bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–01–19
fifteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Chromatin landscape alteration uncovers multiple transcriptional circuits during memory CD8+ T cell differentiation.
  2. Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.
  3. ETV7 limits the antiviral and antitumor efficacy of CD8+ T cells by diverting their fate toward exhaustion.
  4. IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation.
  5. Restimulation by macrophages exhausts T cells.
  6. TRIM28 is an essential regulator of three-dimensional chromatin state underpinning CD8+ T cell activation.
  7. Metabolic Signaling in the Tumor Microenvironment.
  8. Immune cell single-cell RNA sequencing analyses link an age-associated T cell subset to symptomatic benign prostatic hyperplasia.
  9. SHMT2 regulates CD8+ T cell senescence via the reactive oxygen species axis in HIV-1 infected patients on antiretroviral therapy.
  10. T Lymphocyte-Specific Deletion of SHP1 and SHP2 Promotes Activation-Induced Cell Death of CD4+ T Cells and Impairs Antitumor Response.
  11. Aging stem cells limit tumorigenesis.
  12. Immune Aging in Rheumatoid Arthritis.
  13. A PI3Kδ-Foxo1-FasL signaling amplification loop rewires CD4 + T helper cell signaling, differentiation and epigenetic remodeling.
  14. Metabolism and metabolomics in senescence, aging, and age-related diseases: a multiscale perspective.
  15. Zinc Deficiency Exacerbates Lead-Induced Interleukin-2 Suppression by Regulating CREM Expression.
  1. Protein Cell. 2025 Jan 13. pii: pwaf003. [Epub ahead of print]
    Chromatin landscape alteration uncovers multiple transcriptional circuits during memory CD8+ T cell differentiation.
    Qiao Liu, Wei Dong, Rong Liu, Luming Xu, Ling Ran, Ziying Xie, Shun Lei, Xingxing Su, Zhengliang Yue, Dan Xiong, Lisha Wang, Shuqiong Wen, Yan Zhang, Jianjun Hu, Chenxi Qin, Yongchang Chen, Bo Zhu, Xiangyu Chen, Xia Wu, Lifan Xu, Qizhao Huang, Yingjiao Cao, Lilin Ye, Zhonghui Tang.
      Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
    Keywords:  T cell; chromatin; epigenome; interactions; memory
    DOI:  https://doi.org/10.1093/procel/pwaf003
  2. Cell Rep. 2025 Jan 10. pii: S2211-1247(24)01557-2. [Epub ahead of print]44(1): 115206
    Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.
    Jean-Ehrland Ricci.
      Metabolic reprogramming in both immune and cancer cells plays a crucial role in the antitumor immune response. Recent studies indicate that cancer metabolism not only sustains carcinogenesis and survival via altered signaling but also modulates immune cell function. Metabolic crosstalk within the tumor microenvironment results in nutrient competition and acidosis, thereby hindering immune cell functionality. Interestingly, immune cells also undergo metabolic reprogramming that enables their proliferation, differentiation, and effector functions. This review highlights the regulation of antitumor immune responses through metabolic reprogramming in cancer and immune cells and explores therapeutic strategies that target these metabolic pathways in cancer immunotherapy, including using chimeric antigen receptor (CAR)-T cells. We discuss innovative combinations of immunotherapy, cellular therapies, and metabolic interventions that could optimize the efficacy of existing treatment protocols.
    Keywords:  CP: Cancer; CP: Metabolism; antitumor activity of immune cells; cancer; metabolism; therapeutic strategies; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.115206
  3. Nat Cancer. 2025 Jan 13.
    ETV7 limits the antiviral and antitumor efficacy of CD8+ T cells by diverting their fate toward exhaustion.
    Jie Cheng, Yifeng Xiao, Ting Peng, Zijian Zhang, You Qin, Yuqian Wang, Jiangzhou Shi, Jinxin Yan, Zihao Zhao, Liangtao Zheng, Zhijun He, Jianwei Wang, Zemin Zhang, Cheng Li, Haichuan Zhu, Peng Jiang.
