bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–02–18
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Reprogramming T cell metabolism to enhance adoptive cell therapies.
  2. Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.
  3. Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells.
  4. Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
  5. Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.
  6. Unleashing CAR T cells to delay metabolic aging.
  7. Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment.
  8. T cell receptor sequences are the dominant factor contributing to the phenotype of CD8+ T cells with specificities against immunogenic viral antigens.
  9. A silver bullet for ageing medicine?: clinical relevance of T-cell checkpoint receptors in normal human ageing.
  10. The therapeutic perspective of NAD+ precursors in age-related diseases.
  11. Fighting flu: novel CD8+ T-cell targets are required for future influenza vaccines.
  12. Resistant starches from dietary pulses improve neurocognitive health via gut-microbiome-brain axis in aged mice.
  1. Int Immunol. 2024 Feb 14. pii: dxae007. [Epub ahead of print]
    Reprogramming T cell metabolism to enhance adoptive cell therapies.
    Meghan Kates, Samuel D Saibil.
      Adoptive cell therapy (ACT) is an immunotherapeutic approach that involves isolating T cells from a patient, culturing them ex vivo, then re-infusing the cells back into the patient. Although this strategy has shown remarkable efficacy in hematological malignancies, the solid-tumour microenvironment (TME) has presented serious challenges for therapy efficacy. Particularly, the TME has immunosuppressive signaling and presents a metabolically challenging environment that leads to T cell suppression. T cell metabolism is an expanding field of research with a focus on understanding its inherent link to T cell function. Here, we review the current model of T cell metabolism from naïve cells through effector and memory life stages, as well as updates to the model from recent literature. These models of metabolism have provided us with the tools and understanding to explore T cell metabolic and mitochondrial insufficiency in the TME. We discuss manipulations that can be made to these mitochondrial and metabolic pathways to enhance persistence of infused T cells, overcome the metabolically challenging TME and improve the efficacy of therapy in ACT models. Further understanding and investigation of the impact of metabolic pathways on T cell performance could contribute to improving therapy efficacy for patients.
    Keywords:  Cancer Immunology; Immunometabolism; Immunotherapy
    DOI:  https://doi.org/10.1093/intimm/dxae007
  2. bioRxiv. 2024 Feb 02. pii: 2024.01.31.578284. [Epub ahead of print]
    Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.
    Hong Yu, Hiroshi Nishio, Joseph Barbi, Marisa Mitchell-Flack, Paolo D A Vignali, Ying Zheng, Andriana Lebid, Kwang-Yu Chang, Juan Fu, Makenzie Higgins, Ching-Tai Huang, Xuehong Zhang, Zhiguang Li, Lee Blosser, Ada Tam, Charles G Drake, Drew M Pardoll.
      The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.
    DOI:  https://doi.org/10.1101/2024.01.31.578284
  3. Cell Death Dis. 2024 Feb 15. 15(2): 145
    Cystine deprivation triggers CD36-mediated ferroptosis and dysfunction of tumor infiltrating CD8+ T cells.
    Chenfeng Han, Minmin Ge, Pengfei Xing, Tian Xia, Cangang Zhang, Kaili Ma, Yifu Ma, Shicheng Li, Wenhui Li, Xiaowei Liu, Baojun Zhang, Liyuan Zhang, Lianjun Zhang.
      Cancer cells develop multiple strategies to evade T cell-mediated killing. On one hand, cancer cells may preferentially rely on certain amino acids for rapid growth and metastasis. On the other hand, sufficient nutrient availability and uptake are necessary for mounting an effective T cell anti-tumor response in the tumor microenvironment (TME). Here we demonstrate that tumor cells outcompete T cells for cystine uptake due to high Slc7a11 expression. This competition induces T-cell exhaustion and ferroptosis, characterized by diminished memory formation and cytokine secretion, increased PD-1 and TIM-3 expression, as well as intracellular oxidative stress and lipid-peroxide accumulation. Importantly, either Slc7a11 deletion in tumor cells or intratumoral cystine supplementation improves T cell anti-tumor immunity. Mechanistically, cystine deprivation in T cells disrupts glutathione synthesis, but promotes CD36 mediated lipid uptake due to dysregulated cystine/glutamate exchange. Moreover, enforced expression of glutamate-cysteine ligase catalytic subunit (Gclc) promotes glutathione synthesis and prevents CD36 upregulation, thus boosting T cell anti-tumor immunity. Our findings reveal cystine as an intracellular metabolic checkpoint that orchestrates T-cell survival and differentiation, and highlight Gclc as a potential therapeutic target for enhancing T cell anti-tumor function.
