bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–07–27
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. T cells require mitochondria to proliferate, function and generate memory.
  2. Xylulose 5-phosphate fosters sustained antitumor activity of progenitor-like exhausted SLC35E2+ CD8+ T effector cells.
  3. Early methionine availability attenuates T cell exhaustion.
  4. The role of gut microbial metabolites in the T cell lifecycle.
  5. BIRC3 deficiency blocks the ubiquitination and degradation of GOT2 to impede antitumor immune responses in lung squamous cell carcinoma.
  6. Immune cell single-cell RNA sequencing analyses link an age-associated T cell subset to symptomatic benign prostatic hyperplasia.
  7. PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion.
  8. Decoding the metabolic dialogue in the tumor microenvironment: from immune suppression to precision cancer therapies.
  9. Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustion.
  10. Dynamics of virus-specific CD8+ T cells in the human nasal cavity.
  11. Blocking secretion of exosomes by GW4869 dampens CD8+ T cell exhaustion and prostate cancer progression.
  12. CXCL12/CXCR4 axis governs Treg spatial dominance over CD8+ T cells via IL-2 sequestration: a dual therapeutic target in prostate cancer.
  13. The Role of Lactate in Immune Regulation: A Metabolic Rheostat via Transporters, Receptors, and Epigenetic Modifiers.
  14. A gain-of-function PIK3CD variant, R512W, impairs T cell function through polyamine-dependent metabolic dysregulation.
  1. Nat Immunol. 2025 Jul 22.
    T cells require mitochondria to proliferate, function and generate memory.
      
    DOI:  https://doi.org/10.1038/s41590-025-02226-3
  2. Cell Metab. 2025 Jul 14. pii: S1550-4131(25)00324-9. [Epub ahead of print]
    Xylulose 5-phosphate fosters sustained antitumor activity of progenitor-like exhausted SLC35E2+ CD8+ T effector cells.
    Tiezhu Shi, Jialiang Shao, Yufeng Ding, Hong Tang, Xiangyin Tan, Sisi Zhou, Shaoqing Yu, Xiang Wang, Guanzhen Yu, Ninghan Feng, Xiongjun Wang.
      Metabolic adaptations involved in tumor metastasis and immune evasion merit investigation. Here, using in vivo metabolic CRISPR/Cas9 knockout screening, we identified xylulokinase (XYLB) as a tumor suppressor that impairs lung colonialization by producing xylulose 5-phosphate (Xu5P), which promotes CD8+ T cell cytotoxicity. Mechanistically, CD8+ T cells express relatively high levels of solute carrier family 35 member E2 (SLC35E2), a homolog of the plant Xu5P transporter, to facilitate Xu5P uptake and subsequently intensify the pentose phosphate pathway and glycolysis for energy/redox balance. Furthermore, we revealed that Xu5P potentiates CD8+ T cell response by promoting Xu5P-responsive progenitor-like SLC35E2+ CD8+ exhausted T cells via tet methylcytosine dioxygenase 3 (TET3)-mediated DNA demethylation of the Tcf7 promoter. Clinically, elevated XYLB or blood Xu5P correlates with enhanced CD8+ T cell efficacy and reduced metastasis. In murine models, Xu5P supplementation or adopting Xu5P-rich diets synergizes with anti-PD-1 therapy to enhance antitumor immunity. These findings offer insights into the potentiality of dietary interventions for metastatic cancer.
    Keywords:  Xu5P; dietary metabolite; immunotherapy; progenitor-like CD8(+) T cells; tumor metastasis
    DOI:  https://doi.org/10.1016/j.cmet.2025.06.011
  3. Nat Immunol. 2025 Jul 23.
    Early methionine availability attenuates T cell exhaustion.
    Piyush Sharma, Ao Guo, Suresh Poudel, Emilio Boada-Romero, Katherine C Verbist, Gustavo Palacios, Kalyan Immadisetty, Mark J Chen, Dalia Haydar, Ashutosh Mishra, Junmin Peng, M Madan Babu, Giedre Krenciute, Evan S Glazer, Douglas R Green.
