bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–05–12
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Nrf2 regulates the activation-driven expansion of CD4 + T-cells by differentially modulating glucose and glutamine metabolism.
  2. Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.
  3. CCR5 promotes the migration of pathological CD8+ T cells to the leishmanial lesions.
  4. CPT-11 mitigates autoimmune diseases by suppressing effector T cells without affecting long-term anti-tumor immunity.
  5. CD4+ T-Cell Senescence in Neurodegenerative Disease: Pathogenesis and Potential Therapeutic Targets.
  6. Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP.
  7. Rebalancing the aged immune system.
  8. Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses.
  9. Tuning Cellular Metabolism for Cancer Virotherapy.
  10. Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells.
  11. GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.
  12. Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people.
  13. Targeting senescent cells with NKG2D-CAR T cells.
  1. bioRxiv. 2024 Apr 22. pii: 2024.04.18.590146. [Epub ahead of print]
    Nrf2 regulates the activation-driven expansion of CD4 + T-cells by differentially modulating glucose and glutamine metabolism.
    Aprajita Tripathi, Debolina Dasgupta, Anil Pant, Ashlyn Bugbee, Nanda Kumar Yellapu, Ben H Y Choi, Shailendra Giri, Kalyani Pyaram.
      Upon antigenic stimulation, CD4 + T-cells undergo clonal expansion, elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4 + T-cells remains unexplored. Here, we elucidate the role of Nrf2 beyond the traditional antioxidation, in modulating activation-driven expansion of CD4 + T-cells by influencing their nutrient metabolism. T-cell-specific activation of Nrf2 enhances early activation and IL-2 secretion, upregulates TCR-signaling, and increases activation-driven proliferation of CD4 + T-cells. Mechanistically, high Nrf2 inhibits glucose metabolism through glycolysis but promotes glutamine metabolism via glutaminolysis to support increased T-cell proliferation. Further, Nrf2 expression is temporally regulated in activated CD4 + T-cells with elevated expression during the early activation, but decreased expression thereafter. Overall, our findings uncover a novel role of Nrf2 as a metabolic modulator of CD4 + T-cells, thus providing a framework for improving Nrf2-targeting therapies and T-cell immunotherapies.
    DOI:  https://doi.org/10.1101/2024.04.18.590146
  2. Cell Metab. 2024 May 07. pii: S1550-4131(24)00127-X. [Epub ahead of print]36(5): 884-886
    Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.
    Qiang Cai, Yihao Tian, Quazi T H Shubhra.
      Tumors compromise T cell functionality through various mechanisms, including the induction of a nutrient-scarce microenvironment, leading to lipid accumulation and metabolic reprogramming. Hunt et al. elucidate acetyl-CoA carboxylase's crucial role in regulating lipid metabolism in CD8+ T cells, uncovering a novel metabolic strategy to potentiate antitumor immune responses.
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.007
  3. PLoS Pathog. 2024 May 06. 20(5): e1012211
    CCR5 promotes the migration of pathological CD8+ T cells to the leishmanial lesions.
    Laís Amorim Sacramento, Camila Farias Amorim, Claudia G Lombana, Daniel Beiting, Fernanda Novais, Lucas P Carvalho, Edgar M Carvalho, Phillip Scott.
      Cytolytic CD8+ T cells mediate immunopathology in cutaneous leishmaniasis without controlling parasites. Here, we identify factors involved in CD8+ T cell migration to the lesion that could be targeted to ameliorate disease severity. CCR5 was the most highly expressed chemokine receptor in patient lesions, and the high expression of CCL3 and CCL4, CCR5 ligands, was associated with delayed healing of lesions. To test the requirement for CCR5, Leishmania-infected Rag1-/- mice were reconstituted with CCR5-/- CD8+ T cells. We found that these mice developed smaller lesions accompanied by a reduction in CD8+ T cell numbers compared to controls. We confirmed these findings by showing that the inhibition of CCR5 with maraviroc, a selective inhibitor of CCR5, reduced lesion development without affecting the parasite burden. Together, these results reveal that CD8+ T cells migrate to leishmanial lesions in a CCR5-dependent manner and that blocking CCR5 prevents CD8+ T cell-mediated pathology.
    DOI:  https://doi.org/10.1371/journal.ppat.1012211
  4. Cell Death Discov. 2024 May 04. 10(1): 218
    CPT-11 mitigates autoimmune diseases by suppressing effector T cells without affecting long-term anti-tumor immunity.