      Terminal exhaustion is a critical barrier to antitumor immunity. By integrating and analyzing single-cell RNA-sequencing and single-cell assay for transposase-accessible chromatin with sequencing data, we found that ETS variant 7 (ETV7) is indispensable for determining CD8+ T cell fate in tumors. ETV7 introduction drives T cell differentiation from memory to terminal exhaustion, limiting antiviral and antitumor efficacy in male mice. Mechanistically, ETV7 acts as a central transcriptional node by binding to specific memory genes and exhaustion genes and functionally skewing these transcriptional programs toward exhaustion. Clinically, ETV7 expression is negatively correlated with progression and responsiveness to immune checkpoint blockade in various human cancers. ETV7 depletion strongly enhances the antitumor efficacy of CD8+ T cells and engineered chimeric antigen receptor T cells in solid tumors. Thus, these findings demonstrate a decisive role for ETV7 in driving CD8+ T cell terminal exhaustion and reveal that ETV7 may be a promising target and biomarker for improving the efficacy of cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s43018-024-00892-0
  4. Cell Rep. 2025 Jan 11. pii: S2211-1247(24)01550-X. [Epub ahead of print]44(1): 115199
    IL-7 promotes integrated glucose and amino acid sensing during homeostatic CD4+ T cell proliferation.
    Seema Bachoo, Nancy Gudgeon, Rebecca Mann, Victoria Stavrou, Emma L Bishop, Audrey Kelly, Alejandro Huerta Uribe, Jordan Loeliger, Corina Frick, Oliver D K Maddocks, Paul Lavender, Christoph Hess, Sarah Dimeloe.
      Interleukin (IL)-7 promotes T cell expansion during lymphopenia. We studied the metabolic basis in CD4+ T cells, observing increased glucose usage for nucleotide synthesis and oxidation in the tricarboxylic acid (TCA) cycle. Unlike other TCA metabolites, glucose-derived citrate does not accumulate upon IL-7 exposure, indicating diversion into other processes. In agreement, IL-7 promotes glucose-dependent histone acetylation and chromatin accessibility, notable at the loci of the amino acid-sensing Ragulator complex. Consistently, the expression of its subunit late endosomal/lysosomal adaptor, MAPK and mTOR activator 5 (LAMTOR5) is promoted by IL-7 in a glucose-dependent manner, and glucose availability determines amino acid-dependent mechanistic target of rapamycin (mTOR) activation, confirming integrated nutrient sensing. LAMTOR5 deletion impairs IL-7-mediated T cell expansion, establishing that glycolysis in the absence of Ragulator activation is insufficient to support this. Clinically, CD4+ T cells from stem cell transplant recipients demonstrate coordinated upregulation of glycolytic and TCA cycle enzymes, amino acid-sensing machinery, and mTOR targets, highlighting the potential to therapeutically target this pathway to fine-tune lymphopenia-induced T cell proliferation.
    Keywords:  IL-7; Immunology; Metabolism; T cell; T lymphocyte; mTOR; metabolism; nutrient sensing; proliferation
    DOI:  https://doi.org/10.1016/j.celrep.2024.115199
  5. Immunity. 2025 Jan 14. pii: S1074-7613(24)00574-0. [Epub ahead of print]58(1): 12-14
    Restimulation by macrophages exhausts T cells.
    Fernando Fernández-García, Barbara B Maier.
      Inhibiting T cell exhaustion is an attractive cancer immunotherapy strategy. In this issue of Immunity, Waibl Polania et al. examine the microenvironmental signals regulating terminal T cell exhaustion and find that antigen presentation by tumor-associated macrophages, not tumor cells, drives terminal T cell exhaustion in glioblastoma.
    DOI:  https://doi.org/10.1016/j.immuni.2024.12.010
  6. Nat Commun. 2025 Jan 16. 16(1): 750
    TRIM28 is an essential regulator of three-dimensional chromatin state underpinning CD8+ T cell activation.