      T cell receptor (TCR) activation is regulated in many ways, including niche-specific nutrient availability. Here we investigated how methionine (Met) availability and TCR signaling interplay during the earliest events of T cell activation affect subsequent cell fate. Limiting Met during the initial 30 min of TCR engagement increased Ca2+ influx, NFAT1 (encoded by Nfatc2) activation and promoter occupancy, leading to T cell exhaustion. We identified changes in the protein arginine methylome during initial TCR engagement and identified an arginine methylation of the Ca2+-activated potassium transporter KCa3.1, which regulates Ca2+-mediated NFAT1 signaling for optimal activation. Ablation of KCa3.1 arginine methylation increased NFAT1 nuclear localization, rendering T cells dysfunctional in mouse tumor and infection models. Furthermore, acute, early Met supplementation reduced nuclear NFAT1 in tumor-infiltrating T cells and augmented antitumor activity. These findings identify a metabolic event early after T cell activation that affects cell fate.
    DOI:  https://doi.org/10.1038/s41590-025-02223-6
  4. Nat Immunol. 2025 Jul 21.
    The role of gut microbial metabolites in the T cell lifecycle.
    Melissa Tran, Jun R Huh, A Sloan Devlin.
      T cells, a cornerstone of the adaptive immune system, have pivotal roles at the host-microorganism interface. The gut microbiome profoundly influences T cell biology by producing a diverse repertoire of small molecules that are sensed by host cells. These microbial metabolites regulate all aspects of the T cell lifecycle, from cell development to differentiation and activation to exhaustion. Recent studies have uncovered microbially derived molecules, including short-chain fatty acids, secondary bile acids and tryptophan metabolites, as potent regulators of T cell function. However, the full scope of microbial metabolite-T cell interactions remains largely unexplored. This Review presents a mechanistic framework linking gut microbial metabolites to discrete stages of T cell fate and function. Expanding our understanding of these intricate host-microbiome interactions will reveal new aspects of immune regulation and inspire microbiome-guided therapeutic strategies for infections, autoimmune diseases and cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-025-02227-2
  5. J Pathol. 2025 Jul 21.
    BIRC3 deficiency blocks the ubiquitination and degradation of GOT2 to impede antitumor immune responses in lung squamous cell carcinoma.
    Qiang Zhang, Hongxu Sheng, Dongnan Ping, Jixiang Gao.
      In lung squamous cell carcinoma (LUSC), the proportion of exhausted CD8+ T cells is considerably higher than in lung adenocarcinoma (LUAD). The exhaustion of CD8+ T cells is responsible for the failure of immunotherapies, as terminally exhausted CD8+ T cells do not respond to immune checkpoint blockade. Therefore, investigating the regulatory mechanisms underlying CD8+ T-cell exhaustion in LUSC is essential for potentiating the efficacy of immunotherapy in this context. In our study, cellular assays revealed that elevated expression of GOT2 in LUSC reinforced the exhaustion of cocultured CD8+ T cells, as evidenced by elevated levels of TIGIT and TIM-3, while simultaneously impairing tumor-killing capabilities, as indicated by reduced LDH activity and diminished apoptosis. Animal experiments confirmed that knockdown of GOT2 effectively curbed tumor growth and boosted the CD8+ T cell infiltration and tumor-killing function. Mechanistic studies demonstrated that BIRC3, acting as an E3 ubiquitin ligase, can recognize the 366-372 sequence of GOT2, mediating its ubiquitination and degradation. The deficiency of BIRC3 in LUSC interrupted ubiquitination and subsequent degradation of GOT2, leading to elevated GOT2 protein levels, which in turn facilitated CD8+ T-cell exhaustion and ultimately compromised their antitumor immune responses. Collectively, our findings elucidated the regulatory role of protein ubiquitination in CD8+ T cell functionality, highlighting a novel approach to enhance the sensitivity of LUSC to immunotherapy through the intervention of the BIRC3/GOT2 ubiquitination axis. © 2025 The Pathological Society of Great Britain and Ireland.
    Keywords:  BIRC3; CD8+ T cells; GOT2; immune response; lung squamous cell carcinoma; ubiquitination
    DOI:  https://doi.org/10.1002/path.6448
  6. Front Immunol. 2025 ;16 1585446
    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, Simon W Hayward, Timothy L Ratliff.
