bims-traimu Biomed News
on Trained immunity
Issue of 2026–03–29
twenty-one papers selected by
Yantong Wan, Southern Medical University
  1. How to Employ Trained Immunity and Trained Immunity-Based Vaccines to Inhibit Allergic Inflammation.
  2. Bibliometric and Visual Analysis of Trained Immunity from 2005 to 2024.
  3. Trained Immunity in Autoimmunity: Friend, Foe, or Therapeutic Target?
  4. Acsl1-Mediated Fatty Acid Synthesis Impairs Osseointegration in Type 1 Diabetes.
  5. Retraction Note: Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer.
  6. Trained Memory of Uterine Macrophages Improves Subsequent Pregnancy Outcomes.
  7. Post-acute sequelae of COVID-19: A disorder of impaired innate immune resolution - A narrative review.
  8. Epigenetic Mechanisms in Early Life Viral Respiratory Infections.
  9. Lactic Acid Bacteria with Probiotic Potential Regulating Macrophages: Mechanisms, Regulatory Features, and Clinical Applications.
  10. p16High-expressing immune cells control disease tolerance as a defense and health span-extending strategy.
  11. Lactylation of histone H3K18 promotes autophagic gene expression to mitigate immunosuppression in sepsis.
  12. RUNX2 and USP16 stabilize MFRN2 to maintain pulmonary epithelial barrier integrity in sepsis-induced acute lung injury.
  13. IL-4 treatment induces apoptosis of blood monocytes and proliferation of recruited injury-associated macrophages to resolve liver injury.
  14. Pathologic Th1-Treg Cells Exacerbate Acute Lung Injury and Lethality in Sepsis.
  15. T cell memory affects lung responses to cecal ligation and puncture.
  16. Epigenetic memory of colitis promotes tumour growth.
  17. Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
  18. Host Prior Exposure Augments Gene Expression Heterogeneity of Both Host and Pathogen During In Vivo Infection.
  19. Deubiquitinating enzyme MINDY2 regulates TNF-α-induced cell death by targeting RIPK1.
  20. Autoinhibitory control of MLKL governs pseudokinase domain phosphorylation and oligomerization during necroptosis.
  21. Adaptor protein supersaturation drives innate immune signaling and cell fate.
  1. Vaccines (Basel). 2026 Mar 16. pii: 268. [Epub ahead of print]14(3):
    How to Employ Trained Immunity and Trained Immunity-Based Vaccines to Inhibit Allergic Inflammation.
    Wonho Kim, Dooil Jeoung.
      Trained immunity confers protection against subsequent unrelated infections through metabolic and epigenetic reprogramming. Unlike adaptive immunity, trained innate immunity provides broad, non-specific protection against diverse heterologous pathogens. In addition to potentiating inflammatory responses upon secondary challenge, trained innate immune cells can also acquire anti-inflammatory and tolerogenic phenotypes, a property with important implications for chronic inflammatory diseases such as allergic disorders. Trained immunity-based vaccines (TIbVs) have emerged as promising immunomodulatory strategies capable of attenuating allergic inflammation by inducing immune tolerance. Similarly, allergen-specific immunotherapy (AIT) promotes long-term tolerance to allergens through metabolic and epigenetic reprogramming of innate immune cells. AIT drives the differentiation of monocytes into tolerogenic dendritic cells, thereby reshaping downstream adaptive immune responses. This review summarizes the current understanding of trained immunity and its role in protection against the same and heterologous infections. We discuss the molecular mechanisms underlying trained immunity, with an emphasis on metabolic and epigenetic reprogramming. Furthermore, we highlight the therapeutic potential of TIbVs and AIT as next-generation vaccines for allergic diseases. A deeper understanding of AIT-induced immune tolerance, the identification of predictive biomarkers, and the optimization of delivery platforms-such as lipid nanoparticle-based systems-will be critical for improving the safety and efficacy of future anti-allergy vaccines.
    Keywords:  allergen specific immunotherapy; immune tolerance; innate cells; trained immunity; trained immunity-based vaccines
    DOI:  https://doi.org/10.3390/vaccines14030268
  2. J Inflamm Res. 2026 ;19 561807
    Bibliometric and Visual Analysis of Trained Immunity from 2005 to 2024.
    Zhengang Yang, Jingxia Hu, Li Kang, Hao He.
       Purpose: Trained immunity refers to the long-term functional adaptation of innate immune responses following an initial stimulus, representing a conceptual expansion of immune memory beyond adaptive immunity. Given the rapid expansion of this field, this study aimed to systematically map the research landscape of trained immunity and to identify major research hotspots and emerging frontiers using bibliometric approaches.
    Methods: Publications related to trained immunity published between 2005 and 2024 were retrieved from the Web of Science Core Collection (WoSCC). Bibliometric and visualization analyses were performed using CiteSpace, VOSviewer, and Bibliometrix to evaluate publication trends, collaboration patterns, and thematic evolution.
