bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–04–05
twenty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Lipids drive autoinflammation.
  2. Newly found macrophages stand guard inside blood vessels.
  3. A splicing factor's unexpected detour to the mitochondrial surface.
  4. Subcellular orchestration of microglial aging.
  5. Krüppel-like factors 2 and 3 regulate T cell exhaustion by directing T cell residency and migration.
  6. Mitochondrial genomes on a string of pearls.
  7. An atlas to navigate environmental factors and health.
  8. Solving the puzzle of CD8 T cell positive selection.
  9. High-fat diet causes rapid loss of intestinal group 3 innate lymphoid cells through microbiota-driven inflammation and mitochondrial stress.
  10. Neuron-eosinophil circuit explains stress-induced eczema flares.
  11. Inhibition of adipocyte RUNX1/2 enhances adipose tissue thermogenesis through distinct mechanisms.
  12. Copper supports regulatory T cell energetic state to sustain peripheral immune tolerance.
  13. Foxp3 and BATF cooperatively direct cis-regulatory programs and gene expression for effector Treg cell differentiation.
  14. Neuroimmune interferon signals sustain arthritis pain.
  15. The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents diet-induced steatohepatitis and fibrosis in mice.
  16. GLP-1 receptor agonist fails to halt Alzheimer's disease.
  17. Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
  18. Adult patients with autoinflammation of unknown origin partially phenocopy the immune presentation of Still's disease.
  19. Homoharringtonine exhibits senotherapeutic activity that mitigates diet- and age-associated obesity and insulin resistance and extends lifespan in mice.
  20. Obesity Disrupts H3K4me3-Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages.
  21. Agonistic anti-CD40 antibody treatment converts resident regulatory T cells into activated type 1 effectors within the tumor microenvironment.
  22. Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF.
  23. Genome-wide fine-mapping improves identification of causal variants.
  24. Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
  25. Are boys really in crisis? What the science says in the age of the manosphere.
  26. Intake of Fiber From Different Food Sources and Type 2 Diabetes Risk: An Integrated Analysis of Epidemiological and Multiomic Data.
  1. Nat Immunol. 2026 Apr;27(4): 639
    Lipids drive autoinflammation.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-026-02498-3
  2. Nat Immunol. 2026 Apr 03.
    Newly found macrophages stand guard inside blood vessels.
      
    DOI:  https://doi.org/10.1038/s41590-026-02503-9
  3. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00167-X. [Epub ahead of print]86(7): 1195-1196
    A splicing factor's unexpected detour to the mitochondrial surface.
    Ana-Maria Raicu, L Stirling Churchman.
      In this issue of Molecular Cell, Garcia et al.1 reveal an unexpected role for the splicing factor U2AF in repressing translation and influencing the localization of nuclear-encoded mitochondrial mRNAs to the outer mitochondrial membrane.
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.011
  4. Nat Aging. 2026 Mar 31.
    Subcellular orchestration of microglial aging.
    Philipp Schaible, Daniel Erny.
      
    DOI:  https://doi.org/10.1038/s43587-026-01109-y
  5. Immunity. 2026 Mar 27. pii: S1074-7613(26)00091-9. [Epub ahead of print]
    Krüppel-like factors 2 and 3 regulate T cell exhaustion by directing T cell residency and migration.
    Jian Shen, Ryan J Brown, Yuqi Zhang, Kexin Gai, Ashley K Brown, Ashley M Bauer, Ashley Zhu, Siying Lin, Hongshen Niu, Arjun Kharel, Ziyang Xu, Gregory S Cohen, Taylor A Depauw, Eric Fagerberg, Geoffrey S Kansas, Nikhil S Joshi, Stephen C Jameson, Weiguo Cui.