    Hantian Liang, Xinzou Fan, Hao Cheng, Xiao Ma, Yutong Sun, Fang Nan, Jingyang Zhou, Panyin Shu, Wei Zhang, Fengqiong Zuo, Hiroko Nakatsukasa, Dunfang Zhang.
      The incidence of autoimmune diseases has significantly increased over the past 20 years. Excessive host immunoreactions and disordered immunoregulation are at the core of the pathogenesis of autoimmune diseases. The traditional anti-tumor chemotherapy drug CPT-11 is associated with leukopenia. Considering that CPT-11 induces leukopenia, we believe that it is a promising drug for the control of autoimmune diseases. Here, we show that CPT-11 suppresses T cell proliferation and pro-inflammatory cytokine production in healthy C57BL/6 mice and in complete Freund's adjuvant-challenged mice. We found that CPT-11 effectively inhibited T cell proliferation and Th1 and Th17 cell differentiation by inhibiting glycolysis in T cells. We also assessed CPT-11 efficacy in treating autoimmune diseases in models of experimental autoimmune encephalomyelitis and psoriasis. Finally, we proved that treatment of autoimmune diseases with CPT-11 did not suppress long-term immune surveillance for cancer. Taken together, these results show that CPT-11 is a promising immunosuppressive drug for autoimmune disease treatment.
    DOI:  https://doi.org/10.1038/s41420-024-01983-8
  5. Cells. 2024 Apr 25. pii: 749. [Epub ahead of print]13(9):
    CD4+ T-Cell Senescence in Neurodegenerative Disease: Pathogenesis and Potential Therapeutic Targets.
    Yan Gao, Yaoping Lu, Xiaojing Liang, Mengwei Zhao, Xinyue Yu, Haiying Fu, Wei Yang.
      With the increasing proportion of the aging population, neurodegenerative diseases have become one of the major health issues in society. Neurodegenerative diseases (NDs), including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are characterized by progressive neurodegeneration associated with aging, leading to a gradual decline in cognitive, emotional, and motor functions in patients. The process of aging is a normal physiological process in human life and is accompanied by the aging of the immune system, which is known as immunosenescence. T-cells are an important part of the immune system, and their senescence is the main feature of immunosenescence. The appearance of senescent T-cells has been shown to potentially lead to chronic inflammation and tissue damage, with some studies indicating a direct link between T-cell senescence, inflammation, and neuronal damage. The role of these subsets with different functions in NDs is still under debate. A growing body of evidence suggests that in people with a ND, there is a prevalence of CD4+ T-cell subsets exhibiting characteristics that are linked to senescence. This underscores the significance of CD4+ T-cells in NDs. In this review, we summarize the classification and function of CD4+ T-cell subpopulations, the characteristics of CD4+ T-cell senescence, the potential roles of these cells in animal models and human studies of NDs, and therapeutic strategies targeting CD4+ T-cell senescence.
    Keywords:  CD4+ T-cells; immunosenescence; neurodegenerative disease; therapy
    DOI:  https://doi.org/10.3390/cells13090749
  6. Front Med (Lausanne). 2024 ;11 1364778
    Immunotherapeutic implications of negative regulation by protein tyrosine phosphatases in T cells: the emerging cases of PTP1B and TCPTP.
    Luis Alberto Perez-Quintero, Belma Melda Abidin, Michel L Tremblay.
      In the context of inflammation, T cell activation occurs by the concerted signals of the T cell receptor (TCR), co-stimulatory receptors ligation, and a pro-inflammatory cytokine microenvironment. Fine-tuning these signals is crucial to maintain T cell homeostasis and prevent self-reactivity while offering protection against infectious diseases and cancer. Recent developments in understanding the complex crosstalk between the molecular events controlling T cell activation and the balancing regulatory cues offer novel approaches for the development of T cell-based immunotherapies. Among the complex regulatory processes, the balance between protein tyrosine kinases (PTK) and the protein tyrosine phosphatases (PTPs) controls the transcriptional and metabolic programs that determine T cell function, fate decision, and activation. In those, PTPs are de facto regulators of signaling in T cells acting for the most part as negative regulators of the canonical TCR pathway, costimulatory molecules such as CD28, and cytokine signaling. In this review, we examine the function of two close PTP homologs, PTP1B (PTPN1) and T-cell PTP (TCPTP; PTPN2), which have been recently identified as promising candidates for novel T-cell immunotherapeutic approaches. Herein, we focus on recent studies that examine the known contributions of these PTPs to T-cell development, homeostasis, and T-cell-mediated immunity. Additionally, we describe the signaling networks that underscored the ability of TCPTP and PTP1B, either individually and notably in combination, to attenuate TCR and JAK/STAT signals affecting T cell responses. Thus, we anticipate that uncovering the role of these two PTPs in T-cell biology may lead to new treatment strategies in the field of cancer immunotherapy. This review concludes by exploring the impacts and risks that pharmacological inhibition of these PTP enzymes offers as a therapeutic approach in T-cell-based immunotherapies.
