bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–07–30
fiveteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. T cell fate decisions during memory cell generation with aging.
  2. Long live T cells.
  3. The vitamin B5/coenzyme A axis: A target for immunomodulation?
  4. Purinergic receptor P2Y12 boosts autoimmune hepatitis through hexokinase 2-dependent glycolysis in T cells.
  5. A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.
  6. Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.
  7. Metal-Phenolic Nanomedicines Regulate T-Cell Antitumor Function for Sono-Metabolic Cancer Therapy.
  8. The effect of diet and nutrition on T cell function in cancer.
  9. Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation.
  10. The T cell receptor sequence influences the likelihood of T cell memory formation.
  11. Parallel CRISPR-Cas9 screens identify mechanisms of PLIN2 and lipid droplet regulation.
  12. Complex II Biology in Aging, Health, and Disease.
  13. Effect of Boswellic acids on T cell proliferation and activation.
  14. Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.
  15. T memory stem cell characteristics in autoimmune diseases and their promising therapeutic values.
  1. Semin Immunol. 2023 Jul 24. pii: S1044-5323(23)00091-X. [Epub ahead of print]69 101800
    T cell fate decisions during memory cell generation with aging.
    Ines Sturmlechner, Abhinav Jain, Yunmei Mu, Cornelia M Weyand, Jörg J Goronzy.
      The defense against infectious diseases, either through natural immunity or after vaccinations, relies on the generation and maintenance of protective T cell memory. Naïve T cells are at the center of memory T cell generation during primary responses. Upon activation, they undergo a complex, highly regulated differentiation process towards different functional states. Naïve T cells maintained into older age have undergone epigenetic adaptations that influence their fate decisions during differentiation. We review age-sensitive, molecular pathways and gene regulatory networks that bias naïve T cell differentiation towards effector cell generation at the expense of memory and Tfh cells. As a result, T cell differentiation in older adults is associated with release of bioactive waste products into the microenvironment, higher stress sensitivity as well as skewing towards pro-inflammatory signatures and shorter life spans. These maladaptations not only contribute to poor vaccine responses in older adults but also fuel a more inflammatory state.
    Keywords:  Inflammageing; T cell ageing; T cell differentiation; T cell memory; TCF1; mTORC1
    DOI:  https://doi.org/10.1016/j.smim.2023.101800
  2. Nat Immunol. 2023 Aug;24(8): 1211
    Long live T cells.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-023-01581-3
  3. Eur J Immunol. 2023 Jul 22. e2350435
    The vitamin B5/coenzyme A axis: A target for immunomodulation?
    Miallot Richard, Millet Virginie, Galland Franck, Naquet Philippe.
      Coenzyme A (CoA) serves as a vital cofactor in numerous enzymatic reactions involved in energy production, lipid metabolism, and synthesis of essential molecules. Dysregulation of CoA-dependent metabolic pathways can contribute to chronic diseases, such as inflammatory diseases, obesity, diabetes, cancer, and cardiovascular disorders. Additionally, CoA influences immune cell activation by modulating the metabolism of these cells, thereby affecting their proliferation, differentiation, and effector functions. Targeting CoA metabolism presents a promising avenue for therapeutic intervention, as it can potentially restore metabolic balance, mitigate chronic inflammation, and enhance immune cell function. This might ultimately improve the management and outcomes for these diseases. This review will more specifically focus on the contribution of pathways regulating the availability of the CoA precursor Vitamin B5/pantothenate in vivo and modulating the development of Th17-mediated inflammation, CD8-dependent anti-tumor immunity but also tissue repair processes in chronic inflammatory or degenerative diseases.
    Keywords:  Coenzyme A; Inflammation; Tissue repair; Tumor immunity; Vitamin B5
    DOI:  https://doi.org/10.1002/eji.202350435
  4. Int J Biol Sci. 2023 ;19(11): 3576-3594
    Purinergic receptor P2Y12 boosts autoimmune hepatitis through hexokinase 2-dependent glycolysis in T cells.
    Wei Zhuang, Xiucheng Liu, Guangyu Liu, Jie Lv, Hao Qin, Chun Wang, Ling Xie, Kaidireya Saimaier, Sanxing Han, Changjie Shi, Qiuhong Hua, Ru Zhang, Changsheng Du.