      During chronic viral infection, CD8+ progenitor exhausted T (Tpro) cells give rise to either cytotoxic effector-like exhausted T (Teff) cells that are migratory or terminally exhausted T cells (Texh) that reside in the tissue parenchyma. Here, we explored how cellular localization influences exhausted T cell fate. We found that Krüppel-like factor 2 (KLF2) promoted the expression and chromatin accessibility of migratory genes, whereas its counterpart, KLF3, limited these programs and promoted tissue residency. Forcing CD8+ T cells out of the tissue environment biased differentiation from the Texh toward the Teff cell trajectory, suggesting that cellular localization can actively influence cell-fate decisions. Mechanistically, KLF2 induced KLF3, which, in turn, constrained Klf2 transcription and competed for shared chromatin-binding sites. In summary, KLF2 and KLF3 form a reciprocal regulatory circuit that governs CD8+ T cell migration and exhaustion during chronic viral infection.
    Keywords:  KLF2; KLF3; T cell differentiation; T cell exhaustion; T cell migration; chromatin accessibility; chronic viral infection; sphingosine-1-phosphate signaling; tissue residency; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.021
  6. Science. 2026 Apr 02. 392(6793): 26-28
    Mitochondrial genomes on a string of pearls.
    Jelle van den Ameele, Julien Prudent.
      Transient membrane constrictions, or "pearling," underlie the regular spacing of mitochondrial genomes.
    DOI:  https://doi.org/10.1126/science.aeg3426
  7. Nat Med. 2026 Mar 30.
    An atlas to navigate environmental factors and health.
      
    DOI:  https://doi.org/10.1038/s41591-026-04286-w
  8. Nat Immunol. 2026 Apr;27(4): 652-653
    Solving the puzzle of CD8 T cell positive selection.
    Juan Carlos Zúñiga-Pflücker, Anton Dobrin.
      
    DOI:  https://doi.org/10.1038/s41590-026-02476-9
  9. Immunity. 2026 Mar 30. pii: S1074-7613(26)00084-1. [Epub ahead of print]
    High-fat diet causes rapid loss of intestinal group 3 innate lymphoid cells through microbiota-driven inflammation and mitochondrial stress.
    Eva C Torrico, Paulien Kaptein, Fatiha Laalouhmi, Vanessa Mitsialis, Sara El Guendouzi, Abdellatif El Khayari, Chaymae El Baha, Elly D Htite, Sophie Chawluk, Christian D Gauthier, Nadhir M Djekidel, Patrick Da Silva, Toby B Lanser, Ankur Gupta, Kisha Sivanathan, Marilia Garcia De Oliveira, Amir H Maghzi, Ali Tavakkoli, Mozhdeh Sojoodi, Motaz Qadan, Shirong Liu, Rafael M Rezende, Laura M Cox, Lloyd Bod, Alexandra Schnell, Anya Song, Isabelle Pierre, Pegah Jabbari-Lak, Veronika V Heil, Luisa S Lemos, Joshua Keegan, Jenny P Nguyen, Laura A Cahill, Rajesh Krishnan Kumar, Chantal Kuhn, Gaganvir Parmar, Gopal Murugaiyan, James A Lederer, Scott B Snapper, Roni Nowarski, Rachid El Fatimy, Howard L Weiner, Selma Boulenouar.
      Group 3 innate lymphoid cells (ILC3s) are key sensors of the intestinal environment, integrating dietary and microbial cues to maintain intestinal immunity. We found that intestinal ILC3s were reduced in overweight and obese humans and in high-fat diet (HFD)-fed mice. ILC3 loss occurred independently of caloric excess, weight gain, or glucose intolerance. Instead, impairment arose within hours of HFD consumption and was initiated by microbiota-driven intestinal barrier permeability and concomitant activation of inflammatory mononuclear phagocytes (MNPs). This response to inflammation impaired fatty acid oxidation in lipid-loaded ILC3s, resulting in mitochondrial damage and cell death. Intestinal ILC3 cell death was rescued by removal of excess fats from the diet. ILC3s from individuals with obesity also exhibited impaired fatty acid oxidation. Together, our findings define a malleable mechanism whereby dietary fats and microbial cues drive ILC3 maladaptation and death, with consequences for intestinal homeostasis.
