bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–05–11
twenty papers selected by
Dylan Ryan, University of Cambridge
  1. Highlights of 2024: Tregs immunometabolism and how to counter inflammatory niches.
  2. Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.
  3. Bacteria-derived nutrient recycling: How phagocytosed bacteria regulate macrophage metabolism.
  4. Foxp3 confers long-term efficacy of chimeric antigen receptor-T cells via metabolic reprogramming.
  5. Itaconate potentiates hepatic gluconeogenesis through NRF2 induction.
  6. CD27 costimulation supports metabolic fitness of CD4+ T cells by enhancing de novo nucleotide and protein synthesis.
  7. New insights on metabolic reprogramming in macrophage plasticity.
  8. Metabolic reprograming of immune cells in MASH.
  9. Obesity and Autoimmunity Epidemic: The Role of Immunometabolism.
  10. Metabolic reprogramming through histone lactylation in microglia and macrophages recruits CD8+ T lymphocytes and aggravates spinal cord injury.
  11. Metabolic reprogramming of tumor-associated neutrophils in tumor treatment and therapeutic resistance.
  12. Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer.
  13. ZnO Nanoparticle Exposure Disrupted Iron-Sulfur Protein Functions to Increase Macrophage Erythrophagocytosis and Disturb Systemic Iron Recycling.
  14. PTPN2 Negatively Regulates Macrophage Immune Responses and Cellular Bioenergetics.
  15. Diet-induced dyslipidemia enhances IFN-γ production in mycolic acid-specific T cells and affects mycobacterial control.
  16. Compromised Glycolysis in Memory CD4+ T cells Derived from HIV-infected Immunological Non-Responders to Highly Active Antiretroviral Therapy.
  17. A genome-wide CRISPR screen identifies GRA38 as a key regulator of lipid homeostasis during Toxoplasma gondii adaptation to lipid-rich conditions.
  18. Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection.
  19. A preliminary study of serum metabolomic profiling in male patients with acute brucellosis.
  20. 4-Octyl Itaconate Modulates Dendritic Cells Function and Tumor Immunity via NRF2 Activation.
  1. Immunol Cell Biol. 2025 May 04.
    Highlights of 2024: Tregs immunometabolism and how to counter inflammatory niches.
    Nicolas Valentini, Christopher J Requejo Cier, Caroline Lamarche.
      In this article for the Highlights of 2024 Series, we discuss recent discoveries in Treg immunometabolism, which reveal how inflammatory niches alter Treg fate and function through distinct metabolic cues. Key findings include IL-21-driven mitochondrial dysfunction, lactate-enhanced OXPHOS via MGAT1, sphingolipid-dependent Treg differentiation in tumors, ferroptosis susceptibility under high-fat diets, and sex-specific adipose Treg subsets modulating glucose homeostasis. Together, these insights highlight potential metabolic targets to restore Treg function in inflammatory diseases and cancer.
    Keywords:  Tregs; glycolysis; immunometabolism; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/imcb.70027
  2. Nat Commun. 2025 May 08. 16(1): 4292
    Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice.
    Omri Yosef, Leonor Cohen-Daniel, Oded Shamriz, Zahala Bar-On, Wajeeh Salaymeh, Amijai Saragovi, Ifat Abramovich, Bella Agranovich, Veronika Lutz, Joseph Tam, Anna Permyakova, Eyal Gottlieb, Magdalena Huber, Michael Berger.
      T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation.
    DOI:  https://doi.org/10.1038/s41467-025-59310-3
  3. Cell Metab. 2025 May 06. pii: S1550-4131(25)00210-4. [Epub ahead of print]37(5): 1046-1048
    Bacteria-derived nutrient recycling: How phagocytosed bacteria regulate macrophage metabolism.
    Andrea Riviello, Dirk Brenner.
      Macrophages are responsible for sensing, phagocytosing, and destroying bacteria, yet the metabolic fate of these internalized microbes remains largely unexplored. A recent study published by Lesbats et al. in Nature1 uncovers how macrophages recycle some of the components from phagolysosomal degradation, using them as intermediates in various anabolic pathways and as fuel for oxidative phosphorylation.