      Increasing evidence suggests that immunometabolism has started to unveil the role of metabolism in shaping immune function and autoimmune diseases. In this study, our data show that purinergic receptor P2Y12 (P2RY12) is highly expressed in concanavalin A (ConA)-induced immune hepatitis mouse model and serves as a potential metabolic regulator in promoting metabolic reprogramming from oxidative phosphorylation to glycolysis in T cells. P2RY12 deficiency or inhibition of P2RY12 with P2RY12 inhibitors (clopidogrel and ticagrelor) are proved to reduce the expression of inflammatory mediators, cause CD4+ and CD8+ effector T cells hypofunction and protect the ConA-induced immune hepatitis. A combined proteomics and metabolomics analysis revealed that P2RY12 deficiency causes redox imbalance and leads to reduced aerobic glycolysis by downregulating the expression of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway, indicating that HK2 might be a promising candidate for the treatment of diseases associated with T cell activation. Further analysis showed that P2RY12 prevents HK2 degradation by activating the PI3K/Akt pathway and inhibiting lysosomal degradation. Our findings highlight the importance of the function of P2RY12 for HK2 stability and metabolism in the regulation of T cell activation and suggest that P2RY12 might be a pivotal regulator of T cell metabolism in ConA-induced immune hepatitis.
    Keywords:  HK2; P2RY12; T cell metabolism; autoimmune hepatitis; glycolysis
    DOI:  https://doi.org/10.7150/ijbs.85133
  5. bioRxiv. 2023 Jul 07. pii: 2023.07.06.547932. [Epub ahead of print]
    A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.
    Lynn Bonetti, Veronika Horkova, Joseph Longworth, Luana Guerra, Henry Kurniawan, Davide G Franchina, Leticia Soriano-Baguet, Melanie Grusdat, Sabine Spath, Eric Koncina, Anouk Ewen, Carole Binsfeld, Charlène Verschueren, Jean-Jacques Gérardy, Takumi Kobayashi, Catherine Dostert, Sophie Farinelle, Janika Härm, Ying Chen, Isaac S Harris, Philipp A Lang, Vasilis Vasiliou, Ari Waisman, Elisabeth Letellier, Burkhard Becher, Michel Mittelbronn, Dirk Brenner.
      Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc-deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection.
    DOI:  https://doi.org/10.1101/2023.07.06.547932
  6. Cell Metab. 2023 Jul 21. pii: S1550-4131(23)00251-6. [Epub ahead of print]
    Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.
    Lijian Wu, Yiteng Jin, Xi Zhao, Kaiyang Tang, Yaoning Zhao, Linjie Tong, Xuerong Yu, Ke Xiong, Ce Luo, Jiajun Zhu, Fubing Wang, Zexian Zeng, Deng Pan.
      Metabolic reprogramming toward glycolysis is a hallmark of cancer malignancy. The molecular mechanisms by which the tumor glycolysis pathway promotes immune evasion remain to be elucidated. Here, by performing genome-wide CRISPR screens in murine tumor cells co-cultured with cytotoxic T cells (CTLs), we identified that deficiency of two important glycolysis enzymes, Glut1 (glucose transporter 1) and Gpi1 (glucose-6-phosphate isomerase 1), resulted in enhanced killing of tumor cells by CTLs. Mechanistically, Glut1 inactivation causes metabolic rewiring toward oxidative phosphorylation, which generates an excessive amount of reactive oxygen species (ROS). Accumulated ROS potentiate tumor cell death mediated by tumor necrosis factor alpha (TNF-α) in a caspase-8- and Fadd-dependent manner. Genetic and pharmacological inactivation of Glut1 sensitizes tumors to anti-tumor immunity and synergizes with anti-PD-1 therapy through the TNF-α pathway. The mechanistic interplay between tumor-intrinsic glycolysis and TNF-α-induced killing provides new therapeutic strategies to enhance anti-tumor immunity.
    Keywords:  T cell-mediated killing; TNF-α; glycolysis; immune evasion
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.001
  7. ACS Nano. 2023 Jul 24.
    Metal-Phenolic Nanomedicines Regulate T-Cell Antitumor Function for Sono-Metabolic Cancer Therapy.