    Keywords:  ILC3s; MNPs; TLR4; fatty acid oxidation; group 3 innate lymphoid cells; high-fat diet; intestinal inflammation; lipid metabolism; lipid peroxides; lipopolysaccharides; microbiota; mitochondria; mononuclear phagocytes; obesity
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.014
  10. Nat Rev Immunol. 2026 Mar 30.
    Neuron-eosinophil circuit explains stress-induced eczema flares.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-026-01297-z
  11. Nat Commun. 2026 Apr 02.
    Inhibition of adipocyte RUNX1/2 enhances adipose tissue thermogenesis through distinct mechanisms.
    Cuihua Wang, Na He, Shixiang Wang, Miao Lei, Jie Yao, Li Lin, Xue Ding, Jiaman Lin, Yixin Chen, Qiaoyun Long, Hannah Xiaoyan Hui, Liwei Xie, Yun-Shen Chan, Nan Cao, Shanshan Gu, Wenxiang Hu.
      Thermogenic adipocytes hold significant therapeutic promise for combating obesity and metabolic diseases due to their capacity to dissipate energy as heat. However, the transcriptional regulatory mechanisms underlying thermogenic adipocyte activation remain incompletely understood. Here, we identified RUNX1 and RUNX2 as key transcriptional barriers to thermogenic adipocyte differentiation and activation. RUNX1/2 expression is dynamically suppressed by thermal stress and positively associated with adverse metabolic traits. Genetic deletion of RUNX1 or RUNX2 in adipocytes enhances beige fat formation but differentially influences systemic metabolism in male mice. Conversely, enforced RUNX1/2 expression suppresses thermogenic gene programs and blunts thermogenic adipocyte activation. Mechanistically, RUNX1 recruits HDAC1 to enforce epigenetic silencing of thermogenic loci, whereas RUNX2 governs thermogenic cell fate through phase-separation-dependent repression. Notably, pharmacological inhibition of RUNX1/2 enhances adipose thermogenesis and improves energy metabolism. Our findings unveil an unrecognized role for RUNX in adipose thermogenesis, highlighting their potential as therapeutic targets for metabolic disease intervention.
    DOI:  https://doi.org/10.1038/s41467-026-71266-6
  12. Sci Immunol. 2026 Apr 03. 11(118): eaec2573
    Copper supports regulatory T cell energetic state to sustain peripheral immune tolerance.
    Yage Zhang, Fan Shi, Haoyu Tang, Tianyi Wang, Hui Zhao, Jie Chang, Chengyao Zhu, Wei Xu, Zhenli Zhu, Jing-Wen Lin, Yanfang Wang, Xiangguang Shi, Jiucun Wang, Junxia Min, Fudi Wang, Qian Wu, Songmin Ying.
      Fine-tuning of energy metabolism is essential for the survival and suppressive function of regulatory T cells (Treg cells). Here, we show that Treg cells with a high energetic state display enhanced functional capacity. Using a screen of mitochondrial inhibitors, we identified copper chelators and ionophores as modulators of Treg cell energetic state. T cell receptor (TCR) stimulation in vitro and human autoimmune conditions increased the labile copper pool in Treg cells. In murine Treg cells, we characterized Slc31a1 as a major copper transporter that supports oxidative phosphorylation, sustains nicotinamide adenine dinucleotide/reduced NAD+ (NAD+/NADH) homeostasis, and promotes histone acetylation at loci encoding core Treg cell functional molecules. These mechanisms collectively ensured energy production and Treg cell functionality, which were indispensable for peripheral immune tolerance but could be rescued by the copper ionophore elesclomol. Together, our findings identify copper metabolism as a critical regulator of Treg cell functionality and suggest potential therapeutic avenues for autoimmune diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.aec2573
  13. Immunity. 2026 Mar 30. pii: S1074-7613(26)00116-0. [Epub ahead of print]
    Foxp3 and BATF cooperatively direct cis-regulatory programs and gene expression for effector Treg cell differentiation.