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.018
  4. Cell Metab. 2025 Apr 30. pii: S1550-4131(25)00218-9. [Epub ahead of print]
    Foxp3 confers long-term efficacy of chimeric antigen receptor-T cells via metabolic reprogramming.
    Congyi Niu, Huan Wei, Xuanxuan Pan, Yuedi Wang, Huan Song, Congwen Li, Jingbo Qie, Jiawen Qian, Shaocong Mo, Wanwei Zheng, Kameina Zhuma, Zixin Lv, Yiyuan Gao, Dan Zhang, Hui Yang, Ronghua Liu, Luman Wang, Wenwei Tu, Jie Liu, Yiwei Chu, Feifei Luo.
      The tumor microenvironment, characterized by low oxygen tension and scarce nutrients, impairs chimeric antigen receptor (CAR)-T cell metabolism, leading to T cell exhaustion and dysfunction. Notably, Foxp3 confers a metabolic advantage to regulatory T cells under such restrictive conditions. Exploiting this property, we generated CAR-TFoxp3 cells by co-expressing Foxp3 with a third-generation CAR construct. The CAR-TFoxp3 cells exhibited distinct metabolic reprogramming, marked by downregulated aerobic glycolysis and oxidative phosphorylation coupled with upregulated lipid metabolism. This metabolic shift was driven by Foxp3's interaction with dynamin-related protein 1. Crucially, CAR-TFoxp3 cells did not acquire regulatory T cell immunosuppressive functions but instead demonstrated enhanced antitumor potency and reduced expression of exhaustion markers via Foxp3-mediated adaptation. The potent antitumor effect and absence of immunosuppression were confirmed in a humanized immune system mouse model. Our findings establish a metabolic reprogramming-based strategy to enhance CAR-T cell adaptability within the hostile tumor microenvironment while preserving therapeutic efficacy.
    Keywords:  CAR-T cell; Drp1; Foxp3; exhaustion; metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.008
  5. PLoS One. 2025 ;20(5): e0322946
    Itaconate potentiates hepatic gluconeogenesis through NRF2 induction.
    Marwa O El-Derany, Sadeesh K Ramakrishnan, Yingjie Li, Kathryn Buscher, Christina A Jarad, Megan L Schaller, Marc Cantwell, Thomas M Vigil, Ryan A Frieler, Peter Sajjakulnukit, Costas A Lyssiotis, Richard M Mortensen, Yatrik M Shah.
      The interplay between systemic metabolism and immune responses is increasingly recognized as a significant factor in the dysregulation of glucose homeostasis associated with diabetes and obesity. Immune metabolites play crucial roles in mediating this crosstalk, with itaconate emerging as an important immune metabolite involved in the inflammatory response of macrophages. Recent studies have highlighted the role of itaconate as a regulator of glucose metabolism, particularly in the context of obesity, although the underlying mechanisms remain poorly understood. In this study, we identified itaconate as one of the metabolites that significantly increase in the liver during fasting compared to fed conditions. Mechanistically, we found that itaconate enhances glucagon-induced liver gluconeogenesis independently of insulin signaling. Notably, itaconate upregulates the expression of gluconeogenic genes both under basal conditions and in the presence of palmitic acid. Furthermore, our data indicate that the effects of itaconate occur independently of CREB activation. Instead, we demonstrate that these potentiating effects are mediated through the induction of nuclear factor erythroid 2-related factor 2 (NRF2). Our findings demonstrate that itaconate has a glucagon-potentiating effects in the liver, suggesting that itaconate may play a significant role in the pathogenesis of metabolic-associated liver diseases.
    DOI:  https://doi.org/10.1371/journal.pone.0322946
  6. J Immunol. 2025 May 05. pii: vkaf075. [Epub ahead of print]
    CD27 costimulation supports metabolic fitness of CD4+ T cells by enhancing de novo nucleotide and protein synthesis.
    Thi Tran Ngoc Minh, Lotte J Verleng, Ellen Schrama, Julia Busselaar, Mo D Staal, Evert de Vries, Jacqueline D H Anholts, Celia R Berkers, Jannie Borst, Esther A Zaal, Sander de Kivit.
