bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022–07–24
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Functional Restoration of Exhausted CD8 T Cells in Chronic HIV-1 Infection by Targeting Mitochondrial Dysfunction.
  2. Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells.
  3. An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy.
  4. Long-term caloric restriction ameliorates T cell immunosenescence in mice.
  5. Editorial: T Cell Metabolism in Infection.
  6. T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy.
  7. Evaluation of T-cell aging-related immune phenotypes in the context of biological aging and multimorbidity in the Health and Retirement Study.
  8. Mitochondria dysfunction in CD8+ T cells as an important contributing factor for cancer development and a potential target for cancer treatment: a review.
  9. Mitochondrial function and nutrient sensing pathways in ageing: enhancing longevity through dietary interventions.
  10. Nutrient Condition in the Microenvironment Determines Essential Metabolisms of CD8+ T Cells for Enhanced IFNγ Production by Metformin.
  1. Front Immunol. 2022 ;13 908697
    Functional Restoration of Exhausted CD8 T Cells in Chronic HIV-1 Infection by Targeting Mitochondrial Dysfunction.
    Aljawharah Alrubayyi, Elia Moreno-Cubero, Dan Hameiri-Bowen, Rebecca Matthews, Sarah Rowland-Jones, Anna Schurich, Dimitra Peppa.
      CD8 T cell exhaustion is a hallmark of HIV-1 infection, characterized by phenotypic and functional CD8 T cell abnormalities that persist despite years of effective antiretroviral treatment (ART). More recently, the importance of cellular metabolism in shaping T cell antiviral function has emerged as a crucial aspect of immunotherapeutics aimed at re-invigorating exhausted CD8 T cells but remains under-investigated in HIV-1 infection. To gain a better insight into this process and identify new targets for effective CD8 T cell restoration we examined the metabolic profile of exhausted CD8 T cells in HIV-1 infection. We show that relative to HIV-1 elite controllers (EC) and HIV-1 seronegative donors, CD8 T cells from HIV-1 viraemic individuals are skewed toward a PD-1hiEOMEShiT-betlowTIGIT+ phenotype that is maintained during ART. This exhausted signature is enriched in HIV-specific CD8 T cells, compared to CMV-specific CD8 T cell populations, and further delineated by higher expression of the glucose transporter, Glut-1, impaired mitochondrial function and biogenesis, reflecting underlying metabolic defects. A notable improvement in antiviral HIV-specific CD8 T cell function was elicited via mitochondrial antioxidant treatment in combination with pharmacological modulation of mitochondrial dynamics and IL-15 treatment. These findings identify mitochondria as promising targets for combined reconstitution therapies in HIV-1 infection.
    Keywords:  CD8 T cell exhaustion; CMV; HIV-1; immunometabolism; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fimmu.2022.908697
  2. Sci Rep. 2022 Jul 22. 12(1): 12506
    Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells.
    Li Li, Qing Li, Zi-Xun Yan, Ling-Shuang Sheng, Di Fu, Pengpeng Xu, Li Wang, Wei-Li Zhao.
      Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising novel therapeutic approach. However, primary and secondary resistance to CAR-T cell therapy is commonly encountered in various clinical trials. Despite the comprehensive studies to elucidate the mechanisms of resistance, effective resolution in clinical practice is still elusive. Inadequate persistence and subsequent loss of infused CAR-T cells are proposed major resistance mechanism associated with CAR-T cell treatment failure. Thus, we generated CAR-T cells armored with IL-7 to prolong the persistence of infused T-cells, particularly CD4 + T cells, and enhanced anti-tumor response. IL-7 increased CAR-T-cell persistence in vivo and contributed to the distinct T-cell cytotoxicity profile. Using mass cytometry (CyTOF), we further assessed the phenotypic and metabolic profiles of IL-7-secreting CAR-T cells, along with conventional CAR-T cells at the single-cell level. With in-depth analysis, we found that IL-7 maintained CAR-T cells in a less differentiated T-cell state, regulated distinct metabolic activity, and prevented CAR-T-cell exhaustion, which could be essential for CAR-T cells to maintain their metabolic fitness and anti-tumor response. Our findings thus provided clinical rationale to exploit IL-7 signaling for modulation and metabolic reprogramming of T-cell function to enhance CAR-T cell persistence and induce durable remission upon CAR-T cell therapy.
    DOI:  https://doi.org/10.1038/s41598-022-16616-2
  3. Small. 2022 Jul 17. e2202663
    An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy.