       Introduction: Benign prostatic hyperplasia (BPH) is among the most common age-associated diseases in men. Prostatic immune cell infiltration is frequently observed with aging coincident with BPH; however, the contribution of age-related changes in immune cells to BPH is not clear. As T cells are the predominate immune cell in aged prostates, it is hypothesized that age-associated alterations in T cell subsets contribute to BPH symptoms.
    Methods: scRNA-seq data from immune cells isolated from small (≤40g) and large (≥90g) prostates from aged men (>50 years) were combined with previously published scRNA-seq data from three young organ donor prostates to compare young to aged prostate T cells and small to large aged prostate T cells. Cycling and senescent BPH patient-derived fibroblasts were treated with granzyme K and senescence-associated secretory phenotype (SASP)-associated cytokines were measured by ELISA.
    Results: An age-associated CD8+ T cell subset (Taa) with high Granzyme K (GZMKhi) and low Granzyme B (GZMBlow) gene expression infiltrated aged human prostates and positively correlated 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.
    Discussion: 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.
    Keywords:  BPH; SASP; T cells; aging; granzyme K; inflammaging; prostate
    DOI:  https://doi.org/10.3389/fimmu.2025.1585446
  7. J Exp Med. 2025 Oct 06. pii: e20230542. [Epub ahead of print]222(10):
    PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion.
    Kristen E Pauken, Samuel C Markson, Thomas S Conway, Vikram R Juneja, Osmaan Shahid, Kelly P Burke, Jared H Rowe, Thao H Nguyen, Jenna L Collier, Jaclyn M L Walsh, Megan E Fung, Jacob M Luber, Alison E Ringel, Jason M Schenkel, Gordon J Freeman, Marcia C Haigis, Meromit Singer, Arlene H Sharpe.
      Although PD-1 inhibitors are FDA-approved for over 25 different cancers, the mechanisms contributing to response remain incompletely understood. To investigate how PD-1-deleted CD8+ T cells influence PD-1-expressing CD8+ T cells in the same tumor microenvironment, we developed an inducible PD-1 knockout (KO) model in which PD-1 is deleted on ∼50% of cells. PD-1 deletion beginning at day 7 after implantation of MC38 tumor cells led to robust tumor control. Remarkably, PD-1-expressing CD8+ T cells in the tumor had increased functionality similar to PD-1 KO CD8+ T cells. Using single-cell RNA-seq and TCR-seq, we found that the major transcriptional changes following PD-1 deletion were shared by PD-1 KO and PD-1-expressing CD8+ T cells, although PD-1 KO clones preferentially expanded. These data suggest PD-1 inhibitors not only exert cell-intrinsic effects but also may promote increased T cell function through non-cell-autonomous mechanisms, which has important implications for design of PD-1-based cancer immunotherapies.
    DOI:  https://doi.org/10.1084/jem.20230542
  8. Exp Hematol Oncol. 2025 Jul 22. 14(1): 99
    Decoding the metabolic dialogue in the tumor microenvironment: from immune suppression to precision cancer therapies.
    Ruoli Wang, Jincheng Zhuang, Qi Zhang, Wantao Wu, Xinrui Yu, Hao Zhang, Zongyi Xie.
      The tumor microenvironment (TME) represents a metabolic battleground where immune cells and cancer cells vie for essential nutrients, ultimately influencing antitumor immunity and treatment outcomes. Recent advancements have shed light on how the metabolic reprogramming of immune cells, including macrophages, T cells, and DCs, determines their functional polarization, survival, and interactions within the TME. Factors such as hypoxia, acidosis, and nutrient deprivation drive immune cells toward immunosuppressive phenotypes, while metabolic interactions between tumors and stromal cells further entrench therapeutic resistance. This review synthesizes new insights into the metabolic checkpoints that regulate immune cell behavior, focusing on processes like glycolysis, oxidative phosphorylation (OXPHOS), lipid oxidation, and amino acid dependencies. We emphasize how metabolic enzymes (e.g., IDO1, ACLY, CPT1A) and metabolites (e.g., lactate, kynurenine) facilitate immune evasion, and we propose strategies to reverse these pathways. Innovations such as single-cell metabolomics, spatial profiling, and AI-driven drug discovery are transforming our understanding of metabolic heterogeneity and its clinical implications. Furthermore, we discuss cutting-edge therapeutic approaches-from dual-targeting metabolic inhibitors to biomaterial-based delivery systems-that aim to reprogram immune cell metabolism and enhance the effectiveness of immunotherapy. Despite the promise in preclinical studies, challenges persist in translating these findings to clinical applications, including biomarker validation, metabolic plasticity, and interpatient variability. By connecting mechanistic discoveries with translational applications, this review highlights the potential of immunometabolic targeting to overcome resistance and redefine precision oncology.