      T cells undergo many metabolic changes throughout the different phases of their response in lymphoid and nonlymphoid tissues. Cell metabolism meets demands for energy and biosynthesis, particularly during cell division and effector differentiation. As costimulatory receptors, CD28 and various TNF receptor (TNFR) family members shape T-cell clonal expansion, survival and effector functions and are important clinical targets. While CD28 is acknowledged as a metabolic regulator, little is known about how TNFRs shape T-cell metabolism. We here identify TNFR family member CD27 as a metabolic regulator in activated human CD4+ T cells. In the context of CD3 signaling and CD28 costimulation, CD27 proved to regulate specific metabolic functions, as determined by metabolomics and metabolic tracer experiments. CD27 costimulation supported upregulation of glycolysis, the pentose phosphate pathway and the TCA cycle, increasing the use of glucose-derived carbon and glutamine-derived nitrogen as building blocks for de novo nucleotide synthesis. It also promoted uptake of amino acids (AAs) and modulated pathways of AA metabolism. Accordingly, CD27 costimulation boosted protein translation in CD3- and CD3/CD28-activated CD4+ T cells, which proceeded via enhanced mTOR pathway activation. Remarkably, CD27, OX40 and 4-1BB all enhanced CD3-induced mTOR signaling, but only CD27 could overrule inhibitory PD-1 signaling. CD27 costimulation increased IL-2, IFNγ and TNFα production by CD3-activated CD4+ T cells, also in presence of PD-1 signaling. Next to previously defined beneficial effects of CD27 on activated T-cell survival and CTL differentiation and Th1 effector differentiation, these data support its essential contribution to T-cell metabolism and its relevance as a therapeutic target.
    Keywords:  CD27; T cell; TNFR; costimulation; metabolism
    DOI:  https://doi.org/10.1093/jimmun/vkaf075
  7. Int Immunopharmacol. 2025 May 07. pii: S1567-5769(25)00787-8. [Epub ahead of print]157 114797
    New insights on metabolic reprogramming in macrophage plasticity.
    Siyu Zhou, Yutong Zhu, Yu Wu, Xiaonan Zhang, Xin Kong, Xinya Zhao, Hong Xiang, Dong Shang.
      Macrophages are the first line of defense in the innate immune system. Macrophages have two subtypes: classically activated macrophages (M1) and alternatively activated macrophages (M2), with different phenotypes and functions. They play a critical role in defending against pathogens and maintaining internal homeostasis. Macrophages have great plasticity in their biological characteristics. Although the regulation of macrophage plasticity has not been fully elucidated, accumulated evidence supports that microenvironmental differences are the root cause for macrophage differentiation into different subtypes. These differences alter macrophage plasticity by modulating key metabolites, activating downstream gene transcription, and influencing phagocytosis, cytokine secretion, and immune regulation. Herein, we systematically summarize metabolic reprogramming, including glucose, lipid, amino acid, ion, vitamin, nucleotide, and butyrate metabolism, as key regulators affecting macrophage polarization, providing new insights for developing targeted drugs that modulate macrophage plasticity.
    Keywords:  Amino acid metabolism; Glycolipid metabolism; Ion metabolism; Macrophage plasticity; Metabolic reprogramming; Vitamin metabolism
    DOI:  https://doi.org/10.1016/j.intimp.2025.114797
  8. Hepatology. 2025 May 05.
    Metabolic reprograming of immune cells in MASH.
    ChuHan Ma, Shuyue Wang, Bingning Dong, Yu Tian.
      Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), affects approximately 30% of adults worldwide. Approximately 1/6 of MASLD patients progress to metabolic dysfunction-associated steatohepatitis (MASH) and potentially evolve towards cirrhosis and hepatocellular carcinoma (HCC). This condition imposes a significant burden on the global health. Although MASH is primarily a metabolic disorder, immune cells play a crucial role in its development. The activation of immune cells involves alterations in transcription and protein synthesis, which require metabolic adaptation of cellular substrate metabolism, including glucose and lipid metabolism. Moreover, the lipid-rich environment of the liver can affect the metabolism of immune cells. In this review, we delineate the metabolic profiles of immune cells in MASH, focusing on macrophages and T cells, and discuss the impact of targeting cellular metabolism on these cells along with clinical trial outcomes. Macrophages in MASH are characterized by increased glycolysis, compromised oxidative phosphorylation, and augmented lipid uptake, synthesis, and fatty acid oxidation, all of which contribute to their inflammatory phenotype. Lymphocytes, such as T cells and NK cells, exhibit impaired metabolic functions that hamper their immune surveillance capabilities and facilitate the development of HCC. However, research on the metabolic characteristics of other types of immune cells remains limited. With the development of single-cell genomics and animal models of MASH, we anticipate that further studies in this compelling field may shed light on the pathogenesis of MASH and pave the way for novel therapeutic strategies.