    Ryuichi Murakami, Norihito Hayatsu, Takahisa Miyao, Zhenan Liu, Yukito Kino, Shumpei Shibata, Suzu Kawagoe, Masashi Matsuda, Yusuke Iizuka, Hiroki Sugishita, Hideyuki Yoshida, Yoshinori Hasegawa, Wataru Ise, Haruhiko Koseki, Tomohiro Kurosaki, Shohei Hori.
      Mechanisms by which diverse transcription factors (TFs), particularly the master regulator Foxp3, shape the heterogeneous transcriptional and epigenetic landscapes of regulatory T (Treg) cells remain poorly understood. Here, we show that Foxp3 cooperates with BATF to direct cis-regulatory programs and gene expression essential for the differentiation of immunosuppressive effector Treg (eTreg) cells. Simultaneous single-cell chromatin accessibility and transcriptome profiling, combined with topic modeling, identified cis-regulatory elements and associated programs jointly regulated by these TFs in eTreg cells. Genome-wide mapping of Treg-specific BATF and eTreg-specific Foxp3 binding sites revealed their co-binding at some of these cis-elements, synergistically enhancing accessibility and transcription. Furthermore, we provide evidence that Foxp3 cooperates with or counteracts specific TFs to orchestrate diverse cis-regulatory programs across Treg differentiation states. Thus, Foxp3 serves as a master but context-dependent regulator, cooperating with other TFs, including BATF, to shape the heterogeneous cis-regulatory and transcriptional landscapes critical for functional Treg cell differentiation.
    Keywords:  BATF; Foxp3; cis-regulatory elements; heterogeneity; regulatory T cells; transcription factors
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.005
  14. Nat Neurosci. 2026 Mar 30.
    Neuroimmune interferon signals sustain arthritis pain.
    Larissa Staurengo-Ferrari, Calvin Wong, Isaac M Chiu.
      
    DOI:  https://doi.org/10.1038/s41593-026-02251-x
  15. J Clin Invest. 2026 Apr 02. pii: e191101. [Epub ahead of print]
    The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents diet-induced steatohepatitis and fibrosis in mice.
    Young Do Koo, Romilia Tatiana Castillo, Asha Sukumaran Nair, Michael Garneau, Chad Gochee, Zachary V Campbell, Tashya Shreyas Vakil, Jua Ha, Alex Marti, Jamie Soto, Debajyoti Das, Nuria Martinez-Lopez, Shipra Sharma, Yennifer Delgado, Callie Phung, Immy A Ashley, Edmund D Kapelczak, Rashel Jacobo, Eric T Weatherford, Dao-Fu Dai, Jihane N Benhammou, Andrea G Marshall, Antentor Hinton, Ling Yang, Renata O Pereira, Tara TeSlaa, Mehdi Bouhaddou, Rajat Singh, E Dale Abel.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are leading causes of cirrhosis and hepatocellular carcinoma. Defects in autophagy contribute to the development of MASLD, however, the role of the Unc-51-like autophagy-activating kinase 1 (ULK1) in the pathophysiology of MASLD remains unclear. Herein, we show that ULK1, a serine/threonine kinase and core autophagy protein, is significantly repressed in human MASH livers, and that hepatocyte-specific loss of ULK1, unexpectedly, promotes hepatic steatosis and progression to liver fibrosis, without affecting basal autophagy flux. Phospho-proteomics identified the transcriptional coactivator NCOA3 as a downstream phospho-target of ULK1. Mechanistically, ULK1 phosphorylates NCOA3 to repress its transcriptional activity and restrain the CREB/CBP-mediated de novo lipogenic program. Accordingly, a phosphorylation-deficient NCOA3 mutant drives CREB/CBP-mediated lipogenesis, whereas genetic or pharmacological NCOA3 inhibition prevents steatosis, hepatic inflammation, and profibrotic signaling. Hence, ULK1-mediated NCOA3 phosphorylation is a fundamental and druggable checkpoint against the entire MASLD spectrum.