    Keywords:  Immune cells metabolism; Immunotherapy resistance; Metabolic reprogramming; Therapeutic targeting; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40164-025-00689-6
  9. iScience. 2025 Jul 18. 28(7): 112715
    Single cell immune profiling in ankylosing spondylitis reveals resistance of CD8+ T cells to immune exhaustion.
    Michael Tang, Zoya Qaiyum, Melissa Lim, Robert D Inman.
      Persistent chronic inflammation is a hallmark of ankylosing spondylitis (AS), with cytotoxic T cells (CTLs) increasingly implicated in its pathogenesis. Ordinarily, T cell exhaustion follows sustained, persistent T cell activation to limit collateral tissue damage. Using mass cytometry and single-cell RNA sequencing (scRNA-seq), we identified a clonally expanded CTL subset in AS synovial fluid that expresses inhibitory receptors (PD-1, TIGIT, LAG-3) yet retains its effector capacity to express granzymes, perforin, TNF-α, and IFN-γ. Gene expression profile of this CTL subset shows the downregulation of canonical exhaustion markers. At the protein level, TOX, a critical transcription factor regulating CTL exhaustion, is downregulated in PD-1+TIGIT+LAG-3+CTLs. In-silico trajectory analyses suggest that these cells may differentiate into other effector CTL subsets. Our findings reveal a checkpoint-expressing CTL population in AS that resists exhaustion and retains an activated, effector phenotype. We propose that failure to undergo exhaustion may be a fundamental mechanism sustaining AS chronic inflammation.
    Keywords:  Immune response; Immunology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.112715
  10. Mucosal Immunol. 2025 Jul 22. pii: S1933-0219(25)00078-9. [Epub ahead of print]
    Dynamics of virus-specific CD8+ T cells in the human nasal cavity.
    Joey Ming Er Lim, Sabrina Ottolini, Shou Kit Hang, Martin Daniel Qui, Adeline Chia, Jenny Guek Hong Low, Nina Le Bert, Anthony T Tan, Antonio Bertoletti.
      The nasal cavity is the entry site for respiratory viruses. Understanding how the nasal cavity sustains memory CD8+ T cell is essential for improving respiratory virus management and vaccine development. Here, we sampled CD8+ T cells from the upper nasal turbinate and peripheral blood of healthy adults. We analysed their transcriptomic profile and antigen specificity for respiratory (SARS-CoV-2, Influenza) and non-respiratory (HCMV) viruses. Transcriptomic analysis revealed that nasal CD8+ T cells failed to upregulate STAT1 following TCR stimulation, potentially enabling clonal expansion despite the antiproliferative effects of IFN signalling. They also exhibited a cytotoxic, Th1-like profile with tissue-residency markers but lacked TCF7 expression, suggesting limited self-renewal capacity. The CD8+ T cell analysis of antigen specificity demonstrates that local nasal exposure is indispensable for virus-specific CD8+ T cell detection. Only SARS-CoV-2 and influenza-specific but not HCMV-specific CD8+ T cells were detected in the nasal compartment. However, their persistence over time in the nasal cavity appears linked to repetitive viral exposure. Our findings provide insights into the adaptations of nasal-resident CD8+ T cells and highlight challenges in eliciting durable nasal T cell immunity, with important implications for vaccine strategies against respiratory pathogens.
    Keywords:  Influenza virus; Mucosal immunity; Nasal turbinates; SARS-CoV-2; T cells
    DOI:  https://doi.org/10.1016/j.mucimm.2025.07.007
  11. Hum Cell. 2025 Jul 18. 38(5): 131
    Blocking secretion of exosomes by GW4869 dampens CD8+ T cell exhaustion and prostate cancer progression.