    Keywords:  Immune cell; MASH; Metabolism
    DOI:  https://doi.org/10.1097/HEP.0000000000001371
  9. Annu Rev Nutr. 2025 May 05.
    Obesity and Autoimmunity Epidemic: The Role of Immunometabolism.
    Alessandra Colamatteo, Clorinda Fusco, Alessandro Matarese, Giuseppe Matarese.
      The relationship between obesity and autoimmune diseases has attracted significant attention in recent years, highlighting the multifaceted connection between metabolic dysregulation and loss of self-immune tolerance. Compelling epidemiological evidence has revealed an elevated prevalence of autoimmune diseases among overweight or obese individuals, suggesting a potential causal link. Mechanistically, adipose tissue is a key immunometabolic organ that secretes an array of adipocytokines that can facilitate proinflammatory immune responses against self-antigens. Indeed, adipose tissue dysfunction in obesity fosters a state of chronic low-grade inflammation, which may contribute to the so-called accelerator hypothesis, in which circulating self-autoreactive T cells can easily lose their regulatory mechanisms, resulting in self-tissue damage and autoinflammation. In this review, we elucidate the intricate immunometabolic pathomechanisms underlying the obesity and autoimmunity epidemic, and we explore innovative therapeutic avenues that could be pivotal for advancing public health initiatives in the context of this epidemic.
    DOI:  https://doi.org/10.1146/annurev-nutr-111324-122456
  10. Neuron. 2025 Apr 24. pii: S0896-6273(25)00259-4. [Epub ahead of print]
    Metabolic reprogramming through histone lactylation in microglia and macrophages recruits CD8+ T lymphocytes and aggravates spinal cord injury.
    Xuhui Ge, Yufeng Zhu, Junjun Xiong, Yao Gu, Xiaokun Wang, Wu Ye, Haofan Wang, Yu Gao, Weihua Cai, Xuhui Zhou, Wei Liu.
      Crosstalk between the central nervous system (CNS) and the immune system has recently gained increased attention; however, the interaction between innate and adaptive immunity after CNS injury remains unclear. Here, using single-cell RNA sequencing, we identified accumulation of CD8+ T lymphocytes in the cerebrospinal fluid of patients with spinal cord injury (SCI) and in spinal cords of injured mice, thus indicating poor neurological function. Furthermore, through genetic or pharmacologic interruption strategies, we found that CXCL16 chemokines derived from injury-activated microglia and macrophages (IAMs) recruited CXCR6+CD8+ T cells and further contributed to neuronal loss after SCI. Mechanistically, glycolytic reprogramming in IAMs enhanced histone-lactylation-mediated Cxcl16 transcription, whereas suppressing glycolysis through Pkm2 deletion partially reversed this effect. Notably, a pharmacologic intervention targeting the CXCL16-CXCR6 axis with Rutin promoted locomotor restoration after SCI. Our study highlights the crucial role of glycolytically reprogrammed IAM-derived CXCL16 chemokines in modulating a maladaptive innate/adaptive immune axis and reveals several potential therapeutic strategies.
    Keywords:  CD8+ T lymphocytes; CXCL16; adaptive immunity; histone lactylation; metabolic reprogramming; microglia and macrophages
    DOI:  https://doi.org/10.1016/j.neuron.2025.04.003
  11. Front Cell Dev Biol. 2025 ;13 1584987
    Metabolic reprogramming of tumor-associated neutrophils in tumor treatment and therapeutic resistance.
    Jun Lin, Xian-Lu He, Wei-Wei Zhang, Chun-Fen Mo.