    Keywords:  Autophagy; Cell biology; Endocrinology; Hepatology; Obesity
    DOI:  https://doi.org/10.1172/JCI191101
  16. Nat Med. 2026 Mar 31.
    GLP-1 receptor agonist fails to halt Alzheimer's disease.
    Karen O'Leary.
      
    Keywords:  Alzheimer's disease; Biomarkers; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41591-026-00018-2
  17. Aging Cell. 2026 Apr;25(4): e70452
    Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
    Amélia Lalou, Ioanna Daskalaki, Ilias Gkikas, Sandra Rodríguez-López, Jean-David Morel, Giorgia Benegiamo, Adrien Faure, Arwen W Gao, Joaquim Barmaz, Qi Wang, Terytty Yang Li, Feng Gao, Danaé Broustail, Kristina Schoonjans, Giovanni D'Angelo, Johan Auwerx.
      Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.
    Keywords:   Caenorhabditis elegans ; aging; doxycycline; drug repositioning; longevity; miglustat; mitochondria; terbinafine
    DOI:  https://doi.org/10.1111/acel.70452
  18. Nat Commun. 2026 Apr 01.
    Adult patients with autoinflammation of unknown origin partially phenocopy the immune presentation of Still's disease.
    Immunome Project Consortium for Autoinflammatory Disorders (ImmunAID)
      Autoinflammation of unknown origin remains amongst the most enigmatic of systemic autoinflammatory disorders (SAID), with systemic autoinflammatory symptoms in the absence of a molecular or clinical diagnosis with a recognized SAID. Here, we aim to understand the immunological process behind patients with autoinflammation of unknown origin. We collect samples from 36 patients manifesting recent disease activity across 30 European medical centers, and employ deep immunophenotyping and plasma proteomics to compare to 58 healthy controls and an additional demographically similar cohort comprising 92 SAID patients. Machine-learning approaches identify key immunological changes, including the upregulation of CD38 and HLA across T cell subsets and the upregulation of acute-phase plasma proteins in autoinflammation of unknown origin patients. The immunological traits of these previously poorly characterised patients partially phenocopy Still's disease presentation. Thus, this study identifies potential biomarkers and disease mediators in autoinflammation of unknown origin.
    DOI:  https://doi.org/10.1038/s41467-026-70895-1
  19. Nat Commun. 2026 Mar 31. pii: 2700. [Epub ahead of print]17(1):
    Homoharringtonine exhibits senotherapeutic activity that mitigates diet- and age-associated obesity and insulin resistance and extends lifespan in mice.
    Eok-Cheon Kim, Han-Byul Jung, Yu-Kyoung Park, Youlim Son, Hye-Na Cha, Yash Patel, Ju Hee Lee, Minah Choi, Soyoung Park, Il-Kug Kim, Lauren Pickel, Seungju Lee, Yuna Ha, Min-Gyeong Shin, Qiwei Zhang, Jielin Yang, Bruno Rodrigues de Oliveira, Nathaniel Vo, Annie Yew, Jacques Togo, Kafi N Ealey, Su-Ryun Jung, Sunjin Moon, Hye-Jin Yoon, Jee-Young Lee, Hoon-Ki Sung, Jae-Ryong Kim, So-Young Park.