    Jing Liu, Hongyan Guo, Shiqi Liu, Yinying Hu, Yanqin Huang, Jiping Rong, Fang Yuan, Ruping Wang, Zhigang Wang.
      Functional exhaustion of T lymphocytes is considered an important factor in the failure of tumor treatment. Accumulating evidence has shown that tumor cells cultivate their immune microenvironment through secreting exosomes. However, the mechanism through which tumor cell-derived exosomes participate in the regulation of lymphocyte function remains unclear. In this study, we found that exosomes derived from prostate cancer (PCa) cells were able to upregulate the expression of PD-1 and TIM-3 in CD8+ T cells, inducing the secretion of cytokines related to T cell exhaustion and significantly decreasing the ability to kill PCa cells. Importantly, our data indicated that treatment with GW4869 could reverse the effects of PCa-derived exosomes on CD8+ T cells and further inhibit the growth of PCa cells in vivo and in vitro by blocking the generation of exosomes. Our findings support the notion that exosomes derived from PCa cells can induce T cell exhaustion and promote PCa progression, while treatment of GW4869 effectively rejuvenates CD8+ T cells and reverses the effect of PCa exosomes. These findings indicate that GW4869 has potential in the treatment of PCa.
    Keywords:  CD8+ T cell exhaustion; Exosome; GW4869; Prostate cancer
    DOI:  https://doi.org/10.1007/s13577-025-01257-0
  12. Front Immunol. 2025 ;16 1626708
    CXCL12/CXCR4 axis governs Treg spatial dominance over CD8+ T cells via IL-2 sequestration: a dual therapeutic target in prostate cancer.
    Junyi Li, Long Zhang, Ruoyang Liu, Changwen Xu, HuiHui Tang, Yunfei Zou, Qingfei Cao, Weichao Huang.
       Background: Prostate cancer (PCa) is characterized by high incidence and recurrence rates, presenting as an immune 'cold' tumor that exhibits a poor response to immunotherapy. The mechanisms underlying immune suppression and evasion within the tumor microenvironment (TME) of PCa remain inadequately understood.
    Methods: A comprehensive analysis of the immune environment in PCa was conducted using combined single-cell and spatial transcriptomic approaches, encompassing samples from healthy tissue, adjacent normal tissue, and localized tumors. Cell abundance and polarization state analyses were performed to identify pivotal cellular populations. Spatial deconvolution techniques were employed to elucidate cell composition within its spatial context. Additionally, cell niche and spatial colocalization analyses were conducted to evaluate potential cellular interactions. Immune response enrichment analysis was utilized to assess cellular response states. In vivo and in vitro experiments were conducted to validate hypotheses.
    Results: Data indicated a prevalent immunosuppressive state among CD8 T cells, accompanied by variations in cell abundance. Macrophages emerged as key regulators in recruiting CD8+ effector T cells and regulatory T cells (Tregs) into the TME, mediated by the CXCL12/CXCR4 axis. A spatial proximity relationship was established between CD8+ effector T cells and Tregs, suggesting Tregs directly influence CD8+ T cell function. Immune cell state analysis revealed interleukin-2 (IL-2) as a critical cytokine in reshaping the immune microenvironment, with Tregs competitively depleting IL-2 and mediating IL-2/STAT5 signaling to induce CD8+ effector T cell exhaustion. Treatment with CXCR4 inhibitor and IL-2 demonstrated significant antitumor effects and reversed immune dysfunction in both in vivo and in vitro experiments, with combined treatment exhibiting superior efficacy.
    Conclusion: These findings elucidate the role of macrophages in mediating the CXCL12/CXCR4 axis to aggregate CD8+ effector T cells and Tregs, thereby influencing the TME. Furthermore, Tregs competitively deplete IL-2 and mediate IL-2/STAT5 signaling, leading to CD8+ effector T cells exhaustion and the establishment of an immunosuppressive microenvironment.
