bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023‒12‒24
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. T Lymphocyte Metabolic Features and Techniques to Modulate Them.
  2. Implications of Senescent T Cells for Cancer Immunotherapy.
  3. IL-2-STAT5 Activity Antagonizes TOX and Reverses CD8+ T Cell Exhaustion.
  4. Nutrient inputs and social metabolic control of T cell fate.
  5. Harnessing CD8 T cell responses using PD-1-IL-2 combination therapy.
  6. Low glucose availability potentiates the effects of metformin on model T cell activation and exhaustion markers in vitro.
  7. Tim-3 Is Not Required for Establishment of CD8+ T Cell Memory to Lymphocytic Choriomeningitis Virus.
  8. Gut Microbiota Richness and Diversity Track with T Cell Aging in Healthy Adults.
  9. Piezo1 facilitates optimal T cell activation during tumor challenge.
  10. Metabolic interplay: tumor macrophages and regulatory T cells.
  11. NADase CD38 is a key determinant of ovarian aging.
  1. Biochemistry (Mosc). 2023 Nov;88(11): 1857-1873
    T Lymphocyte Metabolic Features and Techniques to Modulate Them.
    Violetta V Vlasova, Konstantin V Shmagel.
      T cells demonstrate high degree of complexity and broad range of functions, which distinguish them from other immune cells. Throughout their lifetime, T lymphocytes experience several functional states: quiescence, activation, proliferation, differentiation, performance of effector and regulatory functions, memory formation, and apoptosis. Metabolism supports all functions of T cells, providing lymphocytes with energy, biosynthetic substrates, and signaling molecules. Therefore, T cells usually restructure their metabolism as they transition from one functional state to another. Strong association between the metabolism and T cell functions implies that the immune response can be controlled by manipulating metabolic processes within T lymphocytes. This review aims to highlight the main metabolic adaptations necessary for the T cell function, as well as the recent progress in techniques to modulate metabolic features of lymphocytes.
    Keywords:  OXPHOS; T lymphocytes; TCA cycle; differentiation; exhaustion; glycolysis; immunological memory; metabolism; mitochondria; proliferation
    DOI:  https://doi.org/10.1134/S0006297923110159
  2. Cancers (Basel). 2023 Dec 14. pii: 5835. [Epub ahead of print]15(24):
    Implications of Senescent T Cells for Cancer Immunotherapy.
    Tetsuhiro Kasamatsu.
      T-cell senescence is thought to result from the age-related loss of the ability to mount effective responses to pathogens and tumor cells. In addition to aging, T-cell senescence is caused by repeated antigenic stimulation and chronic inflammation. Moreover, we demonstrated that T-cell senescence was induced by treatment with DNA-damaging chemotherapeutic agents. The characteristics of therapy-induced senescent T (TIS-T) cells and general senescent T cells are largely similar. Senescent T cells demonstrate an increase in the senescence-associated beta-galactosidase-positive population, cell cycle arrest, secretion of senescence-associated secretory phenotypic factors, and metabolic reprogramming. Furthermore, senescent T cells downregulate the expression of the co-stimulatory molecules CD27 and CD28 and upregulate natural killer cell-related molecules. Moreover, TIS-T cells showed increased PD-1 expression. However, the loss of proliferative capacity and decreased expression of co-stimulatory molecules associated with T-cell senescence cause a decrease in T-cell immunocompetence. In this review, we discuss the characteristics of senescent T-cells, including therapy-induced senescent T cells.
    Keywords:  PD-1; T-cell senescence; therapy-induced cellular senescence
    DOI:  https://doi.org/10.3390/cancers15245835
  3. Cancer Discov. 2023 Dec 21. OF1
    IL-2-STAT5 Activity Antagonizes TOX and Reverses CD8+ T Cell Exhaustion.
      STAT5 functionally reinvigorates exhausted CD8+ T cells and enhances the response to anti-PD-L1.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-203
  4. Cell Metab. 2023 Dec 12. pii: S1550-4131(23)00460-6. [Epub ahead of print]
    Nutrient inputs and social metabolic control of T cell fate.
    Zachary A Bacigalupa, Madelyn D Landis, Jeffrey C Rathmell.