    Results: A total of 1,526 publications were included. Bibliometric indicators demonstrate a marked acceleration in research output following the formal conceptualization of trained immunity. The United States, the Netherlands, and Germany emerged as leading contributors, with Radboud University Nijmegen and the University of Bonn identified as central institutional hubs. Thematic and keyword-based analyses revealed that research hotspots have evolved along three interconnected dimensions: an expansion of cellular targets from classical myeloid cells to hematopoietic stem and progenitor cells and selected non-immune cells; sustained focus on epigenetic and metabolic reprogramming as core mechanistic axes; and a growing body of literature linking trained immunity to infectious diseases, chronic inflammation, and cancer-related applications.
    Conclusion: By integrating multiple bibliometric indicators, this study delineates the developmental trajectory and thematic structure of trained immunity research. The findings provide an updated overview of the field and highlight evolving research priorities, offering a reference framework for future investigations into innate immune memory and its translational potential.
    Keywords:  VOSviewer; bibliometric analysis; citespace; trained immunity
    DOI:  https://doi.org/10.2147/JIR.S561807
  3. Biomedicines. 2026 Feb 26. pii: 526. [Epub ahead of print]14(3):
    Trained Immunity in Autoimmunity: Friend, Foe, or Therapeutic Target?
    Hugo Abreu, Davide Raineri, Annalisa Chiocchetti, Giuseppe Cappellano.
      For decades, immunology has followed a clear paradigm: immunological memory resides only within the adaptive immunity, as a unique property of lymphocytes giving the host the ability to recognize specific antigens and offer long-term protection. However, this raises an important question: how valid is this belief in light of new evidence? The discovery of trained immunity shows that innate immune cells can also develop lasting functional changes. This finding prompts a profound reconsideration of the traditional framework. Trained immunity is a functional reprogramming of the innate immune cells driven by long-term epigenetic and metabolic reprogramming, resulting in enhanced responses upon subsequent exposure to the same pathogen or even to unrelated stimuli. The presence of pattern recognition receptors (PRRs) on innate immune cells already suggested a certain level of specificity in this compartment thanks to the engagement of a PRR by a pathogen-associated molecular pattern (PAMP) inducing memory-like properties in the responding cell. While such partial specificity can enhance protection, it may also amplify aberrant inflammatory circuits, thereby contributing to the initiation or worsening of autoimmune and chronic inflammatory diseases. This dual nature of trained immunity raises important questions for the field: is trained immunity ultimately harmful or beneficial in autoimmunity, and can its mechanisms be harnessed therapeutically rather than pathologically? The present Perspective will address these issues by examining recent findings that reveal the specificity, pathogenic potential, and translational opportunities in given examples of autoimmune diseases (ADs).
    Keywords:  autoimmune diseases; immunological memory; innate immune system; trained immunity
    DOI:  https://doi.org/10.3390/biomedicines14030526
  4. J Dent Res. 2026 Mar 28. 220345261430286
    Acsl1-Mediated Fatty Acid Synthesis Impairs Osseointegration in Type 1 Diabetes.
    X H Zheng, X Y Zhu, X Chen, Q Q He, Q M Zhai, T Chen.
      Diabetes mellitus is considered a relative contraindication to oral implant therapy, as hyperglycemia frequently precipitates vascular and osseous pathologies. Although clinicians routinely prioritize glycemic control before initiating implant-related treatment plans, diabetic patients often exhibit impaired osseointegration. However, the specific mechanisms remain to be elucidated. Emerging evidence suggests that this refractory bone loss is mediated by trained immunity, a process in which innate immune cells retain an epigenetic memory of prior inflammatory stimuli and mount an exaggerated response upon secondary challenge such as the invasive implantation process or inflammatory insult. Here, integrating RNA-seq, metabolomics, and transposase-accessible chromatin using sequencing analyses, we demonstrate that stringent glycemic control in type 1 diabetes fails to normalize the fatty acid biosynthetic process, which remains persistently activated and potentiates macrophage-mediated inflammation and osteoclastogenesis when experiencing the secondary stimuli. Mechanistically, prior hyperglycemic exposure enhances chromatin accessibility while sustaining Acsl1 transcription by H3K4me1 epigenetic modification at the Acsl1 locus in macrophages. This epigenetic imprint augments fatty acid anabolism, amplifies proinflammatory cytokine production, and accelerates osteoclastic differentiation, ultimately compromising osseous repair. Collectively, our findings reveal that diabetes-induced H3K4me1 modification at Acsl1 drives metabolic reprogramming underpinning trained immunity and consequent bone damage. Targeting H3K4me1 or Acsl1 therefore represents a promising therapeutic strategy to improve implant osseointegration and skeletal regeneration in diabetic patients.
