bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–09–10
sixteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. The paradox of aging: Aging-related shifts in T cell function and metabolism.
  2. Heterogeneity of memory T cells in aging.
  3. Stem-like CD4+ T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis.
  4. Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis.
  5. Crosstalk between autophagy and metabolic regulation of (CAR) T cells: therapeutic implications.
  6. Enolase: a metabolic checkpoint behind diverse exhaustion stages of CD8+ T cells in chronic HBV and HCV.
  7. CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology.
  8. CD38hiCD8+ T cells characterize ICI-mediated arthritis.
  9. CD5 Expression Dynamically Changes During the Differentiation of Human CD8+ T Cells Predicting Clinical Response to Immunotherapy.
  10. Creatine supplementation enhances anti-tumor immunity by promoting adenosine triphosphate production in macrophages.
  11. Lipid and glucose metabolism in senescence.
  12. How to supercharge T cells against cancer.
  13. Swiss army knife T cell: one T cell many tumor targets.
  14. Mitochondrial dynamics in health and disease: mechanisms and potential targets.
  15. CD8+ T cells pump the brakes on Alzheimer's disease.
  16. Metabolic elasticity: A new measure of age.
  1. Semin Immunol. 2023 Aug 31. pii: S1044-5323(23)00125-2. [Epub ahead of print]70 101834
    The paradox of aging: Aging-related shifts in T cell function and metabolism.
    Kylie M Quinn, Daniela M Vicencio, Nicole L La Gruta.
      T cell survival, differentiation after stimulation, and function are intrinsically linked to distinct cellular metabolic states. The ability of T cells to readily transition between metabolic states enables flexibility to meet the changing energy demands defined by distinct effector states or T cell lineages. Immune aging is characterized, in part, by the loss of naïve T cells, accumulation of senescent T cells, severe dysfunction in memory phenotype T cells in particular, and elevated levels of inflammatory cytokines, or 'inflammaging'. Here, we review our current understanding of the phenotypic and functional changes that occur with aging in T cells, and how they relate to metabolic changes in the steady state and after T cell activation. We discuss the apparent contradictions in the aging T cell phenotype - where enhanced differentiation states and metabolic profiles in the steady state can correspond to a diminished capacity to adapt metabolically and functionally after T cell activation. Finally, we discuss key recent studies that indicate the enormous potential for aged T cell metabolism to induce systemic inflammaging and organism-wide multimorbidity, resulting in premature death.
    Keywords:  Aging; Metabolism; Organismal aging; T cell dysfunction; T cells; Unconventional T cells
    DOI:  https://doi.org/10.1016/j.smim.2023.101834
  2. Front Immunol. 2023 ;14 1250916
    Heterogeneity of memory T cells in aging.
    Abhinav Jain, Ines Sturmlechner, Cornelia M Weyand, Jörg J Goronzy.
      Immune memory is a requisite and remarkable property of the immune system and is the biological foundation of the success of vaccinations in reducing morbidity from infectious diseases. Some vaccines and infections induce long-lasting protection, but immunity to other vaccines and particularly in older adults rarely persists over long time periods. Failed induction of an immune response and accelerated waning of immune memory both contribute to the immuno-compromised state of the older population. Here we review how T cell memory is influenced by age. T cell memory is maintained by a dynamic population of T cells that are heterogeneous in their kinetic parameters under homeostatic condition and their function. Durability of T cell memory can be influenced not only by the loss of a clonal progeny, but also by broader changes in the composition of functional states and transition of T cells to a dysfunctional state. Genome-wide single cell studies on total T cells have started to provide insights on the influence of age on cell heterogeneity over time. The most striking findings were a trend to progressive effector differentiation and the activation of pro-inflammatory pathways, including the emergence of CD4+ and CD8+ cytotoxic subsets. Genome-wide data on antigen-specific memory T cells are currently limited but can be expected to provide insights on how changes in T cell subset heterogeneity and transcriptome relate to durability of immune protection.
    Keywords:  T cell durability; aging; cytotoxic T cell; memory T cell; vaccine
    DOI:  https://doi.org/10.3389/fimmu.2023.1250916
  3. Sci Transl Med. 2023 Sep 06. 15(712): eadh0380
    Stem-like CD4+ T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis.