    DOI:  https://doi.org/10.1038/s41419-024-06503-1
  4. Cell Rep. 2024 Feb 12. pii: S2211-1247(24)00066-4. [Epub ahead of print]43(2): 113738
    Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
    Debanik Choudhury, Na Rong, Hamsa Vardini Senthil Kumar, Sydney Swedick, Ronel Z Samuel, Pihu Mehrotra, John Toftegaard, Nika Rajabian, Ramkumar Thiyagarajan, Ashis K Podder, Yulun Wu, Shahryar Shahini, Kenneth L Seldeen, Bruce Troen, Pedro Lei, Stelios T Andreadis.
      Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.
    Keywords:  AMPKα; CP: Cell biology; CP: Metabolism; Parkin; aging; amino acid; autophagy; mitochondria; mitophagy; proline; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2024.113738
  5. Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2314561121
    Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.
    Yali Chen, Kun Chen, Ha Zhu, Hua Qin, Juan Liu, Xuetao Cao.
      Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating T cell function and differentiation. However, how the epigenetic modification controls Th17/Treg cell balance via metabolic reprogramming remains obscure. Here, we find that Setd2, a histone H3K36 trimethyltransferase, suppresses Th17 development but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up-regulates transcriptional expression of lysophosphatidylcholine acyltransferase 4 (Lpcat4) via directly catalyzing H3K36me3 of Lpcat4 gene promoter in T cells. Lpcat4-mediated phosphatidylcholine PC(16:0,18:2) generation in turn limits endoplasmic reticulum stress and oxidative stress. These changes decrease HIF-1α transcriptional activity and thus suppress Th17 but enhance Treg development. Consistent with this regulatory paradigm, T cell deficiency of Setd2 aggravates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis due to imbalanced Th17/Treg cell differentiation. Overall, our data reveal that Setd2 acts as an epigenetic brake for T cell-mediated autoimmunity through phospholipid remodeling, suggesting potential targets for treating neuroinflammatory diseases.
    Keywords:  Setd2; autoimmunity; lysophosphatidylcholine acyltransferase 4; phosphatidylcholine
    DOI:  https://doi.org/10.1073/pnas.2314561121
  6. Nat Aging. 2024 Feb 15.
    Unleashing CAR T cells to delay metabolic aging.
    Jenna M Bartley, Ming Xu.
      
    DOI:  https://doi.org/10.1038/s43587-024-00576-5
  7. Cell Rep. 2024 Feb 15. pii: S2211-1247(24)00125-6. [Epub ahead of print]43(2): 113797
    Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment.
    Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Masahito Kawazu, Hiromichi Dansako, Yutaka Suzuki, Hiroyoshi Nishikawa, Takashi Inozume, Joji Nagasaki, Yosuke Togashi.
      Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.
    Keywords:  CP: Cancer; CXCL13; LAG-3; PD-1; T cell exhaustion; TCF1; cancer immunology; cytotoxic CD4(+) T cell; follicular helper T cell; stem-like progenitor exhaustion; terminally differentiated exhaustion
    DOI:  https://doi.org/10.1016/j.celrep.2024.113797
  8. Cell Rep. 2024 Feb 10. pii: S2211-1247(24)00169-4. [Epub ahead of print]43(2): 113841
    T cell receptor sequences are the dominant factor contributing to the phenotype of CD8+ T cells with specificities against immunogenic viral antigens.
    Daniel G Chen, Jingyi Xie, Yapeng Su, James R Heath.
      
    DOI:  https://doi.org/10.1016/j.celrep.2024.113841
  9. Front Immunol. 2024 ;15 1360141
    A silver bullet for ageing medicine?: clinical relevance of T-cell checkpoint receptors in normal human ageing.
    Lucy Rimmer, Derek A Mann, Avan A Sayer, Shoba Amarnath, Antoneta Granic.
      Immunosenescence describes dysregulation of the immune system with ageing manifested in both the innate and adaptive immunity, including changes in T-cell checkpoint signaling. Through complex and nuanced process, T-cells lose excitatory signaling pathways and upregulate their inhibitory signaling, leading to ineffective immune responses that contribute to the formation of the ageing phenotype. Here we expand on the expression, function, and clinical potential of targeting the T-cell checkpoint signaling in age and highlight interventions offering the most benefits to older adults' health. Notably, modifications in vaccination such as with mTOR inhibitors show immediate clinical relevance and good tolerability. Other proposed treatments, including therapies with monoclonal antibodies fail to show clinical efficacy or tolerability needed for implementation at present. Although T-cell co-signaling fits a valuable niche for translational scientists to manage immunosenescence, future study would benefit from the inclusion of older adults with multiple long-term conditions and polypharmacy, ensuring better applicability to actual patients seen in clinical settings.