    Keywords:  CD8+ T cell; CXCL12/CXCR4 axis; IL-2/STAT5 signaling; prostate cancer; regulatory T cells; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1626708
  13. Cells. 2025 Jul 17. pii: 1096. [Epub ahead of print]14(14):
    The Role of Lactate in Immune Regulation: A Metabolic Rheostat via Transporters, Receptors, and Epigenetic Modifiers.
    Eun Jung Choi, Yoon Young Jang, Eun Joo Choi, Chang Joo Oh.
      Lactate, once regarded as a metabolic byproduct, is now recognized as a critical immunometabolic regulator that shapes immune responses in both physiological and pathological contexts. This review examines how lactate accumulation occurs across diverse disease settings, including cancer, sepsis, and diabetes, through mechanisms such as hypoxia, mitochondrial dysfunction, and pharmacologic intervention. We then explore how lactate modulates immunity via four integrated mechanisms: transporter-mediated flux, receptor signaling (e.g., GPR81), context-dependent metabolic rewiring, and histone/protein lactylation. Particular emphasis is placed on the dichotomous effects of endogenous versus exogenous lactate, with the former supporting glycolytic effector functions and the latter reprogramming immune cells toward regulatory phenotypes via redox shifts and epigenetic remodeling. The review also highlights how the directionality of lactate transport, and the metabolic readiness of the cell determine, whether lactate sustains inflammation or promotes resolution. After analyzing emerging data across immune cell subsets and disease contexts, we propose that lactate serves as a dynamic rheostat that integrates environmental cues with intracellular metabolic and epigenetic programming. Understanding these context-dependent mechanisms is essential for the rational design of lactate-targeted immunotherapies that aim to modulate immune responses without disrupting systemic homeostasis.
    Keywords:  anti-inflammation; immunometabolism; lactate
    DOI:  https://doi.org/10.3390/cells14141096
  14. Biochem Biophys Res Commun. 2025 Jul 17. pii: S0006-291X(25)01093-9. [Epub ahead of print]778 152378
    A gain-of-function PIK3CD variant, R512W, impairs T cell function through polyamine-dependent metabolic dysregulation.
    Kyoko Kiyota, Hiroshi Shiraishi, Shiho Ohno, Yasuhiro Soga, Nobuyuki Shimizu, Hiroyuki Yatsuka, Masanori Inoue, Takashi Takeno, Wang Hongxia, Adiana Mutamsari Witaningrum, Reiko Hanada, Yoshiki Yamaguchi, Kenji Ihara, Toshikatsu Hanada.
      We previously reported a patient harboring a novel heterozygous phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) missense variant (p.R512W) who presented with autoimmune features including Kawasaki disease, immune thrombocytopenic purpura, and systemic lupus erythematosus, without the classical signs of immunodeficiency typically associated with activated PI3Kδ syndrome (APDS). To elucidate the molecular mechanisms underlying this phenotype, we conducted functional and structural analyses of the R512W variant. Overexpression of mutant human p110δ (R512W) in a murine T cell line resulted in increased PIP3 accumulation and AKT phosphorylation, consistent with a gain-of-function effect. However, T cells expressing R512W exhibited paradoxical dysfunction, including reduced IL-2 production, impaired proliferation, increased PD-1 expression, and apoptosis, which are hallmarks of a T cell exhaustion-like state. A transcriptomic analysis revealed downregulation of polyamine biosynthesis genes, such as Odc1, Amd1, and Smox, along with reduced intracellular polyamine levels. Supplementation of the culture medium with spermidine partially rescued the proliferative defects, suggesting reversible metabolic insufficiency. Structural modeling indicated that R512W may alter the conformation of the helical domain of p110δ, potentially contributing to its hyperactivation. Unlike canonical APDS-associated mutations, the R512W variant appears to uncouple PI3K hyperactivation from effective T cell responses, resulting in immune dysregulation through both signaling and metabolic pathways. This autoimmune-dominant phenotype underscores mutation-specific clinical heterogeneity within the PIK3CD-associated disease spectrum. These findings reveal a novel link between aberrant PI3K signaling and polyamine metabolism, and suggest that targeting metabolic pathways may hold therapeutic potential in select cases of PI3K-driven autoimmunity.
    Keywords:  APDS; PIK3CD; Polyamines; T cell; p110δ
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152378
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