    Yuki Sato, Abhinav Jain, Shozo Ohtsuki, Hirohisa Okuyama, Ines Sturmlechner, Yoshinori Takashima, Kevin-Phu C Le, Melanie C Bois, Gerald J Berry, Kenneth J Warrington, Jörg J Goronzy, Cornelia M Weyand.
      Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription factor T cell factor 1 (TCF1), had high proliferative potential, and gave rise to two effector populations, Eomesodermin (EOMES)+ cytotoxic T cells and B cell lymphoma 6 (BCL6)+ T follicular helper-like cells. TCF1hiCD4+ T cells expressing the interleukin 7 receptor (IL-7R) sustained vasculitis in serial transplantation experiments. Thus, TCF1hiCD4+ T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4+ T cells instead of only effector T cells.
    DOI:  https://doi.org/10.1126/scitranslmed.adh0380
  4. BMB Rep. 2023 Sep 08. pii: 5938. [Epub ahead of print]
    Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis.
    Seungyeon Yang, Subin Moon, Soojung Claire Hur, Seung Min Jeong.
      Senescence, a cellular process through which damaged or dysfunctional cells suppress their cell cycle, contributes to aging or age-related functional declines. Cell metabolism has been closely correlated with aging processes and it is widely recognized that metabolic changes underlie cellular alterations with aging. Here, we report that fatty acid oxidation (FAO) serves as a critical regulator of cellular senescence and uncover the underlying mechanism by which FAO inhibition induces senescence. Pharmacological or genetic ablation of FAO results in a p53-dependent induction of cellular senescence in human fibroblasts, whereas enhancing FAO suppresses replicative senescence. We find that FAO inhibition promotes cellular senescence through acetyl-CoA, independent of energy depletion. Mechanistically, the increased formation of autophagosome following FAO inhibition leads to a reduction in SIRT1 protein levels, thereby contributing to senescence induction. Finally, we find that the inhibition of autophagy or the enforced expression of SIRT1 can rescue the induction of senescence as a result of FAO inhibition. Collectively, our study reveals a distinctive role for the FAO-autophagy-SIRT1 axis in the regulation of cellular senescence.
  5. Front Immunol. 2023 ;14 1212695
    Crosstalk between autophagy and metabolic regulation of (CAR) T cells: therapeutic implications.
    Ahmad Reza Panahi Meymandi, Behnia Akbari, Tahereh Soltantoyeh, Jamshid Hadjati, Daniel J Klionsky, Behnam Badie, Hamid Reza Mirzaei.
      Despite chimeric antigen receptor (CAR) T cell therapy's extraordinary success in subsets of B-cell lymphoma and leukemia, various barriers restrict its application in solid tumors. This has prompted investigating new approaches for producing CAR T cells with superior therapeutic potential. Emerging insights into the barriers to CAR T cell clinical success indicate that autophagy shapes the immune response via reprogramming cellular metabolism and vice versa. Autophagy, a self-cannibalization process that includes destroying and recycling intracellular components in the lysosome, influences T cell biology, including development, survival, memory formation, and cellular metabolism. In this review, we will emphasize the critical role of autophagy in regulating and rewiring metabolic circuits in CAR T cells, as well as how the metabolic status of CAR T cells and the tumor microenvironment (TME) alter autophagy regulation in CAR T cells to restore functional competence in CAR Ts traversing solid TMEs.
    Keywords:  CAR T cell; adoptive cellular therapy (ACT); autophagy; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1212695
  6. Gut. 2023 Sep 06. pii: gutjnl-2023-330541. [Epub ahead of print]
    Enolase: a metabolic checkpoint behind diverse exhaustion stages of CD8+ T cells in chronic HBV and HCV.
    Nina Le Bert, Paola Fisicaro.
      
    Keywords:  HEPATITIS B; HEPATITIS C; IMMUNE RESPONSE
    DOI:  https://doi.org/10.1136/gutjnl-2023-330541
  7. Nat Immunol. 2023 Sep 07.
    CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology.