    Kun Wei, Ruifeng Li, Xiaohong Zhao, Bowen Xie, Tian Xie, Qinli Sun, Yongzhen Chen, Peng Wei, Wei Xu, Xinyi Guo, Zixuan Zhao, Han Feng, Ling Ni, Chen Dong.
      T cell activation is accompanied by extensive changes in epigenome. However, the high-ordered chromatin organization underpinning CD8+ T cell activation is not fully known. Here, we show extensive changes in the three-dimensional genome during CD8+ T cell activation, associated with changes in gene transcription. We show that CD8+ T-cell-specific deletion of Trim28 in mice disrupts autocrine IL-2 production and leads to impaired CD8+ T cell activation in vitro and in vivo. Mechanistically, TRIM28 binds to regulatory regions of genes associated with the formation of chromosomal loops during activation. At the loop anchor regions, TRIM28-occupancy overlaps with that of CTCF, a factor known for defining the boundaries of topologically associating domains and for forming of the loop anchors. In the absence of Trim28, RNA Pol II and cohesin binding to these regions diminishes, and the chromosomal structure required for the active state is disrupted. These results thus identify a critical role for TRIM28-dependent chromatin topology in gene transcription in activated CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41467-025-56029-z
  7. Cancers (Basel). 2025 Jan 06. pii: 155. [Epub ahead of print]17(1):
    Metabolic Signaling in the Tumor Microenvironment.
    Ryan Clay, Kunyang Li, Lingtao Jin.
      Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS). While this metabolic program produces adequate biosynthetic intermediates, reducing agents, ATP, and epigenetic remodeling cofactors necessary to sustain growth, it also produces large amounts of byproducts that can generate a hostile tumor microenvironment (TME) characterized by low pH, redox stress, and poor oxygenation. In recent years, the focus of cancer metabolic research has shifted from the regulation and utilization of cancer cell-intrinsic pathways to studying how the metabolic landscape of the tumor affects the anti-tumor immune response. Recent discoveries point to the role that secreted metabolites within the TME play in crosstalk between tumor cell types to promote tumorigenesis and hinder the anti-tumor immune response. In this review, we will explore how crosstalk between metabolites of cancer cells, immune cells, and stromal cells drives tumorigenesis and what effects the competition for resources and metabolic crosstalk has on immune cell function.
    Keywords:  cancer metabolism; immune response; oncometabolite; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers17010155
  8. bioRxiv. 2024 Dec 30. pii: 2024.12.30.629739. [Epub ahead of print]
    Immune cell single-cell RNA sequencing analyses link an age-associated T cell subset to symptomatic benign prostatic hyperplasia.
    Meaghan M Broman, Nadia A Lanman, Renee E Vickman, Gregory M Cresswell, Harish Kothandaraman, Andree Kolliegbo, Juan Sebastian Paez Paez, Alexander P Glaser, Brian T Helfand, Gervaise Henry, Douglas W Strand, Omar E Franco, Susan E Crawford, Simon W Hayward, Timothy L Ratliff.
      Benign prostatic hyperplasia (BPH) is among the most common age-associated diseases in men; however, the contribution of age-related changes in immune cells to BPH is not clear. The current study determined that an age-associated CD8 + T cell subset (Taa) with high Granzyme K ( GZMK hi ) and low Granzyme B ( GZMB low ) gene expression infiltrate aged human prostates and positively correlate with International Prostate Symptom Score (IPSS). A velocity analysis indicated that CD8 + T cell differentiation is altered in large BPH prostates compared to small age-matched prostates, favoring Taa accumulation. In vitro granzyme K treatment of human BPH patient-derived large prostate fibroblasts increased secretion of pro-inflammatory senescence-associated secretory phenotype (SASP)-associated cytokines. These data suggest that granzyme K-mediated stimulation of prostate stromal fibroblast SASP cytokine and chemokine production promotes prostate immune cell recruitment and activation. Overall, these results connect symptomatic BPH with immune aging.