    Keywords:  epigenetic memory; immunity; implant dentistry/implantology; inflammation; metabolic reprogramming; osteoclast(s)
    DOI:  https://doi.org/10.1177/00220345261430286
  5. Nat Commun. 2026 Mar 23. pii: 2707. [Epub ahead of print]17(1):
    Retraction Note: Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer.
    Alok Kumar Singh, Monali Praharaj, Kara A Lombardo, Takahiro Yoshida, Andres Matoso, Alex S Baras, Liang Zhao, Geetha Srikrishna, Joy Huang, Pankaj Prasad, Jonathan D Powell, Max Kates, David McConkey, Drew M Pardoll, William R Bishai, Trinity J Bivalacqua.
      
    DOI:  https://doi.org/10.1038/s41467-026-70972-5
  6. Adv Sci (Weinh). 2026 Mar 28. e74889
    Trained Memory of Uterine Macrophages Improves Subsequent Pregnancy Outcomes.
    Jing Wang, Ning Lu, Xin-Xiu Lin, Xu-Hui Fang, Yi-Hui Li, Qing-Peng Luo, Yu-Ting Peng, Gil Mor, Ai-Hua Liao.
      A previously successful pregnancy promotes the fitness of subsequent pregnancies, of which the pregnancy-induced memory is ascribed exclusively to adaptive lymphocytes. However, whether macrophages at maternal-fetal interface acquire pregnancy-specific immune memory remains unclear. Using human decidual samples and complementary mouse models, we identify human leukocyte immunoglobulin-like receptor subfamily B3+ (LILRB3+) and murine paired immunoglobulin-like receptor B+ (PIR-B+) macrophages as a uterine memory subset, which expands progressively with gravidity and gestational age, and exhibits paternal specific immune memory. In both species, these cells exhibited hallmarks of pregnancy-induced trained tolerance, including elevated IL-10, TGF-β, and CD206, together with reduced CD80/CD86 expression and suppression of pro-inflammatory cytokines. Mechanistically, PIR-B-SHP signaling drives macrophage metabolic reprogramming to oxidative phosphorylation/fatty acid oxidation for the formation of memory. Moreover, adoptive transfer of PIR-B+ uterine macrophages into abortion-prone mouse models significantly improves pregnancy outcomes, highlighting their therapeutic potential. Together, our findings uncover a previously unrecognized form of decidual macrophage trained memory in an antigen-specific manner, which opens avenues for therapeutic strategies aimed at preventing or reducing recurrent pregnancy loss.
    Keywords:  decidual macrophages; innate immune memory; leukocyte immunoglobulin‐like receptor subfamily B; maternal‐fetal interface; paired immunoglobulin‐like receptor B
    DOI:  https://doi.org/10.1002/advs.74889
  7. Clin Immunol. 2026 Mar 19. pii: S1521-6616(26)00039-2. [Epub ahead of print]285 110701
    Post-acute sequelae of COVID-19: A disorder of impaired innate immune resolution - A narrative review.
    Mahd Rauf, Ahsan Naveed, Muhammad Umer Asghar.
      Post-acute sequelae of COVID-19 (PASC) affect millions of people worldwide and are increasingly recognized as a disorder of failed innate immune resolution rather than a persistent viral infection. Emerging evidence shows that residual SARS-CoV-2 antigens, host-derived alarmins, reactivated latent viruses, and mucosal microbiome-derived products from oral-nasopharyngeal and gut reservoirs sustain the chronic activation of pattern-recognition receptors, inflammasomes, and complement pathways. In parallel, deficits in specialized pro-resolving mediators, impaired efferocytosis, and persistent tissue injury prevent physiological termination of inflammation. These unresolved cues drive long-lasting epigenetic and metabolic reprogramming of hematopoietic stem cells and myeloid lineages, creating maladaptive trained immunity states characterized by hyper-responsiveness or exhaustion of these cells. Thromboinflammatory processes, including aberrant NETosis and sustained interface signalingling, further reinforce self-perpetuating inflammatory circuits. Together, these pathways give rise to reproducible molecular endotypes, including thromboinflammatory, interferon-driven, and neuroinflammatory phenotypes, which explain clinical heterogeneity. Framing PASC as a disorder of impaired immune resolution within a mucosal microbial viral context provides a unifying mechanistic scaffold for biomarker identification and host-directed therapies. This review proposes that restoring active resolution programs, rebalancing metabolic-epigenetic networks, and dismantling pathogenic innate feedback loops are promising strategies for reversing the chronic immune imprint of PASC.
    Keywords:  Innate immunity; Long COVID; PASC; Post-acute sequelae of COVID-19; SARS-CoV-2; Trained immunity
    DOI:  https://doi.org/10.1016/j.clim.2026.110701
  8. Viruses. 2026 Mar 12. pii: 345. [Epub ahead of print]18(3):
    Epigenetic Mechanisms in Early Life Viral Respiratory Infections.
