes such as OXPHOS, mitochondrial membrane potential and mitochondrial dynamics. These molecules exhibit intriguing preclinical and clinical results and have been proven to be promising antitumor candidates in recent studies.
    Keywords:  Glioblastoma; Mitochondrial dysfunction; OXPHOS inhibitors
    DOI:  https://doi.org/10.1007/s12017-021-08678-8
  7. Biogerontology. 2021 Sep 06.
    Perspectives on the dynamic implications of cellular senescence and immunosenescence on macrophage aging biology.
    Rohit Sharma.
      An intricate relationship between impaired immune functions and the age-related accumulation of tissue senescent cells is rapidly emerging. The immune system is unique as it undergoes mutually inclusive and deleterious processes of immunosenescence and cellular senescence with advancing age. While factors inducing immunosenescence and cellular senescence may be shared, however, both these processes are fundamentally different which holistically influence the aging immune system. Our understanding of the biological impact of immunosenescence is relatively well-understood, but such knowledge regarding cellular senescence in immune cells, especially in the innate immune cells such as macrophages, is only beginning to be elucidated. Tissue-resident macrophages are long-lived, and while functioning in tissue-specific and niche-specific microenvironments, senescence in macrophages can be directly influenced by senescent host cells which may impact organismal aging. In addition, evidence of age-associated immunometabolic changes as drivers of altered macrophage phenotype and functions such as inflamm-aging is also emerging. The present review describes the emerging impact of cellular senescence vis-à-vis immunosenescence in aging macrophages, its biological relevance with other senescent non-immune cells, and known immunometabolic regulators. Gaps in our present knowledge, as well as strategies aimed at understanding cellular senescence and its therapeutics in the context of macrophages, have been reviewed.
    Keywords:  Aging; Immunometabolism; Immunosenescence; Macrophages; Senescence
    DOI:  https://doi.org/10.1007/s10522-021-09936-9
  8. Int J Mol Sci. 2021 Aug 27. pii: 9298. [Epub ahead of print]22(17):
    Deregulated Expression of Immune Checkpoints on Circulating CD4 T Cells May Complicate Clinical Outcome and Response to Treatment with Checkpoint Inhibitors in Multiple Myeloma Patients.
    Anna Kulikowska de Nałęcz, Lidia Ciszak, Lidia Usnarska-Zubkiewicz, Irena Frydecka, Edyta Pawlak, Magdalena Szmyrka, Agata Kosmaczewska.
      Unlike solid-tumor patients, a disappointingly small subset of multiple myeloma (MM) patients treated with checkpoint inhibitors derive clinical benefits, suggesting differential participation of inhibitory receptors involved in the development of T-cell-mediated immunosuppression. In fact, T cells in MM patients have recently been shown to display features of immunosenescence and exhaustion involved in immune response inhibition. Therefore, we aimed to identify the dominant inhibitory pathway in MM patients to achieve its effective control by therapeutic interventions. By flow cytometry, we examined peripheral blood (PB) CD4 T cell characteristics assigned to senescence or exhaustion, considering PD-1, CTLA-4, and BTLA checkpoint expression, as well as secretory effector function, i.e., capacity for IFN-γ and IL-17 secretion. Analyses were performed in a total of 40 active myeloma patients (newly diagnosed and treated) and 20 healthy controls. At the single-cell level, we found a loss of studied checkpoints' expression on MM CD4 T cells (both effector (Teff) and regulatory (Treg) cells) primarily at diagnosis; the checkpoint deficit in MM relapse was not significant. Nonetheless, PD-1 was the only checkpoint distributed on an increased proportion of T cells in all MM patients irrespective of disease phase, and its expression on CD4 Teff cells correlated with adverse clinical courses. Among patients, the relative defect in secretory effector function of CD4 T cells was more pronounced at myeloma relapse (as seen in declined Th1/Treg and Th17/Treg cell rates). Although the contribution of PD-1 to MM clinical outcomes is suggestive, our study clearly indicated that the inappropriate expression of immune checkpoints (associated with dysfunctionality of CD4 T cells and disease clinical phase) might be responsible for the sub-optimal clinical response to therapeutic checkpoint inhibitors in MM.
    Keywords:  CD4 T cells; CTLA-4; PD-1; checkpoint inhibitors; clinical outcome; multiple myeloma
    DOI:  https://doi.org/10.3390/ijms22179298
  9. Nat Commun. 2021 Sep 06. 12(1): 5303
    Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells.
    Mladen Jergović, Christopher P Coplen, Jennifer L Uhrlaub, David G Besselsen, Shu Cheng, Megan J Smithey, Janko Nikolich-Žugich.
      Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide-MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-021-25645-w
  10. Front Mol Biosci. 2021 ;8 711227
    Role of Copper on Mitochondrial Function and Metabolism.
    Lina M Ruiz, Allan Libedinsky, Alvaro A Elorza.
      Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.
    Keywords:  ROS; cancer; copper; differentiation; hematopoietic stem cells (HSCs); metabolic reprograming; mitochondria; proliferation
    DOI:  https://doi.org/10.3389/fmolb.2021.711227
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