      Cells in multicellular organisms experience diverse neighbors, signals, and evolving physical environments that drive functional and metabolic demands. To maintain proper development and homeostasis while avoiding inappropriate cell proliferation or death, individual cells interact with their neighbors via "social" cues to share and partition available nutrients. Metabolic signals also contribute to cell fate by providing biochemical links between cell-extrinsic signals and available resources. In addition to metabolic checkpoints that sense nutrients and directly supply molecular intermediates for biosynthetic pathways, many metabolites directly signal or provide the basis for post-translational modifications of target proteins and chromatin. In this review, we survey the landscape of T cell nutrient sensing and metabolic signaling that supports proper immunity while avoiding immunodeficiency or autoimmunity. The integration of cell-extrinsic microenvironmental cues with cell-intrinsic metabolic signaling provides a social metabolic control model to integrate cell signaling, metabolism, and fate.
    Keywords:  T cells; epigenetics; immunometabolism; metabolic signaling; social control model
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.009
  5. Trends Cancer. 2023 Dec 20. pii: S2405-8033(23)00239-X. [Epub ahead of print]
    Harnessing CD8 T cell responses using PD-1-IL-2 combination therapy.
    Masao Hashimoto, Suresh S Ramalingam, Rafi Ahmed.
      There is considerable interest in developing more effective programmed cell death (PD)-1 combination therapies against cancer. One major obstacle to these efforts is a dysfunctional/exhausted state of CD8 T cells, which PD-1 monotherapy is not able to overcome. Recent studies have highlighted that PD-1+ T cell factor (TCF)-1+ stem-like CD8 T cells are not fate locked into the exhaustion program and their differentiation trajectory can be changed by interleukin (IL)-2 signals. Modifying the CD8 T cell exhaustion program and generating better effectors from stem-like CD8 T cells by IL-2 form the fundamental immunological basis for combining IL-2 with PD-1 therapy. Many versions of IL-2-based products are being tested and each product should be carefully evaluated for its ability to modulate dysfunctional states of anti-tumor CD8 T cells.
    Keywords:  IL-2; PD-1; T cell exhaustion; cancer; chronic infection; immunotherapy
    DOI:  https://doi.org/10.1016/j.trecan.2023.11.008
  6. Front Endocrinol (Lausanne). 2023 ;14 1216193
    Low glucose availability potentiates the effects of metformin on model T cell activation and exhaustion markers in vitro.
    Jernej Repas, Lea Peternel, Harald Sourij, Mojca Pavlin.
      Modulation of immune cell metabolism is one of promising strategies to improve cancer immunotherapies. Metformin is an anti-diabetic drug with potential anti-cancer effects, ranging from normalization of blood glucose and insulin levels, direct anti-proliferative effects on cancer cells to emerging immunomodulatory effects on anti-tumor immunity. Metformin can reduce tumor hypoxia and PD-L1 expression, as well as normalize or improve T cell function and potentiate the effect of immune checkpoint inhibitors, making it a promising adjuvant to immunotherapy of tumors with poor response such as triple negative breast cancer (TNBC). However, although the effects of metformin on cancer cells are glucose-dependent, the role of glucose in modulating its effect on T cells has not been systematically studied. We thus investigated the effect of metformin as a function of glucose level on Jurkat cell and PBMC T cell models in vitro. While low metformin concentrations had little effect on T cell function, high concentration reduced proliferation and IFN-γ secretion in both models and induced a shift in T cell populations from memory to effector subsets. The PD-1/CD69 ratio was improved by high metformin in T cells from PBMC. Low glucose and metformin synergistically reduced PD-1 and CD69 expression and IFN-γ secretion in T cells from PBMC. Low glucose level itself suppressed Jurkat cell function due to their limited metabolic plasticity, but had limited effects on T cells from PBMC apart from reduced proliferation. Conversely, high glucose did not strongly affect either T cell model. Metformin in combination with glycolysis inhibitor 2-deoxy-D-glucose (2DG) reduced PD-1 in Jurkat cells, but also strongly suppressed their function. However, low, physiologically achievable 2DG concentration itself reduced PD-1 while mostly maintaining IL-2 secretion and, interestingly, even strongly increased IFN-γ secretion regardless of glucose level. Overall, glucose metabolism can importantly influence some of the effects of metformin on T cell functionality in the tumor microenvironment. Additionally, we show that 2DG could potentially improve the anti-tumor T cell response.