    Juliana Poppe, Katarzyna Placek, Ana Paula Duarte de Souza.
      Early-life respiratory viral infections represent a major global health burden and are key determinants of long-term susceptibility to chronic respiratory diseases. In neonates the immaturity of the immune system contributes to the high incidence and severity of these infections. Because humans are born with a mainly naive adaptive immune system, the host protection in early life greatly relies on the innate immune cells. Interestingly, innate immune cells have been recently shown to develop traits of immune memory. Both adaptive and innate immune memory formation are, among others, mediated by epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs. This review comprehensively analyzes evidence of the changes in epigenetic modifications before and after respiratory infection in childhood. Understanding how epigenetic programming modulates immune cells in early life may open new avenues for preventive interventions to respiratory viral infection, enhancing antiviral defense in infancy and reducing the long-term consequences of respiratory infections.
    Keywords:  early life; epigenetic; respiratory virus
    DOI:  https://doi.org/10.3390/v18030345
  9. Probiotics Antimicrob Proteins. 2026 Mar 23.
    Lactic Acid Bacteria with Probiotic Potential Regulating Macrophages: Mechanisms, Regulatory Features, and Clinical Applications.
    Zibo Mai, Bosen Wang, Qijun Hu, Zheng Jia, Jiaqing Wang, Boyu Liu, Junwei Ge.
      The significance of the intestinal microbiota in overall health has gained increasing recognition. Probiotic supplementation promotes intestinal microbial homeostasis. As a key component of probiotics, lactic acid bacteria (LAB) are widely utilized in the prevention and management of various diseases owing to their well-established safety profile and remarkable immunomodulatory properties. Their regulatory effect on myeloid cells, particularly macrophages, is critically important. This article systematically reviews the substantial impacts of LAB on macrophages, including effects on macrophage quantity, polarization, autophagy, apoptosis, metabolism, trained immunity, and so on, which contribute to the control of disease progression. The regulation of macrophages by LAB exhibits characteristics such as strain-specificity, dose dependence, and correlation with administration routes, and may mediate systemic effects via the gut-X axis. Furthermore, LAB have demonstrated therapeutic potential in treating macrophage-associated diseases, such as obesity and impaired wound healing. Finally, this review discusses development suggestions for the combined application of LAB and future development directions in this field, including screening and combined application of strains, exploring and utilizing the mechanism of transgenerational effect, aiming to enhance the application of LAB in antibiotic therapy and the development of human and animal health industries.
    Keywords:  Lactic acid bacteria; Macrophage; Mechanism; Regulation; Strain-specificity; Trained immunity
    DOI:  https://doi.org/10.1007/s12602-026-10979-y
  10. Immunity. 2026 Mar 26. pii: S1074-7613(26)00083-X. [Epub ahead of print]
    p16High-expressing immune cells control disease tolerance as a defense and health span-extending strategy.
    Francisco Triana-Martinez, Alessandra Pierantoni, Daisy Graca, Veronica Bergo, Alexander Emelyanov, Alexandre Gallerand, Laurent Grosse, Bogdan B Grigorash, Aikaterini Polyzou, Alexia Castiglione, Shunya Tsuji, Sosuke Nakano, Vesna Brglez, Zakariya Caillot, Pierre Marty, Jean Dellamonica, Stoyan Ivanov, Eiji Hara, Eirini Trompouki, Barbara Seitz-Polski, Dmitry V Bulavin.
      Host survival during infection has traditionally been attributed to pathogen clearance, yet increasing evidence supports a complementary mechanism known as disease tolerance, which limits tissue damage without directly affecting pathogen burden. Here, we identify p16High immune cells as critical mediators of disease tolerance. We show that the FDA-approved BNT162b2 mRNA COVID-19 vaccine rapidly induces p16High immune subsets in mice and humans. These cells are required for protection against lipopolysaccharide-induced endotoxin shock, bacterial sepsis, and ionizing irradiation. Mechanistically, Toll-like receptor 7 (TLR7) activation or low-level STING signaling promotes p16High immune cell induction, reduces adenosine accumulation in part through nicotinamide N-methyltransferase (NNMT)-dependent regulation, and preserves tissue homeostasis. Furthermore, genetic deletion of Ifih1 enhances tonic STING activation and expands p16High immune subsets, improving resilience to severe inflammation and delaying age-related organ deterioration. Our data highlight the beneficial role of the BNT162b2 mRNA COVID-19 vaccine and Ifih1attenuation in inducing disease tolerance through protective p16High immune subsets.
    Keywords:  BNT162b2 mRNA COVID-19 vaccine; Mda5; NNMT; STING; TLR7; adenosine; disease tolerance; healthspan; p16high immune cells
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.013
  11. Int J Biol Macromol. 2026 Mar 25. pii: S0141-8130(26)01593-X. [Epub ahead of print] 151667
    Lactylation of histone H3K18 promotes autophagic gene expression to mitigate immunosuppression in sepsis.