      Tumor-associated neutrophils (TANs), pivotal immune cells within the tumor microenvironment (TME), exhibit dual potential in both pro- and anti-tumorigenic effects. These cells display remarkable heterogeneity and plasticity within the TME, adapting to hypoxic and nutrient-deprived conditions through metabolic reprogramming while critically influencing tumor progression, metastasis, and immune evasion. The metabolic reprogramming of TANs not only modulates their functional phenotypes but also reshapes tumor biological behaviors and therapeutic responses by regulating metabolic intermediates and cellular interactions within the TME. Therefore, elucidating the mechanisms underlying TANs metabolic reprogramming has significant implications for deciphering the molecular basis of tumorigenesis, identifying novel therapeutic targets, and optimizing immunotherapeutic strategies. This review systematically summarizes current knowledge regarding metabolic reprogramming mechanisms of TANs in the TME and their impact on tumor progression. We particularly focus on: 1) TAN-specific alterations in glucose, lipid, and amino acid metabolism within the TME; 2) Emerging immunotherapeutic strategies targeting TANs metabolic pathways; 3) Recent advances in understanding TAN-mediated immune evasion and therapy resistance. Furthermore, this review discusses potential challenges and corresponding solutions in targeting TANs metabolic reprogramming for therapeutic intervention, aiming to provide novel insights for advancing cancer immunotherapy.
    Keywords:  immunotherapy; metabolic reprogramming; therapeutic resistance; tumor microenvironment; tumor-associated neutrophils
    DOI:  https://doi.org/10.3389/fcell.2025.1584987
  12. Sci Immunol. 2025 May 09. 10(107): eadr4795
    Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer.
    Karen Slattery, Cong-Hui Yao, Eimear Mylod, John Scanlan, Barry Scott, Joseph Patrick Crowley, Orla McGowan, Gavin McManus, Martin Brennan, Katie O'Brien, Kate Glennon, Edward Corry, Ann Treacy, Rafael J Argüello, Clair M Gardiner, Marcia C Haigis, Donal J Brennan, Lydia Lynch.
      High-grade serous ovarian cancer (HGSOC) remains an urgent unmet clinical need, with more than 70% of patients presenting with metastatic disease. Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. Immunotherapy trials have shown limited success, highlighting the need to better understand HGSOC immunology. Here, we analyzed cytotoxic lymphocytes [natural killer (NK), T, and innate T cells] from patients with HGSOC and observed widespread dysfunction across primary and metastatic sites. Although nutrient rich, ascites was immunosuppressive for all lymphocyte subsets. NK cell dysfunction was driven by uptake of polar lipids, with associated dysregulation in lipid storage. Phosphatidylcholine was a key immunosuppressive metabolite, disrupting NK cell membrane order and cytotoxicity. Blocking lipid uptake through SR-B1 protected NK cell antitumor functions in ascites. These findings offer insights into immune suppression in HGSOC and have important implications for the design of future immunotherapies.
    DOI:  https://doi.org/10.1126/sciimmunol.adr4795
  13. ACS Nano. 2025 May 07.
    ZnO Nanoparticle Exposure Disrupted Iron-Sulfur Protein Functions to Increase Macrophage Erythrophagocytosis and Disturb Systemic Iron Recycling.
    Xiumei Jiang, Yujie Ren, Chengquan Huang, Shunchang Hu, Zitong Gao, Jianmin Gao, Dongxiao Ma, Gang Liu.
      Although anemia is a common systemic toxicological manifestation of zinc product overload, the underlying mechanisms remain elusive. Therefore, we explored the mechanisms underlying the anemia caused by exposure to zinc oxide nanoparticles (ZnO NPs), which are a widely utilized Zn product. We observed that ZnO NP-exposed mice developed evident anemia due to disrupted spleen iron metabolism. Since spleen iron metabolism relies on macrophages, we further investigated how ZnO NP exposure affected macrophage function. Results indicated that ZnO NP exposure triggered macrophage metabolic reprogramming to facilitate erythrophagocytosis and blunted the response of iron exporter ferroportin to enhanced erythrophagocytosis, thereby causing iron retention and ultimately impeding macrophage iron recycling. Mechanistically, Zn2+ released from ZnO NPs occupied the cluster-binding cysteines of iron-sulfur proteins, regulating glucose metabolism and ferroportin expression to suppress their activity, thereby inducing metabolic reprogramming and suppressing iron export. Our research unveils a category of nanobio interactions underlying ZnO NPs biotoxicity.