      The accumulation of senescent cells in white adipose tissue (WAT) is closely associated with the functional decline of WAT and plays a causal role in the pathogenesis of metabolic diseases. Therefore, the elimination of senescent cells in WAT holds promise for the treatment and prevention of age-related metabolic diseases. Using a drug-repositioning strategy for 2150 clinically applied compounds, we discover that homoharringtonine (HHT), an FDA-approved anti-leukemic drug, manifests senotherapeutic activity in vitro in multiple cell types including human preadipocytes, while inflicting minimal cytotoxicity to non-senescent cells. HHT treatment prevents diet- or age-induced metabolic abnormalities in male mice targeting senescent adipocytes and preadipocytes to improve WAT function and reduce WAT inflammation. Moreover, HHT treatment attenuates age-associated phenotypes of human adipose tissue. Mechanistically, the senotherapeutic effects of HHT are mediated through the direct interaction of HHT with heat shock protein family A member 5 (HSPA5). Importantly, we found that HHT treatment delays aging and extends the lifespan in progeroid and aged mice. Our study demonstrates the novel senotherapeutic potential of HHT to mitigate age- and obesity-related metabolic dysfunction and extend longevity in mice.
    DOI:  https://doi.org/10.1038/s41467-026-70475-3
  20. FASEB J. 2026 Apr 15. 40(7): e71591
    Obesity Disrupts H3K4me3-Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages.
    Kentaro Takahashi, Julia Drolet, Jinghua Liu, Jasmine R Jackson, Madison Babcock, Muthusamy Thiruppathi, Milie Fang, Tyler Paul, Gayathri Ganesh, Yuri Fukasawa, Yoshikiyo Akasaka, Giamila Fantuzzi, Elizaveta V Benevolenskaya, Timothy J Koh, Norifumi Urao.
      Dysregulated macrophage function drives the development of obesity-associated pathologies. While macrophages adapt to their surrounding environment to maintain tissue homeostasis, the impact of obesity on macrophage adaptation to low oxygen levels remains elusive. Here, we show that hypoxia rapidly increases histone 3 lysine-4 trimethylation (H3K4me3) in bone marrow-derived macrophages (BMDMs) and that this response is impaired in BMDMs from high-fat diet (HFD)-induced obese mice, which significantly affected the expression of genes involved in metabolic pathways, resulting in decreased lactate accumulation, histone lactylation, and expression of genes involved in the maintenance of metabolic homeostasis. Moreover, altered adaptation to hypoxia in BMDMs from HFD mice led to a decreased efferocytosis capacity under hypoxia, which was reversed by supplementation with glucose or lactate. Serial bone marrow transplantation indicated that the maladapted hypoxia response for efferocytosis was imprinted in macrophage precursors in the bone marrow of HFD mice. In BMDMs, genetic disruption of the H3K4me3 demethylase KDM5A further enhances hypoxia-induced H3K4me3 and gene expression, along with lactate accumulation. In a dorsal skin biopsy model, while extracellular lactate levels decreased immediately after wounding but sharply increased in the early phase in normal mice, whereas lactate levels remained low in HFD mice, resulting in delayed wound healing. Our findings suggest that metabolic adaptation to hypoxia involves H3K4me3 and lactate accumulation in macrophages to perform efferocytosis under hypoxic conditions. Diet-induced obesity disrupts this pathway, resulting in impaired efferocytosis and delayed healing, with implications for altered macrophage functions in pathologies associated with obesity.
    Keywords:  bone marrow‐derived macrophages; epigenetics; high‐fat diet; histone modification; hypoxia; metabolism; obesity
    DOI:  https://doi.org/10.1096/fj.202502626R
  21. Immunity. 2026 Apr 02. pii: S1074-7613(26)00122-6. [Epub ahead of print]
    Agonistic anti-CD40 antibody treatment converts resident regulatory T cells into activated type 1 effectors within the tumor microenvironment.
    Vivien I Maltez, Charu Arora, Kyle P Gribbin, Breanna Caruso, Margaret E Haerr, Rina Sor, Qiaoshi Lian, Katie E Blise, Shamilene Sivagnanam, Rosalie C Sears, Lisa M Coussens, Robert H Vonderheide, Ronald N Germain, Katelyn T Byrne.