    Ting Yang, Sijia Liu, Qingsong Jiang, Ning Wang, Liang Zhang, Xinhui Shi, Hongmei Qiu, Yongling Lu, Wen Jun Li, Chong Ni, Junxia Yang, Jiang Zheng, Hong Zhou, Xiaoli Li, Xin Liu.
      Sepsis-induced immunosuppression is associated with both autophagy impairment and glycolytic dysfunction. However, it is unclear how metabolic dysfunction drives epigenetic reprogramming, thereby reducing autophagy in sepsis. Here, we demonstrate that glycolytic dysfunction and consequent lactate deficiency epigenetically silence autophagy by reducing histone H3 lysine 18 lactylation (H3K18la). Using LPS-tolerant macrophages and CLP-induced immunosuppressive murine models, we observed that reduced lactate levels and global lactylation correlated with impaired autophagic flux and diminished bacterial clearance, with H3K18la emerging as the most consistently downregulated histone lactylation mark. Mechanistically, CUT&Tag-seq revealed ATG5 and ATG16L1 as direct transcriptional targets of H3K18la. Moreover, lactate supplementation restored H3K18la deposition, upregulated ATG5/ATG16L1 expression, and rescued autophagy and bactericidal function. Then a lactylation-deficient H3K18R mutation abolished lactate-mediated rescue, while overexpression of ATG5/ATG16L1 restored autophagy even under H3K18la-deficient conditions. Overall, these findings implicate H3K18la as a metabolic-epigenetic checkpoint linking glycolysis to autophagy gene expression, providing a mechanistic framework for understanding how metabolic dysfunction may contribute to immunosuppression in sepsis.
    Keywords:  Autophagy; H3K18la; Immunosuppression; Macrophages; Sepsis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151667
  12. Cell Rep. 2026 Mar 26. pii: S2211-1247(26)00262-7. [Epub ahead of print]45(4): 117184
    RUNX2 and USP16 stabilize MFRN2 to maintain pulmonary epithelial barrier integrity in sepsis-induced acute lung injury.
    Wei Lai, Wanli Jiang.
      Sepsis is a life-threatening condition characterized by high morbidity and mortality, with acute lung injury (ALI) being one of its most common and severe complications. However, the precise molecular mechanisms underlying ALI remain unclear. Here, we identify RUNX2 as a critical mediator of epithelial injury in sepsis-induced ALI, independent of macrophage activation. Mechanistically, lipopolysaccharide (LPS) stimulation enhances the binding of RUNX2 to the USP16 promoter, thereby transcriptionally activating USP16 expression. This activation reduces K27-linked ubiquitin chains on mitoferrin-2 (MFRN2) at lysine 97, leading to mitochondrial iron dyshomeostasis and promoting epithelial ferroptosis. Moreover, aryl hydrocarbon receptor (AHR) interacts with RUNX2 to suppress its activation, thereby attenuating epithelial apoptosis. Collectively, our study uncovers a previously unrecognized mechanism by which LPS triggers epithelial cell death in ALI and suggests that targeting RUNX2 transcriptional activation may enhance epithelial resistance to injury induced by sepsis.
    Keywords:  CP: immunology; CP: molecular biology; MFRN2; RUNX2; USP16; acute lung injury; deubiquitination; ferroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117184
  13. Cell Rep. 2026 Mar 20. pii: S2211-1247(26)00214-7. [Epub ahead of print]45(4): 117136
    IL-4 treatment induces apoptosis of blood monocytes and proliferation of recruited injury-associated macrophages to resolve liver injury.
    Ruairi W Lynch, Pieter A Louwe, Liesbet Martens, Maria Elena Candela, Calum C Bain, Catherine Hawley, Neil C Henderson, Prakash Ramachandran, Cécile Bénézech, Charlotte L Scott, Martin Guilliams, Yvan Saeys, Stuart J Forbes, Judith E Allen, Stephen J Jenkins.
      IL-4 can have significant therapeutic benefit in many injury settings, but its mechanism of action is unclear. Using a model of carbon tetrachloride (CCl4)-mediated acute liver injury, we find that exogenous IL-4 causes a dramatic shift from recruited Ly6Chi monocytes to an abundance of monocyte-derived macrophages (MoMFs) within the injured tissue that is accompanied by reduced indices of hepatic damage and enhanced hepatic regeneration. Rather than altering the recruitment or differentiation of monocytes, treatment with IL-4 triggers monocyte apoptosis alongside proliferation of MoMFs. Single-cell RNA sequencing reveals injury and cell-type-specific responses to IL-4 treatment across hepatic myeloid lineages and a largely pro-reparative gene signature in the expanded pool of MoMFs. IL-4 treatment fails to enhance hepatic repair when the accrual of MoMFs is limited using Ccr2-deficient monocytopenic mice. Together, these data reveal a pathway through which therapeutic IL-4 alters the composition, number, and function of injury-associated myeloid cells to resolve liver injury.