    Keywords:  ZnO NPs; anemia; iron recycling; iron−sulfur protein assembly; macrophage
    DOI:  https://doi.org/10.1021/acsnano.5c01592
  14. FASEB J. 2025 May 15. 39(9): e70536
    PTPN2 Negatively Regulates Macrophage Immune Responses and Cellular Bioenergetics.
    Valerie Vinette, Yevgen Zolotarov, Alexandre Poirier, Zuzet Martinez Cordova, Isabelle Aubry, Michel L Tremblay.
      PTPN2 is encoded by the protein tyrosine phosphatase N2 (also known as TC-PTP) and is a negative regulator of cytokine signaling and macrophage differentiation. In the past decade, our work and others, including several pharmaceuticals, have emphasized that inhibition of PTPN2 and PTPN1 (also known as PTP1B) may act as a new first-of-class cancer immunotherapeutic. Although the potential roles of these two enzymes in various immune cells have been broadly reported, the specific activity of PTPN2 in regulating macrophage immune and metabolic responses has yet to be fully elucidated. Hence, we sought to investigate the function of PTPN2 in macrophage polarization and on their activities. We used two different mouse models to systematically and specifically inhibit the expression of PTPN2 in macrophages and utilized a chemical inhibitor with a macrophage human cell line to assess their immune and metabolic profiles. We demonstrated that PTPN2 ablation in macrophages alters their immunometabolic transcriptome and enhances their proinflammatory response, as observed by increased IFN-ɣ and nitric oxide production. PTPN2 deficiency also leads to a dysregulation of mitochondrial respiration, as observed by decreased oxygen consumption and ATP production. We establish herein that PTPN2 dampens the proinflammatory response of macrophages while altering their mitochondrial respiration, validating its macrophage inhibition as a contributing factor in the potency of systemic dual inhibition of PTPN1 and PTPN2 against cancer.
    Keywords:  LysM‐Cre; PTPN1; PTPN2; macrophages; proinflammation; protein tyrosine phosphatases
    DOI:  https://doi.org/10.1096/fj.202402405R
  15. Mucosal Immunol. 2025 May 03. pii: S1933-0219(25)00047-9. [Epub ahead of print]
    Diet-induced dyslipidemia enhances IFN-γ production in mycolic acid-specific T cells and affects mycobacterial control.
    Yen-Lin Lin, Chyung-Ru Wang.
      Dyslipidemia, characterized by altered lipid profiles, influences host immune responses against infections, including Mycobacterium tuberculosis (Mtb). While the effects of dyslipidemia on conventional T cell responses are well documented, its impact on group 1-CD1 restricted T cells, a distinct subset of lipid antigen-specific unconventional T cells, during Mtb infection remains unclear. In this study, we developed a double-transgenic mouse model expressing human group 1 CD1 (hCD1Tg) and mycolic acid (MA)-specific CD1b-restricted T cell receptor (DN1Tg) in a Rag-deficient and low-density lipoprotein receptor-deficient background to investigate how diet-induced dyslipidemia affects the functionality of MA-specific T cells and their role in anti-Mtb immunity. We found that diet-induced dyslipidemia led to increased IFN-γ production by MA-specific T cells, which promoted mycobacterial clearance in vitro. Mechanistically, this enhanced IFN-γ production was associated with increased TCR signaling and enhanced glycolysis in DN1 T cells, rather than changes in antigen presentation by dendritic cells. However, dyslipidemia also increased apoptosis in DN1 T cells, which may have impaired their ability to control mycobacterial infection in vivo, resulting in reduced bacterial clearance. These findings highlight a complex interplay between diet-induced dyslipidemia and lipid antigen-specific T-cell responses in Mtb infection, providing insights for potential therapeutic strategies to mitigate dyslipidemia-induced changes in T-cell functions.