    Di Zhang, Qian Li, Xiangwu Chen, Xinxin Nie, Fumin Xue, Wei Xu, Yuxia Luan.
      T cell exhaustion caused by mitochondrial dysfunction is the major obstacle of T cells-based cancer immunotherapy. Besides exhausted T cells, the insufficient major histocompatibility complex class I (MHC I) on tumor cells leads to inefficient T cell recognition of tumor cells, compromising therapeutic efficacy. Therapeutic platform to regulate T cell exhaustion and MHC I expression for boosting T cells-based cancer immunotherapy has not been realized up to date. Herein, an injectable hydrogel is designed to simultaneously tune T cell exhaustion and MHC I expression for amplified cancer immunotherapy. The hydrogel is in situ constructed in tumor site by utilizing oxidized sodium alginate-modified tumor cell membrane vesicle (O-TMV) as a gelator, where axitinib is encapsulated in the lipid bilayer of O-TMV while 4-1BB antibody and proprotein convertase subtilisin/kexin type 9 inhibitor PF-06446846 nanoparticles are present in the cavities of hydrogel. After immune response trigged by O-TMV antigen, the 4-1BB antibody-promoted T cell mitochondrial biogenesis and the axitinib-lowered hypoxia synergistically reverse T cell exhaustion while the PF-06446846-amplified MHC I expression facilitates T cell recognition of tumor cells, demonstrating a powerful immunotherapeutic efficacy. This strategy on reprograming T cell exhaustion and improving T cell potency offers new concept for T cells-based cancer immunotherapy.
    Keywords:  T cell exhaustion; T cell recognition; hydrogels; immunotherapy; mitochondria
    DOI:  https://doi.org/10.1002/smll.202202663
  4. Mech Ageing Dev. 2022 Jul 19. pii: S0047-6374(22)00092-6. [Epub ahead of print] 111710
    Long-term caloric restriction ameliorates T cell immunosenescence in mice.
    Takuya Asami, Katsunori Endo, Rina Matsui, Toko Sawa, Yuna Tanaka, Takeru Saiki, Naotaka Tanba, Hadsuki Haga, Sachi Tanaka.
      Aging is associated with a decrease in the function of the immune system, a phenomenon known as immunosenescence, which results in reduced resistance to infection. Caloric restriction (CR) is known to prolong lifespan and to regulate immune function. However, whether and how CR affects immunosenescence remains unclear. Here, we evaluated the effect of long- and short-term CR on immunosenescence by subjecting wild-type mice to CR between 6 and 18 months of age or between 17 and 18 months of age, respectively. Compared with a normal diet or short-term CR, long-term CR induced marked or complete attenuation of age-related decreases in the frequency of spleen NK cells and NKT cells; naïve CD4+ and CD8+ T cells; and cytokine- and granzyme B-secreting T cells. In contrast, both long- and short-term CR significantly suppressed age-related upregulation of the T cell exhaustion markers PD-1, Tim-3, and KLRG1, as well as the transcription factors NR4A1 and TOX, which regulate the expression of genes associated with the T cell exhaustion phenotype. These results suggest that CR might suppress age-associated immunosenescence by regulating the expression of transcription factors and target genes that control T cell exhaustion.
    Keywords:  Aging; Caloric restriction; Immunosenescence; T cell exhaustion
    DOI:  https://doi.org/10.1016/j.mad.2022.111710
  5. Front Immunol. 2022 ;13 958276
    Editorial: T Cell Metabolism in Infection.
    Duojiao Wu, Jin-Fu Xu.
      
    Keywords:  Immune function; Infection; Metabolism; T cell; pathogen
    DOI:  https://doi.org/10.3389/fimmu.2022.958276
  6. Front Immunol. 2022 ;13 935465
    T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy.
    Fumihiro Fujiki, Soyoko Morimoto, Akiko Katsuhara, Akane Okuda, Saeka Ogawa, Eriko Ueda, Maki Miyazaki, Ayako Isotani, Masahito Ikawa, Sumiyuki Nishida, Hiroko Nakajima, Akihiro Tsuboi, Yoshihiro Oka, Jun Nakata, Naoki Hosen, Atsushi Kumanogoh, Yusuke Oji, Haruo Sugiyama.
      Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.