      In pancreatic ductal adenocarcinoma (PDAC), agonistic anti-CD40 (αCD40) reduces frequencies of intratumoral regulatory T (Treg) cells despite a lack of CD40 expression on Treg cells. Here, we leveraged spatiotemporal imaging and lineage tracing approaches to examine intratumoral Treg cell fate in a mouse model of PDAC, where immune checkpoint blockade (ICB) (αPD-1 + αCTLA-4) combined with αCD40 controls tumor growth. Intratumoral Foxp3+ Treg cell numbers collapsed upon treatment, dependent on CD40-activated dendritic cells (DCs) and induction of interleukin (IL)-12 and interferon (IFN)-γ. This reduction corresponded with cellular alterations; Treg cells acquired an "ExTreg" phenotype characterized by loss of Foxp3 expression and acquisition of T helper 1 (Th1)-like features (Tbet+IFN-γ+). αCD40 promoted a spatially reorganized tumor microenvironment (TME), with Cxcr3⁺ Treg and ExTreg cells localized to the tumor periphery with Cxcl9-expressing DCs. Through in situ analyses of T cell receptor (TCR) signaling, we found that ExTreg cells had the highest antigen-driven activation among tumor-infiltrating T cells. Reprogramming of intratumoral Treg cells into Th1-like effectors reveals plasticity and an anti-tumor capacity of these cells.
    Keywords:  CD40 agonist; interferon-γ; regulatory T cell; reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.011
  22. Sci Immunol. 2026 Apr 03. 11(118): eaeb6484
    Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF.
    Biao Ma, Wenxin Lyu, John Rizk, Xiaoyue Han, Majken Kjær, Vinnycius Pereira Almeida, Malin Jessen, Max Benjamin Sauerland, Carol Sze Ki Leung, Benoit J Van den Eynde, Xin Lu, Mads Gyrd-Hansen.
      Tumor necrosis factor (TNF) orchestrates immune responses but can also drive inflammation-associated tissue damage. However, the mechanisms governing tissue tolerance to TNF remain poorly understood. Here, we reveal that TNF receptor 1 (TNFR1) abundance is regulated by two upstream open reading frames (uORFs) in the 5' untranslated region of TNFRSF1A and demonstrate that this is a key determinant of TNF tolerance. uORF2 dominantly limits TNFR1 translation, and its disruption increases TNFR1 levels, leading to excessive TNF-induced gene activation and cell death in cell culture. By contrast, uORF1 dynamically regulates TNFR1 levels in response to inflammatory and stress signals. In mice, uORF2 protects against TNF-driven systemic inflammatory response syndrome and liver pathology. We additionally report that the translation of other immune receptor messenger RNAs, including TLR4, IFNAR1, and IFNGR2, is also controlled by uORFs. Thus, regulation of TNFR1 levels and possibly of other immune receptors emerges as a mechanism safeguarding against excessive immune responses and tissue damage.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb6484
  23. Nat Genet. 2026 Mar 30.
    Genome-wide fine-mapping improves identification of causal variants.
    Yang Wu, Zhili Zheng, Loic Thibaut, Tian Lin, Qian Feng, Hao Cheng, Loic Yengo, Michael E Goddard, Naomi R Wray, Peter M Visscher, Jian Zeng.
      Fine-mapping refines genotype-phenotype association signals to identify causal variants underlying complex traits. However, current methods typically focus on individual genomic loci and do not account for the global genetic architecture. Here we demonstrate the advantages of performing genome-wide fine-mapping (GWFM) with functional annotations and develop methods to facilitate GWFM. In simulations and real data analyses, GWFM outperforms current methods across several metrics, including error control, mapping power, resolution, precision, replication rate and trans-ancestry phenotype prediction. Across 48 complex traits, we identify credible sets that collectively explain 18% of the SNP-based heritability (hSNP2) on average, with 30% credible sets located outside genome-wide significant loci. Leveraging the genetic architecture estimated from GWFM, we predict that fine-mapping over 50% of hSNP2 would require an average of 2 million samples. Finally, as proof-of-principle, we highlight a known causal variant at FTO influencing body mass index and identify new missense causal variants influencing schizophrenia and Crohn's disease risk.