    Jie Yan, Wenxi Li, Hao Tian, Bei Li, Xinying Yu, Guohao Wang, Wei Sang, Yunlu Dai.
      Cancer cells outcompete tumor-infiltrating T lymphocytes (TILs) for glucose uptake, manipulating a glucose-deprived tumor microenvironment (TME) with high accumulation of lactate, which impairs CD8+ TIL effector function, however supports the immune suppression of regulatory T (Treg) cells. Aerobic glycolysis inhibition coupled with mitochondrial dysfunction in cancer cells may reprogram TME to destabilize Treg cells and, more importantly, facilitate CD8+ T cell activation and cytotoxic killing. Here, a sono-metabolic cancer therapy via hyaluronic acid (HA)-modified metal-phenolic nanomedicine (HPP-Ca@GSK) is proposed to accomplish the aforementioned goals. Abrogating lactate dehydrogenase A (LDHA) by delivering GSK2837808A (GSK, LDHA inhibitor) successfully suppresses aerobic glycolysis in cancer cells and creates high-glucose, low-lactate conditions, satisfying the glucose nutrition required by CD8+ TILs but destabilizing Treg cells. Meanwhile, depending on ultrasound-mediated oxidative stress, more than 3-fold of calcium (from HPP-Ca@GSK) is mitochondrion-overloaded, amplifying mitochondrial dysfunction and promoting the cancer cellular release of damage-associated molecular patterns for more CD8+ T cell activation and tumor infiltration. In vitro and in vivo studies demonstrate that HPP-Ca@GSK-based sono-metabolic treatment exhibits impressive anticancer activity. Cooperating with anticytotoxic T lymphocyte-associated protein-4 antibodies for enhanced Treg cell destabilization further improves therapeutic efficacy. These findings provide a metabolic intervention strategy for cancer immunotherapy.
    Keywords:  CTLA-4 blockade; TME reprogramming; Treg cell destabilization; mitochondrial dysfunction; sono-metabolic therapy
    DOI:  https://doi.org/10.1021/acsnano.3c02428
  8. Int J Cancer. 2023 Jul 28.
    The effect of diet and nutrition on T cell function in cancer.
    Xinyi Zhou, Zhen Wang, Kefei Yuan.
      Cancer can be considered one of the most threatening diseases to human health, and immunotherapy, especially T-cell immunotherapy, is the most promising treatment for cancers. Diet therapy is widely concerned in cancer because of its safety and fewer side effects. Many studies have shown that both the function of T cells and the progression of cancer can be affected by nutrients in the diet. In fact, it is challenging for T cells to infiltrate and eliminate cancer cells in tumor microenvironment, because of the harsh metabolic condition. The intake of different nutrients has a great influence on the proliferation, activation, differentiation and exhaustion of T cells. In this review, we summarize the effects of typical amino acids, lipids, carbohydrates and other nutritional factors on T cell functions and provide future perspectives for dietary treatment of cancer based on modifications of T cell functions.
    Keywords:  T cell; cancer; diet; immunity; nutrition
    DOI:  https://doi.org/10.1002/ijc.34668
  9. iScience. 2023 Jul 21. 26(7): 107230
    Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation.
    Vugar Azizov, Michel Hübner, Michael Frech, Jörg Hofmann, Marketa Kubankova, Dennis Lapuente, Matthias Tenbusch, Jochen Guck, Georg Schett, Mario M Zaiss.
      Alcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart, and brain. Alcohol also has strong immunoregulatory properties. Here, we report how alcohol impairs T cell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. T cells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces T cell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescues the acetate-induced inhibition of T cell migration, primary mouse cortactin knockout T cells exhibited impaired migration. Acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells in vitro and in vivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of T cell driven autoimmune diseases.
    Keywords:  Immunology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107230
  10. bioRxiv. 2023 Jul 23. pii: 2023.07.20.549939. [Epub ahead of print]
    The T cell receptor sequence influences the likelihood of T cell memory formation.
    Kaitlyn A Lagattuta, Aparna Nathan, Laurie Rumker, Michael E Birnbaum, Soumya Raychaudhuri.