    Keywords:  PTP1B (PTPN1); T cells; TCPTP (PTPN2); immunotherapy; protein tyrosine phosphatases; signaling
    DOI:  https://doi.org/10.3389/fmed.2024.1364778
  7. Nat Aging. 2024 May 08.
    Rebalancing the aged immune system.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00637-9
  8. iScience. 2024 May 17. 27(5): 109775
    Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses.
    Nikhila S Bharadwaj, Nicholas A Zumwalde, Arvinder Kapur, Manish Patankar, Jenny E Gumperz.
      The transition of naive T lymphocytes into antigenically activated effector cells is associated with a metabolic shift from oxidative phosphorylation to aerobic glycolysis. This shift facilitates production of the key anti-tumor cytokine interferon (IFN)-γ; however, an associated loss of mitochondrial efficiency in effector T cells ultimately limits anti-tumor immunity. Memory phenotype (MP) T cells are a newly recognized subset that arises through homeostatic activation signals following hematopoietic transplantation. We show here that human CD4+ MP cell differentiation is associated with increased glycolytic and oxidative metabolic activity, but MP cells retain less compromised mitochondria compared to effector CD4+ T cells, and their IFN-γ response is less dependent on glucose and more reliant on glutamine. MP cells also produced IFN-γ more efficiently in response to weak T cell receptor (TCR) agonism than effectors and mediated stronger responses to transformed B cells. MP cells may thus be particularly well suited to carry out sustained immunosurveillance against neoplastic cells.
    Keywords:  cell biology; immunity
    DOI:  https://doi.org/10.1016/j.isci.2024.109775
  9. Cancer Lett. 2024 May 06. pii: S0304-3835(24)00317-3. [Epub ahead of print] 216924
    Tuning Cellular Metabolism for Cancer Virotherapy.
    Dian Xiong, Qing Wang, Wei-Ming Wang, Zhi-Jun Sun.
      Oncolytic viruses (OVs) represent an emerging immunotherapeutic strategy owing to their capacity for direct tumor lysis and induction of antitumor immunity. However, hurdles like transient persistence and moderate efficacy necessitate innovative approaches. Metabolic remodeling has recently gained prominence as a strategic intervention, wherein OVs or combination regimens could reprogram tumor and immune cell metabolism to enhance viral replication and oncolysis. In this review, we summarize recent advances in strategic reprogramming of tumor and immune cell metabolism to enhance OV-based immunotherapies. Specific tactics include engineering viruses to target glycolytic, glutaminolytic, and nucleotide synthesis pathways in cancer cells, boosting viral replication and tumor cell death. Additionally, rewiring T cell and NK cell metabolism of lipids, amino acids, and carbohydrates shows promise to enhance antitumor effects. Further insights are discussed to pave the way for the clinical implementation of metabolically enhanced oncolytic platforms, including balancing metabolic modulation to limit antiviral responses while promoting viral persistence and tumor clearance.
    Keywords:  Cancer immunotherapy; Cancer metabolism; Immune cell metabolism; Immunosuppressive tumor microenvironment; Oncolytic viruses
    DOI:  https://doi.org/10.1016/j.canlet.2024.216924
  10. Aging (Albany NY). 2024 May 09. 16
    Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells.
    Somaiah Chinnapaka, Hamid Malekzadeh, Zayaan Tirmizi, Asim Ejaz.
      Adipose tissue regulates metabolic balance, but aging disrupts it, shifting fat from insulin-sensitive subcutaneous to insulin-resistant visceral depots, impacting overall metabolic health. Adipose-derived stem cells (ASCs) are crucial for tissue regeneration, but aging diminishes their stemness and regeneration potential. Our findings reveal that aging is associated with a decrease in subcutaneous adipose tissue mass and an increase in the visceral fat depots mass. Aging is associated with increase in adipose tissue fibrosis but no significant change in adipocyte size was observed with age. Long term caloric restriction failed to prevent fibrotic changes but resulted in significant decrease in adipocytes size. Aged subcutaneous ASCs displayed an increased production of ROS. Using mitochondrial membrane activity as an indicator of stem cell quiescence and senescence, we observed a significant decrease in quiescence ASCs with age exclusively in subcutaneous adipose depot. In addition, aged subcutaneous adipose tissue accumulated more senescent ASCs having defective autophagy activity. However, long-term caloric restriction leads to a reduction in mitochondrial activity in ASCs. Furthermore, caloric restriction prevents the accumulation of senescent cells and helps retain autophagy activity in aging ASCs. These results suggest that caloric restriction and caloric restriction mimetics hold promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using controlled interventions in animals and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established approach for enhancing the stemness of aged stem cells.