    Keywords:  2-deoxy-D-glucose; PD-1/PD-L1 axis; T cell exhaustion; T cells; glucose level; metformin
    DOI:  https://doi.org/10.3389/fendo.2023.1216193
  7. J Immunol. 2023 Dec 18. pii: ji2300401. [Epub ahead of print]
    Tim-3 Is Not Required for Establishment of CD8+ T Cell Memory to Lymphocytic Choriomeningitis Virus.
    Priyanka Manandhar, Andrea L Szymczak-Workman, Lawrence P Kane.
      Tim-3 is a transmembrane protein that is best known for being highly expressed on terminally exhausted CD8+ T cells associated with chronic infection and tumors, although its expression is not limited to those settings. Tim-3 is also expressed by CD8+ T cells during acute infection and by multiple other immune cell types, including CD4+ Th1 and regulatory T cells, dendritic cells, and mast cells. In this study, we investigated the role of Tim-3 signaling on CD8+ T cell memory using a Tim-3 conditional knockout mouse model and mice lacking the signaling portion of the Tim-3 cytoplasmic domain. Together, our results indicate that Tim-3 has at most a modest effect on the formation and function of CD8+ memory T cells.
    DOI:  https://doi.org/10.4049/jimmunol.2300401
  8. J Gerontol A Biol Sci Med Sci. 2023 Dec 20. pii: glad276. [Epub ahead of print]
    Gut Microbiota Richness and Diversity Track with T Cell Aging in Healthy Adults.
    Annelise A Madison, Christin E Burd, Rebecca Andridge, Stephanie J Wilson, Michael T Bailey, Martha Belury, Daniel J Spakowicz, William Malarkey, Janice K Kiecolt-Glaser.
      BACKGROUND: This study examined how gut microbiota diversity and richness relate to T cell aging among 96 healthy adults of all ages. It also explored whether these links differed throughout the lifespan.METHODS: Peripheral blood was obtained from 96 study participants (N=96, aged 21-72) to assess mRNA markers of T cell aging (p16ink4a, p14ARF, B3gat1, Klrg1) and DNA methylation. T cell aging mRNA markers were combined into an aging index and the Horvath epigenetic clock algorithm was used to calculate epigenetic age based on DNA methylation status of over 500 loci. Participants also collected a stool sample from which the V4 region of the 16S rRNA gene was sequenced to derive the Shannon and Simpson diversity indices, and the total count of observed operational taxonomic units (richness). Models controlled for BMI, comorbidities, sex, dietary quality, smoking status, physical activity, and sleep quality.
    RESULTS: Lower microbiota richness was associated with higher T cell age based on mRNA markers, but when probing the region of significance, this relationship was only significant among adults 45 years and older (p=.03). Lower Shannon diversity (p=.05) and richness (p=.07) marginally correlated with higher epigenetic age (i.e., greater T cell DNA methylation).
    CONCLUSION: Gut microbiota complexity may correspond with the rate of T cell aging, especially in mid-to-late life. These results suggest an interplay between the gut microbiome and immunological aging that warrants further experimental work.
    Keywords:  Gut microbiota; T cell aging; accelerated aging; diversity; richness
    DOI:  https://doi.org/10.1093/gerona/glad276
  9. Oncoimmunology. 2023 ;12(1): 2281179
    Piezo1 facilitates optimal T cell activation during tumor challenge.
    Muta Abiff, Mohammad Alshebremi, Melissa Bonner, Jay T Myers, Byung-Gyu Kim, Suzanne L Tomchuck, Alicia Santin, Daniel Kingsley, Sung Hee Choi, Alex Y Huang.