    Keywords:  CP: immunology; IL-4; apoptosis; liver; macrophage; monocyte; proliferation; regeneration; repair
    DOI:  https://doi.org/10.1016/j.celrep.2026.117136
  14. Cells. 2026 Mar 14. pii: 521. [Epub ahead of print]15(6):
    Pathologic Th1-Treg Cells Exacerbate Acute Lung Injury and Lethality in Sepsis.
    Takuya Murao, Atsushi Murao, Monowar Aziz, Ping Wang.
      Sepsis is characterized by dysregulated immune responses induced by damage-associated molecular patterns, such as extracellular cold-inducible RNA-binding protein (eCIRP), that frequently lead to acute lung injury (ALI) and high mortality. Recently, a subset of CD4+ T cells possessing both T helper 1 (Th1) and regulatory T cell (Treg) phenotypes, termed Th1-Treg cells, has been identified; however, their function in sepsis remains unknown. In this study, we investigated the dynamics, induction mechanisms, and functional roles of Th1-Treg cells in the development of sepsis-induced ALI. Polymicrobial sepsis was induced in mice using cecal ligation and puncture. In vivo, Th1-Treg cell accumulation in the lungs was analyzed in WT and CIRP-/- mice following sepsis. In vitro, isolated CD4+ T cells from WT and TLR4-/- mice were treated with eCIRP to evaluate Th1-Treg cell differentiation and downstream signaling pathways. STAT1 and STAT5 activation were evaluated, and pharmacological inhibitors were used to assess their involvement. Adoptive transfer of Th1-Treg cells was conducted to determine their functional impact on ALI and mortality in septic mice. We observed a significant accumulation of Th1-Treg cells in the lungs of WT septic mice compared to sham mice. eCIRP drove the induction of Th1-Treg cells in vitro, and CIRP-/- mice exhibited decreased Th1-Treg cell accumulation in the lungs compared to WT mice after sepsis. In parallel to Th1-Treg cell induction, eCIRP activated signal transducer and activator of transcription, STAT1 and STAT5. Both the induction of Th1-Treg cells and the activation of STAT1/5 proteins were significantly attenuated in TLR4-/- mice. Furthermore, pharmacological inhibition of STAT1/5 signaling significantly reduced eCIRP-induced Th1-Treg cell differentiation. Intriguingly, adoptive transfer of Th1-Treg cells significantly exacerbated ALI, resulting in increased mortality in sepsis. Our findings indicate Th1-Treg cells induced by the eCIRP-TLR4-STAT1/5 axis aggravate ALI, worsening mortality in sepsis. Targeting these pathogenic cells potentially alleviates sepsis-induced ALI.
    Keywords:  ALI; STAT1; STAT5; TLR4; Th1-Treg cells; eCIRP; sepsis
    DOI:  https://doi.org/10.3390/cells15060521
  15. Shock. 2026 Mar 16.
    T cell memory affects lung responses to cecal ligation and puncture.
    Mariana R Brewer, Clifford S Deutschman, Matthew D Taylor.
      Murine sepsis models are limited by an inability to recapitulate several common features of human sepsis. One possible explanation is that laboratory mice lack the robust preexisting memory T cell repertoire that is a key feature of the human immune system. We therefore investigated how inducing T cell memory by treating C57BL6 mice with anti-CD3ε activating antibody ("Immune-Educated" mice) affected the pulmonary immune response to the cecal ligation and puncture (CLP)1 model of sepsis. Twenty-four hours after CLP, Immune-Educated mice had higher alveolar inflammatory cytokine and chemokine concentrations and more pulmonary interstitial macrophages than what was observed in untreated ("Uneducated") animals. After 72 hours, there were more alveolar macrophages in the lungs of Educated mice. In a separate experiment, we performed adoptive transfer of memory CD4 and CD8 T cells from immunized C57Bl/6J to B6.SJL mice. Interstitial macrophage recruitment 24 hours post-CLP was more pronounced in mice undergoing adoptive transfer of memory T cells compared to mice that did not undergo adoptive transfer. Finally, to evaluate whether observed differences in CLP-induced lung inflammation between Educated and Uneducated mice are driven by IFN we subjected Educated and Uneducated mice to IFN blockade at the time of CLP. IFN blockade resulted in higher absolute numbers of T cells, memory T cells, and innate cells in the lungs of Educated mice 24 hours post-CLP suggesting that IFN acts as an immune-regulator and curbs an overactive immune response in these mice. In conclusion, the presence of memory T cells affects the course of the lung immune response to CLP.
    Keywords:  immune memory; interferon gamma; lung inflammation; memory T cells; murine model of sepsis
    DOI:  https://doi.org/10.1097/SHK.0000000000002844
  16. Nature. 2026 Mar 25.
    Epigenetic memory of colitis promotes tumour growth.