    DOI:  https://doi.org/10.1038/s41588-026-02549-3
  24. Science. 2026 Apr 02. 392(6793): eaea8782
    Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
    Lucas C Reineke, Ping Jun Zhu, Udit Dalwadi, Sean W Dooling, Yuwei Liu, I-Ching Wang, Sara Young-Baird, James Okoh, Santosh Kumar Kuncha, Hongyi Zhou, Akshara Kannan, Hyekyung Park, Nicolas A Debeaubien, Tristan Croll, D John Lee, Christopher Arthur, Thomas E Dever, Peter Walter, Jin Chen, Adam Frost, Mauro Costa-Mattioli.
      The integrated stress response (ISR) is essential for cellular homeostasis and cognitive function. We investigated how persistent ISR activation affects cognitive performance by studying the PPP1R15BR658C genetic variant associated with intellectual disability. To model this condition, we generated a mouse line with the pathogenic allele inserted. This variant destabilized the PPP1R15B•PP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. We demonstrated that the cognitive and synaptic impairments in Ppp1r15bR658C mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral ortholog of PPP1R15B, which acted as a potent pan-ISR inhibitor. DP71L reversed the cognitive and synaptic deficits across mouse models of Down syndrome, Alzheimer's disease, and aging, and enhanced synaptic plasticity and memory in healthy mice.
    DOI:  https://doi.org/10.1126/science.aea8782
  25. Nature. 2026 Apr;652(8108): 22-25
    Are boys really in crisis? What the science says in the age of the manosphere.
    Helen Pearson.
      
    Keywords:  Media; Public health; Society
    DOI:  https://doi.org/10.1038/d41586-026-00968-0
  26. Diabetes Care. 2026 Apr 01. pii: dc252957. [Epub ahead of print]
    Intake of Fiber From Different Food Sources and Type 2 Diabetes Risk: An Integrated Analysis of Epidemiological and Multiomic Data.
    Yi Wan, Hala B Alessa, Marta Guasch-Ferré, Deirdre K Tobias, Kyu Ha Lee, JoAnn E Manson, Walter C Willett, Qi Sun, Frank B Hu.
       OBJECTIVE: To examine the association between fiber from various food sources and type 2 diabetes (T2D) risk, as well as the molecular profiles involved.
    RESEARCH DESIGN AND METHODS: Using data from three large prospective U.S. cohorts comprising 195,222 participants observed for up to 34 years, we evaluated the association between fiber from various food sources and T2D risk. We also assessed the association between fiber intake, plasma metabolic biomarkers, and a metabolomic profile indicative of T2D risk. Additionally, we examined gut microbial features related to fiber intake and the T2D metabolomic profile.
    RESULTS: During follow-up, we documented 18,369 incident T2D cases. Higher intakes of total fiber (hazard ratio [HR] comparing extreme quintiles 0.88; 95% CI 0.82, 0.94), cereal fiber (HR 0.77; 95% CI 0.73, 0.82), and fruit fiber (HR 0.82; 95% CI 0.78, 0.87) were each associated with a lower T2D risk. Greater intakes of total fiber, cereal fiber, and fruit fiber, but not vegetable fiber, were linked to more favorable plasma profiles of insulinemic, lipid, and inflammatory biomarkers and a metabolomic profile indicative of a lower T2D risk. We also identified multiple gut microbial species, such as Faecalibacterium prausnitzii, Ruminococcus lactaris, and Gemmiger formicilis, along with relevant butyric acid-producing enzymes, all of which were associated with higher fruit fiber intake and a metabolomic profile indicating a lower likelihood of T2D development.
    CONCLUSIONS: Higher intakes of total, cereal, and fruit fiber are associated with a lower risk of T2D and a more favorable metabolic profile, with the gut microbiome potentially contributing to the beneficial association of fruit fiber.
    DOI:  https://doi.org/10.2337/dc25-2957
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒05 at 8:37.