    Keywords:  T-cell; checkpoint; healthy ageing; immunosenescence; translational research
    DOI:  https://doi.org/10.3389/fimmu.2024.1360141
  10. Biochem Biophys Res Commun. 2024 Feb 02. pii: S0006-291X(24)00125-6. [Epub ahead of print]702 149590
    The therapeutic perspective of NAD+ precursors in age-related diseases.
    Tooba Iqbal, Takashi Nakagawa.
      Nicotinamide adenine dinucleotide (NAD+) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD+ decreases with age in certain tissues, and age-related NAD+ depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD+ precursor significantly elevates NAD+ levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD+ in animal studies, the efficacy of NAD+ precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD+ precursor treatment efficiently increases NAD+ levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD+ precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD+ intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD+ metabolism. Also, the reduced form of NAD+ precursor shows their potential to raise NAD+, though preclinical studies have yet to discover their efficacy. This review sheds light on NAD+ therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD+ metabolism.
    Keywords:  Aging; Gut microbiota; NAD(+); NAD(+) precursors; Nicotinamide mononucleotide NMN; Nicotinamide riboside NR
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149590
  11. Clin Transl Immunology. 2024 ;13(2): e1491
    Fighting flu: novel CD8+ T-cell targets are required for future influenza vaccines.
    Samuel Liwei Leong, Stephanie Gras, Emma J Grant.
      Seasonal influenza viruses continue to cause severe medical and financial complications annually. Although there are many licenced influenza vaccines, there are billions of cases of influenza infection every year, resulting in the death of over half a million individuals. Furthermore, these figures can rise in the event of a pandemic, as seen throughout history, like the 1918 Spanish influenza pandemic (50 million deaths) and the 1968 Hong Kong influenza pandemic (~4 million deaths). In this review, we have summarised many of the currently licenced influenza vaccines available across the world and current vaccines in clinical trials. We then briefly discuss the important role of CD8+ T cells during influenza infection and why future influenza vaccines should consider targeting CD8+ T cells. Finally, we assess the current landscape of known immunogenic CD8+ T-cell epitopes and highlight the knowledge gaps required to be filled for the design of rational future influenza vaccines that incorporate CD8+ T cells.
    Keywords:  CD8+ T cells; HLA‐I; epitopes; influenza; vaccines
    DOI:  https://doi.org/10.1002/cti2.1491
  12. Front Nutr. 2024 ;11 1322201
    Resistant starches from dietary pulses improve neurocognitive health via gut-microbiome-brain axis in aged mice.
    Saurabh Kadyan, Gwoncheol Park, Nathaniel Hochuli, Katelyn Miller, Bo Wang, Ravinder Nagpal.
       Introduction: Cognitive decline is a common consequence of aging. Dietary patterns that lack fibers and are high in saturated fats worsen cognitive impairment by triggering pro-inflammatory pathways and metabolic dysfunctions. Emerging evidence highlights the neurocognitive benefits of fiber-rich diets and the crucial role of gut-microbiome-brain signaling. However, the mechanisms of this diet-microbiome-brain regulation remain largely unclear.
    Methods: Accordingly, we herein investigated the unexplored neuroprotective mechanisms of dietary pulses-derived resistant starch (RS) in improving aging-associated neurocognitive function in an aged (60-weeks old) murine model carrying a human microbiome.
    Results and discussion: Following 20-weeks dietary regimen which included a western-style diet without (control; CTL) or with 5% w/w fortification with RS from pinto beans (PTB), black-eyed-peas (BEP), lentils (LEN), chickpeas (CKP), or inulin fiber (INU), we find that RS, particularly from LEN, ameliorate the cognitive impairments induced by western diet. Mechanistically, RS-mediated improvements in neurocognitive assessments are attributed to positive remodeling of the gut microbiome-metabolome arrays, which include increased short-chain fatty acids and reduced branched-chain amino acids levels. This microbiome-metabolite-brain signaling cascade represses neuroinflammation, cellular senescence, and serum leptin/insulin levels, while enhancing lipid metabolism through improved hepatic function. Altogether, the data demonstrate the prebiotic effects of RS in improving neurocognitive function via modulating the gut-brain axis.
    Keywords:  aging; metabolic diseases; microbiota; neuroinflammation; plant polysaccharides
    DOI:  https://doi.org/10.3389/fnut.2024.1322201
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