      T cell differentiation depends on activation through the T cell receptor (TCR), whose amino acid sequence varies cell to cell. Particular TCR amino acid sequences nearly guarantee Mucosal-Associated Invariant T (MAIT) and Natural Killer T (NKT) cell fates. To comprehensively define how TCR amino acids affects all T cell fates, we analyze the paired αβTCR sequence and transcriptome of 819,772 single cells. We find that hydrophobic CDR3 residues promote regulatory T cell transcriptional states in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features, concentrated in CDR2α, that promotes positive selection in the thymus as well as transition from naïve to memory in the periphery. Even among T cells that recognize the same antigen, these TCR sequence features help to explain which T cells form immunological memory, which is essential for effective pathogen response.
    DOI:  https://doi.org/10.1101/2023.07.20.549939
  11. Dev Cell. 2023 Jul 18. pii: S1534-5807(23)00331-3. [Epub ahead of print]
    Parallel CRISPR-Cas9 screens identify mechanisms of PLIN2 and lipid droplet regulation.
    Melissa A Roberts, Kirandeep K Deol, Alyssa J Mathiowetz, Mike Lange, Dara E Leto, Julian Stevenson, Sayed Hadi Hashemi, David W Morgens, Emilee Easter, Kartoosh Heydari, Mike A Nalls, Michael C Bassik, Martin Kampmann, Ron R Kopito, Faraz Faghri, James A Olzmann.
      Despite the key roles of perilipin-2 (PLIN2) in governing lipid droplet (LD) metabolism, the mechanisms that regulate PLIN2 levels remain incompletely understood. Here, we leverage a set of genome-edited human PLIN2 reporter cell lines in a series of CRISPR-Cas9 loss-of-function screens, identifying genetic modifiers that influence PLIN2 expression and post-translational stability under different metabolic conditions and in different cell types. These regulators include canonical genes that control lipid metabolism as well as genes involved in ubiquitination, transcription, and mitochondrial function. We further demonstrate a role for the E3 ligase MARCH6 in regulating triacylglycerol biosynthesis, thereby influencing LD abundance and PLIN2 stability. Finally, our CRISPR screens and several published screens provide the foundation for CRISPRlipid (http://crisprlipid.org), an online data commons for lipid-related functional genomics data. Our study identifies mechanisms of PLIN2 and LD regulation and provides an extensive resource for the exploration of LD biology and lipid metabolism.
    Keywords:  CRISPR; ERAD; MARCH6; PLIN2; endoplasmic reticulum; genetic screen; lipid droplet; metabolism; perilipin; resource
    DOI:  https://doi.org/10.1016/j.devcel.2023.07.001
  12. Antioxidants (Basel). 2023 Jul 24. pii: 1477. [Epub ahead of print]12(7):
    Complex II Biology in Aging, Health, and Disease.
    Eric Goetzman, Zhenwei Gong, Bob Zhang, Radhika Muzumdar.
      Aging is associated with a decline in mitochondrial function which may contribute to age-related diseases such as neurodegeneration, cancer, and cardiovascular diseases. Recently, mitochondrial Complex II has emerged as an important player in the aging process. Mitochondrial Complex II converts succinate to fumarate and plays an essential role in both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). The dysfunction of Complex II not only limits mitochondrial energy production; it may also promote oxidative stress, contributing, over time, to cellular damage, aging, and disease. Intriguingly, succinate, the substrate for Complex II which accumulates during mitochondrial dysfunction, has been shown to have widespread effects as a signaling molecule. Here, we review recent advances related to understanding the function of Complex II, succinate signaling, and their combined roles in aging and aging-related diseases.
    Keywords:  Complex II; aging; reactive oxygen species; succinate dehydrogenase
    DOI:  https://doi.org/10.3390/antiox12071477
  13. Int Immunopharmacol. 2023 Jul 22. pii: S1567-5769(23)00993-1. [Epub ahead of print]122 110668
    Effect of Boswellic acids on T cell proliferation and activation.
    Abdo Meyiah, Murtada Y Shawkat, Najeeb Ur Rehman, Ahmed Al-Harrasi, Eyad Elkord.