    Wei Su, Jordy Saravia, Isabel Risch, Sherri Rankin, Cliff Guy, Nicole M Chapman, Hao Shi, Yu Sun, Anil Kc, Wei Li, Hongling Huang, Seon Ah Lim, Haoran Hu, Yan Wang, Danting Liu, Yun Jiao, Ping-Chung Chen, Hadeer Soliman, Koon-Kiu Yan, Jonathan Zhang, Peter Vogel, Xueyan Liu, Geidy E Serrano, Thomas G Beach, Jiyang Yu, Junmin Peng, Hongbo Chi.
      Neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8+ T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8+ T cells restrict AD pathologies, including β-amyloid deposition and cognitive decline. Ligand-receptor interaction analysis identifies CXCL16-CXCR6 intercellular communication between microglia and CD8+ T cells. Further, Cxcr6 deficiency impairs accumulation, tissue residency programming and clonal expansion of brain PD-1+CD8+ T cells. Ablation of Cxcr6 or CD8+ T cells ultimately increases proinflammatory cytokine production from microglia, with CXCR6 orchestrating brain CD8+ T cell-microglia colocalization. Collectively, our study reveals protective roles for brain CD8+ T cells and CXCR6 in mouse AD pathogenesis and highlights that microenvironment-specific, intercellular communication orchestrates tissue homeostasis and protection from neuroinflammation.
    DOI:  https://doi.org/10.1038/s41590-023-01604-z
  8. Nat Rev Rheumatol. 2023 Sep 06.
    CD38hiCD8+ T cells characterize ICI-mediated arthritis.
    Robert Phillips.
      
    DOI:  https://doi.org/10.1038/s41584-023-01025-0
  9. Immune Netw. 2023 Aug;23(4): e35
    CD5 Expression Dynamically Changes During the Differentiation of Human CD8+ T Cells Predicting Clinical Response to Immunotherapy.
    Young Ju Kim, Kyung Na Rho, Saei Jeong, Gil-Woo Lee, Hee-Ok Kim, Hyun-Ju Cho, Woo Kyun Bae, In-Jae Oh, Sung-Woo Lee, Jae-Ho Cho.
      Defining the molecular dynamics associated with T cell differentiation enhances our understanding of T cell biology and opens up new possibilities for clinical implications. In this study, we investigated the dynamics of CD5 expression in CD8+ T cell differentiation and explored its potential clinical uses. Using PBMCs from 29 healthy donors, we observed a stepwise decrease in CD5 expression as CD8+ T cells progressed through the differentiation stages. Interestingly, we found that CD5 expression was initially upregulated in response to T cell receptor stimulation, but diminished as the cells underwent proliferation, potentially explaining the differentiation-associated CD5 downregulation. Based on the proliferation-dependent downregulation of CD5, we hypothesized that relative CD5 expression could serve as a marker to distinguish the heterogeneous CD8+ T cell population based on their proliferation history. In support of this, we demonstrated that effector memory CD8+ T cells with higher CD5 expression exhibited phenotypic and functional characteristics resembling less differentiated cells compared to those with lower CD5 expression. Furthermore, in the retrospective analysis of PBMCs from 30 non-small cell lung cancer patients, we found that patients with higher CD5 expression in effector memory T cells displayed CD8+ T cells with a phenotype closer to the less differentiated cells, leading to favorable clinical outcomes in response to immune checkpoint inhibitor (ICI) therapy. These findings highlight the dynamics of CD5 expression as an indicator of CD8+ T cell differentiation status, and have implications for the development of predictive biomarker for ICI therapy.
    Keywords:  : CD5 antigen; CD8-positive T-lymphocyte; Immune checkpoint inhibitor; Non-small cell lung cancer; Peripheral blood mononuclear cell; T-lymphocyte differentiation
    DOI:  https://doi.org/10.4110/in.2023.23.e35
  10. Front Immunol. 2023 ;14 1176956
    Creatine supplementation enhances anti-tumor immunity by promoting adenosine triphosphate production in macrophages.
    Zhenzi Peng, Suguru Saito.