    DOI:  https://doi.org/10.1101/2024.12.30.629739
  9. EBioMedicine. 2025 Jan 13. pii: S2352-3964(24)00569-3. [Epub ahead of print]112 105533
    SHMT2 regulates CD8+ T cell senescence via the reactive oxygen species axis in HIV-1 infected patients on antiretroviral therapy.
    Qi-Sheng Zhang, Jia-Ning Wang, Tian-Ling Yang, Si-Yao Li, Jia-Qi Li, Ding-Ning Liu, Hong Shang, Zi-Ning Zhang.
       BACKGROUND: Although antiretroviral therapy (ART) effectively inhibits viral replication, it does not fully mitigate the immunosenescence instigated by HIV infection. Cellular metabolism regulates cellular differentiation, survival, and senescence. Serine hydroxymethyltransferase 2 (SHMT2) is the first key enzyme for the entry of serine into the mitochondria from the de novo synthesis pathway that orchestrates its conversion glutathione (GSH), a key molecule in neutralising ROS and ensuring the stability of the immune system. It remains incompletely understood whether SHMT2 is involved in the senescence of CD8+ T cells, crucial for immune vigilance against HIV.
    METHODS: HIV-infected individuals receiving antiretroviral therapy were enrolled in our study. SHMT2-siRNA was electroporated into T cells to disrupt the gene expression of SHMT2, followed by the quantification of mRNA levels of crucial serine metabolism enzymes using real-time PCR. Immunophenotyping, proliferation, cellular and mitochondrial function, and senescence-associated signalling pathways were examined using flow cytometry in CD8+ T cell subsets.
    FINDINGS: Our findings revealed that CD8+ T cells in HIV-infected subjects are inclined towards senescence, and we identified that SHMT2, a key enzyme in serine metabolism, plays a role in CD8+ T cell senescence. SHMT2 can regulate glutathione (GSH) synthesis and protect mitochondrial function, thus effectively controlling intracellular reactive oxygen species (ROS) levels. Moreover, SHMT2 significantly contributes to averting immunosenescence and sustaining CD8+ T cell competence by modulating downstream DNA damage and phosphorylation cascades in pathways intricately linked to cellular senescence. Additionally, our study identified glycine can ameliorate CD8+ T cell senescence in HIV-infected individuals.
    INTERPRETATION: Decreased SHMT2 levels in HIV-infected CD8+ T cells affect ROS levels by altering mitochondrial function and GSH content. Increased ROS levels activate senescence-related signalling pathways in the nucleus. However, glycine supplementation counteracts these effects and moderates senescence.
    FUNDING: This study was supported by grants from the National Key R&D Program of China (2021YFC2301900-2021YFC2301901), National Natural Science Foundation of China (82372240), and Department of Science and Technology of Liaoning Province Project for the High-Quality Scientific and Technological Development of China Medical University (2022JH2/20200074).
    Keywords:  Antiretroviral therapy (ART); Human immunodeficiency virus (HIV); SHMT2; Senescence
    DOI:  https://doi.org/10.1016/j.ebiom.2024.105533
  10. bioRxiv. 2025 Jan 04. pii: 2025.01.03.631277. [Epub ahead of print]
    T Lymphocyte-Specific Deletion of SHP1 and SHP2 Promotes Activation-Induced Cell Death of CD4+ T Cells and Impairs Antitumor Response.
    Connor J R Foster, Jasper Du, Oscar Pundel, Mitchell J Geer, Ryan C Ripert, Jia Liu, Taylor A Heim, Kiyomi Y Araki, Amanda W Lund, Jun Wang, Benjamin G Neel.
      SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSMs). These PTPs bind overlapping sets of ITIM/ITSM-bearing proteins, suggesting that they might have some redundant functions. By studying T cell-specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain naïve T cell differentiation to effector and central memory phenotypes, with SHP1 playing the dominant role. Surprisingly, loss of SHP2 alone in T cells enhanced the antitumor effects of anti-PD-1 antibodies, whereas there was no effect of SHP1 deletion. Also unexpectedly, the absence of both PTPs resulted in poorer tumor control and failure to respond to PD-1 blockade, associated with reduced frequency and activation of T cells and dendritic cells. Mechanistic studies revealed that CD4+, but not CD8+ T cells lacking SHP1 and SHP2 show increased activation-induced cell death upon anti-CD3/CD28 stimulation. Adoptive transfer of antigen-specific CD4+ T cells restored normal levels of tumor control in mice lacking both PTPs. Together, our results demonstrate that SHP1 or SHP2 is required to prevent activation-induced cell death of CD4+ T cells and is critical for tumor immunity, raising the possibility that inhibition of SHP2 might augment the therapeutic efficacy of PD-1-based immune therapy.
    SIGNIFICANCE STATEMENT: SHP1 and SHP2 are related protein tyrosine phosphatases that associate with several of the same ITIM/ITSM-containing receptors or T cell receptor (TCR) signaling molecules. The individual roles of SHP1 and SHP2 in T cells have been reported previously, but potentially redundant functions are less well understood. Here we uncover an essential function in CD4+ T cells that is manifest only in the absence of both enzymes and is critical for the control of tumors.
    DOI:  https://doi.org/10.1101/2025.01.03.631277
  11. Nat Aging. 2025 Jan 15.
    Aging stem cells limit tumorigenesis.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-025-00805-5
  12. Arthritis Rheumatol. 2025 Jan 12.
    Immune Aging in Rheumatoid Arthritis.
    Cornelia M Weyand, Jörg J Goronzy.
      Rheumatoid arthritis (RA) is a life-long autoimmune disease caused by the confluence of genetic and environmental variables that lead to loss of self-tolerance and persistent joint inflammation. RA occurs at the highest incidence in individuals >65 years old, implicating the aging process in disease susceptibility. Transformative approaches in molecular immunology and in functional genomics have paved the way for pathway paradigms underlying the replacement of immune homeostasis with auto-destructive immunity in affected patients, including the process of immune aging. Patients with RA have a signature of premature immune aging, best understood for CD4+ T cells which function as pathogenic effectors in this HLA class II-associated disease. Premature immune aging is present in healthy HLA-DRB1*04+ individuals, placing accelerated immune aging prior to joint inflammation. Aging-related molecular abnormalities directly implicated in turning RA CD4+ T cells into pro-inflammatory effector cells are linked to malfunction of subcellular organelles, such as mitochondria, lysosomes, lipid droplets and the endoplasmic reticulum. Resulting changes in T cell behavior include cellular hypermobility; tissue invasiveness; unopposed mTORC activation; excessive release of tumor necrosis factor α (TNF); lysosomal failure; clonal expansion and immunogenic cell death. Aged and metabolically reprogrammed T cells in RA patients are accompanied by age-associated B cells (ABC), which specialize in autoantibody production. Clonal hematopoiesis drives myeloid cell aging by producing aged monocytes and hypermetabolic macrophages (Mϕ) that sustain the process of inflammaging. Here, we synthesize insights into the relationship of RA risk and immune aging and discuss mechanisms through which immune aging can cause autoimmunity.
    DOI:  https://doi.org/10.1002/art.43105
  13. bioRxiv. 2024 Nov 02. pii: 2024.10.28.620691. [Epub ahead of print]
    A PI3Kδ-Foxo1-FasL signaling amplification loop rewires CD4 + T helper cell signaling, differentiation and epigenetic remodeling.
    Dominic P Golec, Pedro Gazzinelli-Guimaraes, Daniel Chauss, Hiroyuki Nagashima, Kang Yu, Tom Hill, Luis Nivelo, Jennifer L Cannons, Jillian Perry, Ilin Joshi, Nicolas Pereira, Fabrício Marcus Silva Oliveira, Anthony C Cruz, Kirk M Druey, Justin B Lack, Thomas B Nutman, Alejandro V Villarino, John J O'Shea, Behdad Afzali, Pamela L Schwartzberg.