    Surya Nagaraja, Lety Ojeda-Miron, Ruochi Zhang, Ena Oreskovic, Conrad Hock, Yan Hu, Daniel Zeve, Karina Sharma, Roni R Hyman, Qiming Zhang, Andrew Castillo, David T Breault, Ömer H Yilmaz, Jason D Buenrostro.
      Chronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear1,2. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for more than 100 days. Here we find that memory of colitis is characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity, with durable changes to chromatin accessibility. Further, we develop SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high-resolution tracking of epigenomic memory. This approach reveals that memory of colitis is propagated cell-intrinsically and inherited through stem cell divisions, with some clones demonstrating stronger memory than others. Finally, we show that colitis primes stem cells for increased expression of an AP-1-regulated gene program following oncogenic mutation that accelerates tumour growth, a phenotype dependent on AP-1 activity. Together, our findings provide a mechanistic link between chronic inflammation and malignancy, revealing how long-lived epigenetic alterations in regenerative tissues may contribute to disease susceptibility and suggesting potential diagnostic and therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions.
    DOI:  https://doi.org/10.1038/s41586-026-10258-4
  17. Science. 2026 Mar 26. 391(6792): eadz6830
    Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
    Christopher J Cowley, Sairaj M Sajjath, Luis F Soto-Ugaldi, Mara Steiger, Samantha B Larsen, Thomas Carroll, Douglas Barrows, Alexandra Mattei, Kevin A U Gonzales, Wei Wang, Kevin Li, Alexander Meissner, Helene Kretzmer, Dana Pe'er, Elaine Fuchs.
      Tissues harbor memories of inflammation, which heighten sensitivity to diverse future assaults. Whether and how these adaptations are sustained through time and cell division remain poorly understood. We show that in mice, epidermal stem cells store lifelong, functional epigenetic records of psoriasis-like skin flares. Applying deep learning to investigate these chromatin dynamics, we unearth CpG dinucleotide density as a major driver of memory persistence. Although unnecessary for inflammation-induced transcription factors to open and establish memories, CpG-enriched sequences thereafter become essential, reinforcing accessibility across cellular generations by integrating DNA demethylation, methylation-sensitive transcription factors, sequence-intrinsic nucleosome disaffinity, and the nucleosome-destabilizing histone variant H2A.Z. Thus, once activated by inflammation-induced transcription factors, DNA sequences orchestrate persistent poise, imparting long-lasting memory to stress-sensitive genes and profoundly affecting tissue fitness upon recall.
    DOI:  https://doi.org/10.1126/science.adz6830
  18. Mol Ecol. 2026 Mar;35(6): e70319
    Host Prior Exposure Augments Gene Expression Heterogeneity of Both Host and Pathogen During In Vivo Infection.
    Anna A Pérez-Umphrey, Jeremy Miller, Edan R Tulman, Jesse Garrett-Larsen, Michal Vinkler, Kate Langwig, Steven J Geary, James S Adelman, Dana M Hawley.
      Variability in acquired protection, whether from prior infection or vaccination, helps drive inter-individual level variation in disease traits. It remains unclear, however, whether this extends to the within-host regulatory environment and what the consequences are for reinfecting pathogens. Here, we asked whether prior pathogen exposure of hosts induces gene expression heterogeneity in host and/or pathogen during infection. We quantified gene expression in vivo following a high-dose challenge of house finches (Haemorhous mexicanus) previously given controlled, varied exposures to a bacterial pathogen (Mycoplasma gallisepticum). To measure gene expression heterogeneity, we collected transcriptomic data from two host tissues (conjunctiva and spleen), and simultaneously, from pathogen at the primary site of infection (conjunctiva). In conjunctiva, but not spleen, prior pathogen exposure induced significant heterogeneity in host gene expression relative to pathogen-naïve hosts, even when accounting for effects of sex. Hosts given a lower versus higher prior exposure dose showed the greatest within-group heterogeneity in expression during re-challenge. Functional enrichment analyses for significantly variable host genes indicated an over-representation of terms involved in the immune response among birds with prior exposure. Infecting pathogen from the conjunctiva followed similar heterogeneity patterns, with more heterogeneous expression among pathogens infecting previously exposed hosts than those infecting naïve hosts. While the mechanisms underlying these patterns remain unresolved, our results indicate that prior exposure induces a within-host environment that promotes heterogeneous gene expression across both hosts and pathogens. This suggests that gene expression variation in host and pathogen should be considered alongside sequence variation to understand the coevolutionary dynamics of infectious diseases.
    Keywords:  gene regulation; heterogeneity; host‐pathogen interactions; prior exposure
    DOI:  https://doi.org/10.1111/mec.70319
  19. Cell Rep. 2026 Mar 20. pii: S2211-1247(26)00212-3. [Epub ahead of print]45(4): 117134
    Deubiquitinating enzyme MINDY2 regulates TNF-α-induced cell death by targeting RIPK1.