      Boswellic acids have been recognized as anti-inflammatory and immunomodulatory agents with potentials to control autoimmune and inflammatory diseases. However, their effects on T cell proliferation and activation are not fully elucidated. In this study, we investigated effects of individual compounds including β-Boswellic acids (β-BA), 11-keto-β-Boswellic acid (β-KBA), 3-O-acetyl β-Boswellic acids (β-ABA), and 3-O-acetyl-11-keto-β-Boswellic acid (β-AKBA) on human peripheral blood mononuclear cells (PBMCs) and their potential role in modulating immune responses. We showed that β-BA, KBA, and AKBA at a 0.025 µM concentration significantly reduced T cell proliferation without inducing cytotoxicity, however, ABA showed cytotoxic effects at this concentration. β-BA and KBA showed significantly reduced T cell proliferation at 0.05 µM concentration without cytotoxic effects. Interestingly, we found that AKBA at 0.025 µM concentration significantly reduced CD25 expression on both CD4+ and CD8+ T cells without cytotoxic effects. Additionally, β-BA reduced CD25 expression on both CD4+ and CD8+ T cells at 0.05 µM concentration with no cytotoxicity. In this study, we determined the optimum concentration of each of these compounds that have the potential to reduce T cell activation without cytotoxic effects. Our findings show that both β-BA and AKBA have the ability to inhibit T cell proliferation and activation without inducing cytotoxicity. Further investigations are required to fully understand the mechanisms underlying these effects and the potential therapeutic benefits of these compounds in different autoimmune and inflammatory settings.
    Keywords:  AKBA; Boswellic acids; CD25; KBA; Proliferation; T cells; β-ABA; β-BA
    DOI:  https://doi.org/10.1016/j.intimp.2023.110668
  14. Sci Immunol. 2023 Jul 28. 8(85): eadd1591
    Clonally expanded CD38hi cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor-associated arthritis.
    Runci Wang, Anvita Singaraju, Kathryne E Marks, Lorien Shakib, Garrett Dunlap, Ifeoluwakiisi Adejoorin, Stinne R Greisen, Lin Chen, Aidan K Tirpack, Carlos Aude, Miriam R Fein, Derrick J Todd, Lindsey MacFarlane, Susan M Goodman, Edward F DiCarlo, Elena M Massarotti, Jeffrey A Sparks, A Helena Jonsson, Michael B Brenner, Michael A Postow, Karmela K Chan, Anne R Bass, Laura T Donlin, Deepak A Rao.
      Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38hiCD127- CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38hiCD127- T cells, which were frequently bound by the therapeutic anti-PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.
    DOI:  https://doi.org/10.1126/sciimmunol.add1591
  15. Front Immunol. 2023 ;14 1204231
    T memory stem cell characteristics in autoimmune diseases and their promising therapeutic values.
    Pooria Fazeli, Mehdi Kalani, Maryam Hosseini.
      Memory T cells are conventionally subdivided into T central memory (TCM) and T effector memory (TEM) cells. However, a new subset of memory T cells named T memory stem cell (TSCM) cells has been recognized that possesses capabilities of both TCM and TEM cells including lymphoid homing and performing effector roles through secretion of cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFN-γ). The TSCM subset has some biological properties including stemness, antigen independency, high proliferative potential, signaling pathway and lipid metabolism. On the other hand, memory T cells are considered one of the principal culprits in the pathogenesis of autoimmune diseases. TSCM cells are responsible for developing long-term defensive immunity against different foreign antigens, alongside tumor-associated antigens, which mainly derive from self-antigens. Hence, antigen-specific TSCM cells can produce antitumor responses that are potentially able to trigger autoimmune activities. Therefore, we reviewed recent evidence on TSCM cell functions in autoimmune disorders including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, acquired aplastic anemia, immune thrombocytopenia, and autoimmune uveitis. We also introduced TSCM cell lineage as an innovative prognostic biomarker and a promising therapeutic target in autoimmune settings.
    Keywords:  T memory stem cell; autoimmune diseases; hepatitis C virus; rheumatoid arthritis; sickle cell disease; type 1 diabetes
    DOI:  https://doi.org/10.3389/fimmu.2023.1204231
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