    Keywords:  CD1-restricted T cells; Diet-induced dyslipidemia; Mycobacterium tuberculosis; Mycolic acid; Transgenic mice
    DOI:  https://doi.org/10.1016/j.mucimm.2025.04.009
  16. Curr HIV Res. 2025 May 06.
    Compromised Glycolysis in Memory CD4+ T cells Derived from HIV-infected Immunological Non-Responders to Highly Active Antiretroviral Therapy.
    Violetta V Vlasova, Larisa B Korolevskaya, Evgeniya V Saidakova, Konstantin V Shmagel.
      HAART-treated HIV-infected individuals, known as «immunological non-responders» (INR), fail to restore CD4+ T cell counts despite effective viral control. Incomplete immune restoration in INR is usually linked to low-productive proliferation of memory CD4+ T lymphocytes. Given that CD4+ T cell ability to divide critically depends on the glycolytic pathway, we aimed to determine the levels of glucose uptake and glycolysis in memory CD4+ T cells of INR. Two groups of HIV-infected HAART-treated subjects were studied: INR and immunological responders, with a healthy controls group comprising uninfected volunteers. The results showed that INR had the highest activation level in memory CD4+ T cells and the greatest glucose uptake. Short-term phytohemagglutinin stimulation provoked an increase in aerobic glycolysis in memory CD4+ T lymphocytes. Nevertheless, we found significantly reduced aerobic glycolysis in activated memory CD4+ Т cells of INR. Hence in INR, there is a discrepancy between the highly activated phenotype of memory CD4+ T lymphocytes and their glycolytic activity.
    Keywords:  HAART; HIV-infection; glucose; immunological non-responHIV-infection; immunological non-responders; metabolism
    DOI:  https://doi.org/10.2174/011570162X361238250421120542
  17. Res Sq. 2025 Apr 18. pii: rs.3.rs-6436164. [Epub ahead of print]
    A genome-wide CRISPR screen identifies GRA38 as a key regulator of lipid homeostasis during Toxoplasma gondii adaptation to lipid-rich conditions.
    Mebratu A Bitew, Tatiana C Paredes-Santos, Parag Maru, Shruthi Krishnamurthy, Yifan Wang, Lamba O Sangaré, Samuel Duley, Yoshiki Yamaryo-Botté, Cyrille Botte, Jeroen P J Saeij.
      Intracellular parasites like Toxoplasma gondii scavenge host nutrients, particularly lipids, to support their growth and survival. Although Toxoplasma is known to adjust its metabolism based on nutrient availability, the mechanisms that mediate lipid sensing and metabolic adaptation remain poorly understood. Here, we performed a genome-wide CRISPR screen under lipid-rich (10% Fetal Bovine Serum (FBS)) and lipid-limited (1% FBS) conditions to identify genes critical for lipid-responsive fitness. We identified the Toxoplasma protein GRA38 as a lipid-dependent regulator of parasite fitness. GRA38 exhibits phosphatidic acid (PA) phosphatase (PAP) activity in vitro, which is significantly reduced by mutation of its conserved DxDxT/V catalytic motif. Disruption of GRA38 led to the accumulation of PA species and widespread alterations in lipid composition, consistent with impaired PAP activity. These lipid imbalances correlated with reduced parasite virulence in mice. Our findings identify GRA38 as a metabolic regulator important for maintaining lipid homeostasis and pathogenesis in Toxoplasma gondii.
    Keywords:  CRISPR screen; GRA38; Toxoplasma gondii; host-parasite metabolic interactions; lipidomics; metabolic adaptation; phosphatidic acid phosphatase
    DOI:  https://doi.org/10.21203/rs.3.rs-6436164/v1
  18. medRxiv. 2025 Apr 17. pii: 2025.04.16.25325949. [Epub ahead of print]
    Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection.
    Silvia Lucena Lage, Katherine Bricker-Holt, Joseph M Rocco, Adam Rupert, Frank X Donovan, Yevgeniya A Abramzon, Settara C Chandrasekharappa, Colton McNinch, Logan Cook, Eduardo Pinheiro Amaral, Gabriel Rosenfeld, Thomas Dalhuisen, Avery Eun, Rebecca Hoh, Emily Fehrman, Jeffrey N Martin, Steven G Deeks, Timothy J Henrich, Michael J Peluso, Irini Sereti.
      SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood. In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58). Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC. Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.
    Keywords:  COVID-19; Long COVID; immunosenescence; inflammation; metabolism; post-acute sequelae of SARS-CoV-2
    DOI:  https://doi.org/10.1101/2025.04.16.25325949
  19. Sci Rep. 2025 May 06. 15(1): 15771
    A preliminary study of serum metabolomic profiling in male patients with acute brucellosis.
    Shenglian Niu, Qiang Li, Jianling Wang, Jiquan Li, Yanmei Zhao, Hongmei Xue, Li Ma, Zhijun Zhao, Qingwen Zhang.
      Brucellosis is a significant zoonotic disease that may lead to metabolic profile changes, which remain insufficiently studied. This study utilized an ultra-high performance liquid chromatography coupled with Q Exactive-Orbitrap mass spectrometry (UHPLC-QExactive-Orbitrap MS/MS) to investigate serum samples of acute brucellosis in 32 male patients against 32 well-matched healthy controls. The results revealed nine differential metabolites that correlated with human acute brucellosis, all showing increased levels, except cis-4-hydroxy-D-proline, inosine, hypoxanthine and azelaic acid. These differential metabolites were predominantly involved in metabolic pathways, such as primary bile acid biosynthesis, purine metabolism, taurine and hypotaurine metabolism, and d-amino acid metabolism. This study identified potential metabolite biomarkers of acute brucellosis and laid the foundation for its early diagnosis and prognostic assessment, thus helping to prevent the chronicity of acute brucellosis.
    Keywords:  Brucellosis; Metabolites; Qinghai Province; Serum metabolomics
    DOI:  https://doi.org/10.1038/s41598-025-00661-8
  20. J Inflamm Res. 2025 ;18 5699-5713
    4-Octyl Itaconate Modulates Dendritic Cells Function and Tumor Immunity via NRF2 Activation.
    Bo Zhu, Lihua Zhu, Zongxia Ge, Songhang Zheng, Xiaoqiu Dai, Dingqi Feng, Lu Tan, Pengfei Sha, Yizheng Yao.
       Objective: Dendritic cells (DCs) play a pivotal role in orchestrating anti-tumor immune responses. However, various factors can suppress DCs function and compromise anti-tumor immunity. Itaconate, a metabolite activated during inflammation and infection, has been identified to possess immunomodulatory properties, but its role on DCs remains largely unexplored. In this study, we aimed to investigate the role of itaconate in regulating the maturation and function of DCs and its underlying molecular mechanism.
    Methods: Bone marrow-derived dendritic cells (BMDCs) were treated with 4-octyl itaconate (4OI). The expression levels of CD40, CD80, CD86, and MHC-II on BMDCs were analyzed by flow cytometry. The mRNA expression of cytokines was assessed using RT-qPCR. BMDCs with different treatment were adoptively transferred to B16-OVA tumor-bearing mice. The production of IFN-γ, IL-2, and TNF-α in CD4+ T and CD8+ T cells were analyzed by flow cytometry. The protein level of NRF2 in BMDCs was analyzed by Western blot.
    Results: Treatment with 4OI represses DC maturation and function. Specifically, 4OI-treated DCs exhibited impaired phenotypic and functional maturation, characterized by decreased expression of co-stimulatory molecules CD40, CD80, and CD86, as well as lower levels of pro-inflammatory cytokines IL-12, IL-6, TNF-α and IL-1β. Furthermore, these DCs demonstrated a diminished capacity to stimulate T cell responses both in vitro and in vivo. Mechanistically, 4OI inhibits DCs maturation and function through enhancing and activating KEAP1/NRF2 pathway.
    Conclusion: This study reveals that 4OI inhibits DC function through NRF2 activation, elucidating the immunomodulatory mechanisms of itaconate and emphasizing its pivotal role in developing targeted DC-based tumor immunotherapy strategies.
    Keywords:  4-octyl itaconate; dendritic cells; immune response; tumor immunotherapy
    DOI:  https://doi.org/10.2147/JIR.S516085
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