      Functional effector T cells in the tumor microenvironment (TME) are critical for successful anti-tumor responses. T cell anti-tumor function is dependent on their ability to differentiate from a naïve state, infiltrate into the tumor site, and exert cytotoxic functions. The factors dictating whether a particular T cell can successfully undergo these processes during tumor challenge are not yet completely understood. Piezo1 is a mechanosensitive cation channel with high expression on both CD4+ and CD8+ T cells. Previous studies have demonstrated that Piezo1 optimizes T cell activation and restrains the CD4+ regulatory T cell (Treg) pool in vitro and under inflammatory conditions in vivo. However, little is known about the role Piezo1 plays on CD4+ and CD8+ T cells in cancer. We hypothesized that disruption of Piezo1 on T cells impairs anti-tumor immunity in vivo by hindering inflammatory T cell responses. We challenged mice with T cell Piezo1 deletion (P1KO) with tumor models dependent on T cells for immune rejection. P1KO mice had the more aggressive tumors, higher tumor growth rates and were unresponsive to immune-mediated therapeutic interventions. We observed a decreased CD4:CD8 ratio in both the secondary lymphoid organs and TME of P1KO mice that correlated inversely with tumor size. Poor CD4+ helper T cell responses underpinned the immunodeficient phenotype of P1KO mice. Wild type CD8+ T cells are sub-optimally activated in vivo with P1KO CD4+ T cells, taking on a CD25loPD-1hi phenotype. Together, our results suggest that Piezo1 optimizes T cell activation in the context of a tumor response.
    Keywords:  Cancer immunology; Piezo1; T cell mechanobiology; rhabdomyosarcoma
    DOI:  https://doi.org/10.1080/2162402X.2023.2281179
  10. Trends Cancer. 2023 Dec 22. pii: S2405-8033(23)00238-8. [Epub ahead of print]
    Metabolic interplay: tumor macrophages and regulatory T cells.
    Stefania Vilbois, Yingxi Xu, Ping-Chih Ho.
      The tumor microenvironment (TME) contains a complex cellular ecosystem where cancer, stromal, vascular, and immune cells interact. Macrophages and regulatory T cells (Tregs) are critical not only for maintaining immunological homeostasis and tumor growth but also for monitoring the functional states of other immune cells. Emerging evidence reveals that metabolic changes in macrophages and Tregs significantly influence their pro-/antitumor functions through the regulation of signaling cascades and epigenetic reprogramming. Hence, they are increasingly recognized as therapeutic targets in cancer immunotherapy. Specific metabolites in the TME may also affect their pro-/antitumor functions by intervening with the metabolic machinery. We discuss how metabolites influence the immunosuppressive phenotypes of tumor-associated macrophages (TAMs) and Tregs. We then describe how TAMs and Tregs, independently or collaboratively, utilize metabolic mechanisms to suppress the activity of CD8+ T cells. Finally, we highlight promising metabolic interventions that can improve the outcome of current cancer therapies.
    Keywords:  cancer immunotherapy; immunometabolism; immunosuppression; macrophage; regulatory T cell; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2023.11.007
  11. Nat Aging. 2023 Dec 21.
    NADase CD38 is a key determinant of ovarian aging.
    Qingling Yang, Wenhui Chen, Luping Cong, Mengchen Wang, Hui Li, Huan Wang, Xiaoyan Luo, Jing Zhu, Xinxin Zeng, Zhenye Zhu, Yining Xu, Min Lei, Yanqing Zhao, Chenlu Wei, Yingpu Sun.
      The ovary ages earlier than most other tissues, yet the underlying mechanisms remain elusive. Here a comprehensive analysis of transcriptomic landscapes in different organs in young and middle-aged mice revealed that the ovaries showed earlier expression of age-associated genes, identifying increased NADase CD38 expression and decreased NAD+ levels in the ovary of middle-aged mice. Bulk and single-cell RNA sequencing revealed that CD38 deletion mitigated ovarian aging, preserving fertility and follicle reserve in aged mice by countering age-related gene expression changes and intercellular communication alterations. Mechanistically, the earlier onset of inflammation induced higher expression levels of CD38 and decreased NAD+ levels in the ovary, thereby accelerating ovarian aging. Consistently, pharmacological inhibition of CD38 enhanced fertility in middle-aged mice. Our findings revealed the mechanisms underlying the earlier aging of the ovary relative to other organs, providing a potential therapeutic target for ameliorating age-related female infertility.
    DOI:  https://doi.org/10.1038/s43587-023-00532-9
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