    Keywords:  adipose stem cells; adipose tissue; autophagy; caloric restriction; differentiation; reactive oxygen species; senescence; stemness
    DOI:  https://doi.org/10.18632/aging.205812
  11. Mol Ther. 2024 May 07. pii: S1525-0016(24)00303-4. [Epub ahead of print]
    GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.
    Yuzhe Shi, Ivan S Kotchetkov, Anton Dobrin, Sophie A Hanina, Vinagolu K Rajasekhar, John H Healey, Michel Sadelain.
      The tumor microenvironment presents many obstacles to effective CAR T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Rα2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes Tscm formation and prolongs survival. RNA sequencing of these CAR T cells reveals that overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR T cells improve tumor control and response to rechallenge in an RCC patient derived xenograft model. Furthermore, IL13Rα2-BBz CAR T cells overexpressing GLUT1 prolong survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR T cells in harsh tumor environments where glucose is limiting.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.05.006
  12. Immun Ageing. 2024 May 07. 21(1): 28
    Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people.
    Johanne Poisson, Carine El-Sissy, Arnaud Serret-Larmande, Nikaïa Smith, Morgane Lebraud, Jean-Loup Augy, Catherine Conti, Cécile Gonnin, Benjamin Planquette, Jean-Benoît Arlet, Bertrand Hermann, Bruno Charbit, Jean Pastre, Floriane Devaux, Cyrielle Ladavière, Lydie Lim, Pauline Ober, Johanna Cannovas, Lucie Biard, Marie-Christelle Gulczynski, Noémie Blumenthal, Hélène Péré, Camille Knosp, Alain Gey, Nadine Benhamouda, Juliette Murris, David Veyer, Eric Tartour, Jean-Luc Diehl, Darragh Duffy, Elena Paillaud, Clémence Granier.
       BACKGROUND: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity.
    RESULTS: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1β, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity.
    CONCLUSIONS: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.
    Keywords:  CD8-positive T-lymphocytes; COVID-19; CXCL10; GMCSF; Geriatrics; Immune-ageing; Immunosenescence; Infections; Inflammaging; Senescence-associated secretory phenotype; TSCM
    DOI:  https://doi.org/10.1186/s12979-024-00430-7
  13. Cell Death Discov. 2024 May 04. 10(1): 217
    Targeting senescent cells with NKG2D-CAR T cells.
    Yushuang Deng, Avadh Kumar, Kan Xie, Kristina Schaaf, Enzo Scifo, Sarah Morsy, Tao Li, Armin Ehninger, Daniele Bano, Dan Ehninger.
      This study investigates the efficacy of NKG2D chimeric antigen receptor (CAR) engineered T cells in targeting and eliminating stress-induced senescent cells in vitro. Cellular senescence contributes to age-related tissue decline and is characterized by permanent cell cycle arrest and the senescence-associated secretory phenotype (SASP). Immunotherapy, particularly CAR-T cell therapy, emerges as a promising approach to selectively eliminate senescent cells. Our focus is on the NKG2D receptor, which binds to ligands (NKG2DLs) upregulated in senescent cells, offering a target for CAR-T cells. Using mouse embryonic fibroblasts (MEFs) and astrocytes (AST) as senescence models, we demonstrate the elevated expression of NKG2DLs in response to genotoxic and oxidative stress. NKG2D-CAR T cells displayed potent cytotoxicity against these senescent cells, with minimal effects on non-senescent cells, suggesting their potential as targeted senolytics. In conclusion, our research presents the first evidence of NKG2D-CAR T cells' ability to target senescent brain cells, offering a novel approach to manage senescence-associated diseases. The findings pave the way for future investigations into the therapeutic applicability of NKG2D-targeting CAR-T cells in naturally aged organisms and models of aging-associated brain diseases in vivo.
    DOI:  https://doi.org/10.1038/s41420-024-01976-7
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