      While inputs regulating CD4 + T helper cell (Th) differentiation are well-defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th-lineage identity remain unresolved. PI3K signaling is a critical regulator of T cell function; activating mutations affecting PI3Kδ result in an immunodeficiency with multiple T cell defects. Using mice expressing activated-PI3Kδ, we found aberrant expression of proinflammatory Th1-signature genes under Th2-inducing conditions, both in vivo and in vitro . This dysregulation was driven by a robust PI3Kδ-IL-2-Foxo1 signaling loop, fueling Foxo1-inactivation, loss of Th2-lineage restriction, altered chromatin accessibility and global impairment of CTCF-DNA interactions. Surprisingly, ablation of Fasl , a Foxo1-repressed gene, restored normal Th2 differentiation, TCR signaling and CTCF expression. BioID revealed Fas interactions with TCR- signaling components, which were supported by Fas-mediated potentiation of TCR signaling. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated-PI3Kδ, thereby linking two key pathways of immune dysregulation.
    DOI:  https://doi.org/10.1101/2024.10.28.620691
  14. Front Med. 2025 Jan 17.
    Metabolism and metabolomics in senescence, aging, and age-related diseases: a multiscale perspective.
    Ziyi Wang, Hongying Zhu, Wei Xiong.
      The pursuit of healthy aging has long rendered aging and senescence captivating. Age-related ailments, such as cardiovascular diseases, diabetes, and neurodegenerative disorders, pose significant threats to individuals. Recent studies have shed light on the intricate mechanisms encompassing genetics, epigenetics, transcriptomics, and metabolomics in the processes of senescence and aging, as well as the establishment of age-related pathologies. Amidst these underlying mechanisms governing aging and related pathology metabolism assumes a pivotal role that holds promise for intervention and therapeutics. The advancements in metabolomics techniques and analysis methods have significantly propelled the study of senescence and aging, particularly with the aid of multiscale metabolomics which has facilitated the discovery of metabolic markers and therapeutic potentials. This review provides an overview of senescence and aging, emphasizing the crucial role metabolism plays in the aging process as well as age-related diseases.
    Keywords:  age-related diseases; aging; metabolism; metabolomics; senescence
    DOI:  https://doi.org/10.1007/s11684-024-1116-0
  15. Int J Mol Sci. 2024 Dec 30. pii: 254. [Epub ahead of print]26(1):
    Zinc Deficiency Exacerbates Lead-Induced Interleukin-2 Suppression by Regulating CREM Expression.
    Hannah E Trojan, Lothar Rink, Jana Jakobs.
      Lead, a prevalent heavy metal, impairs the immune system by affecting T cell function. Similarly, zinc deficiency adversely affects T cells, with zinc deficiency and lead exposure being linked to reduced interleukin-2 (IL-2) production. Zinc deficiency has been associated with increased expression of the transcription factor CREM 100 kDa, which downregulates IL-2. Previous research suggests zinc may mitigate lead's toxic effects. This study explored the molecular mechanism underlying IL-2 reduction in lead-exposed T cells and examined the role of zinc status. The effects of lead exposure were investigated in Jurkat T cells in zinc-adequate, zinc-deficient, and zinc-supplemented conditions. Results showed that lead exposure increased CREM 100 kDa expression, which was amplified under zinc-deficient conditions. Consequently, IL-2 production was significantly lower in cells exposed to both lead and zinc deficiency compared to lead exposure alone. However, zinc supplementation counteracted these effects, preventing CREM 100 kDa overexpression and restoring IL-2 levels. In conclusion, we identified CREM 100 kDa as a potential molecular mechanism behind the lead-induced IL-2 decrease in Jurkat T cells, with zinc deficiency exacerbating this effect. These findings highlight the protective role of zinc in counteracting lead toxicity and emphasize the importance of maintaining adequate zinc levels for immune health.
    Keywords:  CREM; IL-2; T cells; lead; zinc
    DOI:  https://doi.org/10.3390/ijms26010254
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