      Creatine is an indispensable organic compound utilized in physiological environments; however, its role in immunity is still poorly understood. Here, we show that creatine supplementation enhances anti-tumor immunity through the functional upregulation of macrophages by increasing adenosine triphosphate (ATP) production. Creatine supplementation significantly suppressed B16-F10-originated tumor growth in mice compared with the control treatment. Under these conditions, intratumor macrophages polarized towards the M1 phenotype rather than the M2 phenotype, and there was an increase in tumor antigen-specific CD8+ T cells in the mice. The cytokine production and antigen-presenting activity in the macrophages were enhanced by creatine supplementation, resulting in a substantial increase in tumor antigen-specific CD8+ T cells. ATP upregulation was achieved through the cytosolic phosphocreatine (PCr) system via extracellular creatine uptake, rather than through glycolysis and mitochondrial oxidative phosphorylation in the macrophages. Blockade of the creatine transporter (CrT) failed to upregulate ATP and enhance the immunological activity of macrophages in creatine supplementation, which also impaired CD8+ T cell activity. Consequently, CrT blockade failed to suppress tumor growth in the creatine-supplemented mice. Thus, creatine is an important nutrient that promotes macrophage function by increasing ATP levels, ultimately contributing to enhanced anti-tumor immunity orchestrated by CD8+ T cells.
    Keywords:  ATP; CD8+ T cells; anti-tumor immunity; creatine; macrophages
    DOI:  https://doi.org/10.3389/fimmu.2023.1176956
  11. Front Nutr. 2023 ;10 1157352
    Lipid and glucose metabolism in senescence.
    Bin Liu, Qingfei Meng, Xin Gao, Huihui Sun, Zhixiang Xu, Yishu Wang, Honglan Zhou.
      Senescence is an inevitable biological process. Disturbances in glucose and lipid metabolism are essential features of cellular senescence. Given the important roles of these types of metabolism, we review the evidence for how key metabolic enzymes influence senescence and how senescence-related secretory phenotypes, autophagy, apoptosis, insulin signaling pathways, and environmental factors modulate glucose and lipid homeostasis. We also discuss the metabolic alterations in abnormal senescence diseases and anti-cancer therapies that target senescence through metabolic interventions. Our work offers insights for developing pharmacological strategies to combat senescence and cancer.
    Keywords:  ACC; ACOX1; CPT1; PPP; TCA; glycolysis; lipid metabolism; senescence
    DOI:  https://doi.org/10.3389/fnut.2023.1157352
  12. Nature. 2023 Sep 06.
    How to supercharge T cells against cancer.
    Nick Petrić Howe.
      
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1038/d41586-023-02763-7
  13. Cell Res. 2023 Sep 04.
    Swiss army knife T cell: one T cell many tumor targets.
    Abdulla Berjis, Deeksha Muthumani, Neil C Sheppard, Carl H June.
      
    DOI:  https://doi.org/10.1038/s41422-023-00871-7
  14. Signal Transduct Target Ther. 2023 Sep 06. 8(1): 333
    Mitochondrial dynamics in health and disease: mechanisms and potential targets.
    Wen Chen, Huakan Zhao, Yongsheng Li.
      Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature. These abilities allow them to effectively coordinate various cellular functions. Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. We also delve into the changes that occur in mitochondrial dynamics during health and disease, and offer novel perspectives on how to target the modulation of mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41392-023-01547-9
  15. Nat Immunol. 2023 Sep 07.
    CD8+ T cells pump the brakes on Alzheimer's disease.
    Katie L Reagin, Kristen E Funk.
      
    DOI:  https://doi.org/10.1038/s41590-023-01622-x
  16. Cell Metab. 2023 09 05. pii: S1550-4131(23)00301-7. [Epub ahead of print]35(9): 1495-1497
    Metabolic elasticity: A new measure of age.
    Samuel Bennett, Shogo Sato.
      Promoting healthy aging is contingent on understanding the underlying mechanisms for the age-associated decline in metabolic physiology. Through developing a novel concept of "metabolic elasticity" to evaluate metabolic adaptability in response to cyclical changes in energy balance, Zhou et al. present an impactful gauge of metabolic health that is particularly relevant to aging.
    DOI:  https://doi.org/10.1016/j.cmet.2023.08.006
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