    Wenyang Huang, Yushi Chen, Danni Chen, Yuanyuan Liu, Jiaqin Lu, Jianting Feng, Juan Lin, Lisheng Li.
      Ubiquitination plays a crucial role in the tumor necrosis factor (TNF)-α signaling pathway. To identify mechanisms by which ubiquitination regulates TNF-α signaling, we perform a screen using a gene expression library of ubiquitination-modifying enzymes. We find that the deubiquitinating enzyme MINDY2 inhibits TNF-α-induced cell death. MINDY2 modulates ubiquitination at the K612 site of RIPK1, which in turn attenuates RIPK1 recruitment by TNFR1, thereby influencing the complex 1 signaling pathway and RIPK1-dependent cell death. To investigate the in vivo function of MINDY2, we generate MINDY2-knockout mice. Compared to wild-type mice, MINDY2-deficient mice exhibit more severe hypothermia, mortality, and intestinal damage after TNF-α challenge. Collectively, our work reveals that MINDY2 is a checkpoint in RIPK1-dependent cell death, and that its deficiency exacerbates TNF-mediated tissue damage in vivo.
    Keywords:  CP: Immunology; MINDY2; RIPK1; TNF-α; necroptosis; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2026.117134
  20. Cell Rep. 2026 Mar 20. pii: S2211-1247(26)00208-1. [Epub ahead of print]45(4): 117130
    Autoinhibitory control of MLKL governs pseudokinase domain phosphorylation and oligomerization during necroptosis.
    Michelle J Pan, Derek W Abbott.
      Necroptotic cell death triggers the release of inflammatory mediators but the exact mechanisms controlling its activation are not fully understood. Previous studies have identified key steps during necroptosis, which are believed to be coupled: MLKL phosphorylation by RIPK3, release of N-terminal autoinhibition, and MLKL oligomerization. Yet, ectopic expression of phosphomimetic MLKL is insufficient to induce necroptosis in human cells. Here, we employ five different pharmacological, biological, and genetic methods to demonstrate that inhibiting the MLKL N terminus prevents both phosphorylation and oligomerization. Conversely, loss of interaction between the N-terminal four-helical bundle and brace domains demonstrates basal MLKL phosphorylation, even in the absence of necroptotic stimuli. Moreover, we show that MLKL phosphorylation is not necessary for maintaining MLKL oligomer stability. We propose that MLKL is released from autoinhibition prior to phosphorylation, explaining why phosphomimetic MLKL lacks cytotoxic activity.
    Keywords:  CP: immunology; MLKL; RIPK1; RIPK3; autoinhibition; cell death; cytotoxicity; kinase; necroptosis; oligomerization; pseudokinase
    DOI:  https://doi.org/10.1016/j.celrep.2026.117130
  21. Elife. 2026 Mar 24. pii: RP107962. [Epub ahead of print]14
    Adaptor protein supersaturation drives innate immune signaling and cell fate.
    Alejandro Rodriguez Gama, Tayla Miller, Shriram Venkatesan, Jeffrey J Lange, Jianzheng Wu, Xiaoqing Song, William D Bradford, Malcolm Cook, Jay R Unruh, Randal Halfmann.
      How minute pathogenic signals trigger decisive immune responses is a fundamental question in biology. Classical signaling often relies on ATP-driven enzymatic cascades, but innate immunity frequently employs death fold domain (DFD) self-assembly. The energetic basis of this assembly is unknown. Here, we show that specific DFDs function as energy reservoirs through metastable supersaturation. Characterizing all 109 human DFDs, we identified sequence-encoded nucleation barriers specifically in the central adaptors of inflammatory signalosomes, allowing them to accumulate far above their saturation concentration while remaining soluble and poised for activation. We demonstrate that the inflammasome adaptor ASC is constitutively supersaturated in vivo, retaining energy that powers on-demand cell death. Swapping a non-supersaturable DFD in the apoptosome with a supersaturable one sensitized cells to sublethal stimuli. Mapping all DFD nucleating interactions revealed that supersaturated adaptors are triggered to polymerize specifically by other DFDs in their respective pathways, limiting potentially deleterious crosstalk. Across human cell types, adaptor supersaturation strongly correlates with cell turnover, implicating this thermodynamic principle in the trade-off between immunity and longevity. Profiling homologues from fish and sponge, we find nucleation barriers to be conserved across metazoa. These findings reveal DFD adaptors as biological phase change materials in thermal batteries to power cellular life-or-death decisions on demand.
    Keywords:  S. cerevisiae; immunology; inflammation; innate immunity; molecular biophysics; nucleation barrier; programmed cell death; signalosome; structural biology; supersaturation
    DOI:  https://doi.org/10.7554/eLife.107962
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