    Keywords:  RDH10; cancer immunotherapy; effector T cell; memory T cell; retinoic acid; vitamin A; vitamin A metabolism
    DOI:  https://doi.org/10.3389/fimmu.2022.935465
  7. Immun Ageing. 2022 Jul 20. 19(1): 33
    Evaluation of T-cell aging-related immune phenotypes in the context of biological aging and multimorbidity in the Health and Retirement Study.
    Ramya Ramasubramanian, Helen C S Meier, Sithara Vivek, Eric Klopack, Eileen M Crimmins, Jessica Faul, Janko Nikolich-Žugich, Bharat Thyagarajan.
       BACKGROUND: Cellular changes in adaptive immune system accompany the process of aging and contribute to an aging-related immune phenotype (ARIP) characterized by decrease in naïve T-cells (TN) and increase in memory T-cells (TM). A population-representative marker of ARIP and its associations with biological aging and age-related chronic conditions have not been studied previously.
    METHODS: We developed two ARIP indicators based on well understood age-related changes in T cell distribution: TN/(TCM (Central Memory) + TEM (Effector Memory) + TEFF (Effector)) (referred as TN/TM) in CD4 + and CD8 + T-cells. We compared them with existing ARIP measures including CD4/CD8 ratio and CD8 + TN cells by evaluating associations with chronological age and the Klemera Doubal measure of biological age (measured in years) using linear regression, multimorbidity using multinomial logistic regression and two-year mortality using logistic regression.
    RESULTS: CD8 + TN and CD8 + TN/TM had the strongest inverse association with chronological age (beta estimates: -3.41 and -3.61 respectively; p-value < 0.0001) after adjustment for sex, race/ethnicity and CMV status. CD4 + TN/TM and CD4 + TN had the strongest inverse association with biological age (β = -0.23; p = 0.003 and β = -0.24; p = 0.004 respectively) after adjustment for age, sex, race/ethnicity and CMV serostatus. CD4/CD8 ratio was not associated with chronological age or biological age. CD4 + TN/TM and CD4 + TN was inversely associated with multimorbidity. For CD4 + TN/TM, people with 2 chronic conditions had an odds ratio of for 0.74 (95%CI: 0.63-0.86 p = 0.0003) compared to those without any chronic conditions while those with 3 chronic conditions had an odds ratio of 0.75 (95% CI: 0.63-0.90; p = 0.003) after adjustment for age, sex, race/ethnicity, CMV serostatus, smoking, and BMI. The results for the CD4 + TN subset were very similar to the associations seen with the CD4 + TN/TM. CD4 + TN/TM and CD4 + TN were both associated with two-year mortality (OR = 0.80 (95% CI: 0.67-0.95; p = 0.01) and 0.81 (0.70-0.94; p = 0.01), respectively).
    CONCLUSION: CD4 + TN/TM and CD4 + TN had a stronger association with biological age, age-related morbidity and mortality compared to other ARIP measures. Future longitudinal studies are needed to evaluate the utility of the CD4 + subsets in predicting the risk of aging-related outcomes.
    Keywords:  Adaptive immunity; Biological aging; Health and Retirement Study; Immune aging; Multimorbidity
    DOI:  https://doi.org/10.1186/s12979-022-00290-z
  8. J Exp Clin Cancer Res. 2022 Jul 21. 41(1): 227
    Mitochondria dysfunction in CD8+ T cells as an important contributing factor for cancer development and a potential target for cancer treatment: a review.
    Lu Zhang, Wen Zhang, Ziye Li, Shumeng Lin, Tiansheng Zheng, Bingjie Hao, Yaqin Hou, Yanfei Zhang, Kai Wang, Chenge Qin, Liduo Yue, Jing Jin, Ming Li, Lihong Fan.
      CD8+ T cells play a central role in anti-tumor immunity. Naïve CD8+ T cells are active upon tumor antigen stimulation, and then differentiate into functional cells and migrate towards the tumor sites. Activated CD8+ T cells can directly destroy tumor cells by releasing perforin and granzymes and inducing apoptosis mediated by the death ligand/death receptor. They also secrete cytokines to regulate the immune system against tumor cells. Mitochondria are the central hub of metabolism and signaling, required for polarization, and migration of CD8+ T cells. Many studies have demonstrated that mitochondrial dysfunction impairs the anti-tumor activity of CD8+ T cells through various pathways. Mitochondrial energy metabolism maladjustment will cause a cellular energy crisis in CD8+ T cells. Abnormally high levels of mitochondrial reactive oxygen species will damage the integrity and architecture of biofilms of CD8+ T cells. Disordered mitochondrial dynamics will affect the mitochondrial number and localization within cells, further affecting the function of CD8+ T cells. Increased mitochondria-mediated intrinsic apoptosis will decrease the lifespan and quantity of CD8+ T cells. Excessively low mitochondrial membrane potential will cause the release of cytochrome c and apoptosis of CD8+ T cells, while excessively high will exacerbate oxidative stress. Dysregulation of mitochondrial Ca2+ signaling will affect various physiological pathways in CD8+ T cells. To some extent, mitochondrial abnormality in CD8+ T cells contributes to cancer development. So far, targeting mitochondrial energy metabolism, mitochondrial dynamics, mitochondria-mediated cell apoptosis, and other mitochondrial physiological processes to rebuild the anti-tumor function of CD8+ T cells has proved effective in some cancer models. Thus, mitochondria in CD8+ T cells may be a potential and powerful target for cancer treatment in the future.
    Keywords:  Anti-tumor immunity; CD8+ T cells; Mitochondria; cancer development; cancer treatment
    DOI:  https://doi.org/10.1186/s13046-022-02439-6
  9. Biogerontology. 2022 Jul 16.
    Mitochondrial function and nutrient sensing pathways in ageing: enhancing longevity through dietary interventions.
    Elangbam Tomtheelnganbee, Puja Sah, R Sharma.
      Ageing is accompanied by alterations in several biochemical processes, highly influenced by its environment. It is controlled by the interactions at various levels of biological hierarchy. To maintain homeostasis, a number of nutrient sensors respond to the nutritional status of the cell and control its energy metabolism. Mitochondrial physiology is influenced by the energy status of the cell. The alterations in mitochondrial physiology and the network of nutrient sensors result in mitochondrial damage leading to age related metabolic degeneration and diseases. Calorie restriction (CR) has proved to be as the most successful intervention to achieve the goal of longevity and healthspan. CR elicits a hormetic response and regulates metabolism by modulating these networks. In this review, the authors summarize the interdependent relationship between mitochondrial physiology and nutrient sensors during the ageing process and their role in regulating metabolism.
    Keywords:  AMPK; Ageing; Dietary restriction; Mitochondria; Sirtuins; mTOR
    DOI:  https://doi.org/10.1007/s10522-022-09978-7
  10. Front Immunol. 2022 ;13 864225
    Nutrient Condition in the Microenvironment Determines Essential Metabolisms of CD8+ T Cells for Enhanced IFNγ Production by Metformin.
    Ruoyu Chao, Mikako Nishida, Nahoko Yamashita, Miho Tokumasu, Weiyang Zhao, Ikuru Kudo, Heiichiro Udono.
      Metformin (Met), a first-line drug for type 2 diabetes, lowers blood glucose levels by suppressing gluconeogenesis in the liver, presumably through the liver kinase B1-dependent activation of AMP-activated protein kinase (AMPK) after inhibiting respiratory chain complex I. Met is also implicated as a drug to be repurposed for cancers; its mechanism is believed identical to that of gluconeogenesis inhibition. However, AMPK activation requires high Met concentrations at more than 1 mM, which are unachievable in vivo. The immune-mediated antitumor response might be the case in a low dose Met. Thus, we proposed activating or expanding tumor-infiltrating CD8+ T cells (CD8TILs) in a mouse model by orally administering Met in free drinking water. Here we showed that Met, at around 10 μM and a physiologically relevant concentration, enhanced production of IFNγ,TNFα and expression of CD25 of CD8+ T cells upon TCR stimulation. Under a glucose-rich condition, glycolysis was exclusively involved in enhancing IFNγ production. Under a low-glucose condition, fatty acid oxidation or autophagy-dependent glutaminolysis, or both, was also involved. Moreover, phosphoenolpyruvate carboxykinase 1 (PCK1), converting oxaloacetate to phosphoenolpyruvate, became essential. Importantly, the enhanced IFNγ production was blocked by a mitochondrial ROS scavenger and not by an inhibitor of AMPK. In addition, IFNγ production by CD8TILs relied on pyruvate translocation to the mitochondria and PCK1. Our results revealed a direct effect of Met on IFNγ production of CD8+ T cells that was dependent on differential metabolic pathways and determined by nutrient conditions in the microenvironment.
    Keywords:  CD8+ T lymphocytes; FAO; IFNg; autophagy +T; glutaminolysis; glycolysis; metformin
    DOI:  https://doi.org/10.3389/fimmu.2022.864225
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