bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–10–20
forty-four papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Weak enhancer allows autoactivation of Irf8 to control cDC1 versus cDC2 lineage commitment.
  2. Glucose metabolism controls monocyte homeostasis and migration but has no impact on atherosclerosis development in mice.
  3. AlphaFold reveals how sperm and egg hook up in intimate detail.
  4. Structural basis of respiratory complex adaptation to cold temperatures.
  5. Now it's getting bloody in cardiac organoids.
  6. Metabolic-epigenetic rewiring in CD8+ T cells via lactate-dependent histone lactylation.
  7. The hippocampal CA2 region discriminates social threat from social safety.
  8. Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma.
  9. Spatial cytokine microniches direct T helper cell pathways that drive allergic asthma.
  10. Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
  11. Genome integrity sensing by the broad-spectrum Hachiman antiphage defense complex.
  12. Pioneering discovery and therapeutics at the brain-vascular-immune interface.
  13. The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.
  14. Your diet can change your immune system - here's how.
  15. Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome.
  16. Depletion of loss-of-function germline mutations in centenarians reveals longevity genes.
  17. Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.
  18. Spatial transcriptomics of a parasitic flatworm provides a molecular map of drug targets and drug resistance genes.
  19. Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
  20. Scientific papers that mention AI get a citation boost.
  21. Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology.
  22. Lung and liver editing by lipid nanoparticle delivery of a stable CRISPR-Cas9 ribonucleoprotein.
  23. A sequence of memories.
  24. Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling.
  25. Waste management and cell death in T cells.
  26. Centrioles are frequently amplified in early B cell development but dispensable for humoral immunity.
  27. Prosocial preferences can escalate intergroup conflicts by countering selfish motivations to leave.
  28. Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
  29. Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity.
  30. The huge protein database that spawned AlphaFold and biology's AI revolution.
  31. Quantifying constraint in the human mitochondrial genome.
  32. Dynamic patterns of functional connectivity in the human brain underlie individual memory formation.
  33. The lifespan and kinetics of human dendritic cell subsets and their precursors in health and inflammation.
  34. No bandage needed: electrical impulses to major nerve help stop bleeding.
  35. Season's mis-greetings: why timing matters in global academia.
  36. Unraveling mechanisms of human brain evolution.
  37. SEA-AD is a multimodal cellular atlas and resource for Alzheimer's disease.
  38. Neuronal sequences in population bursts encode information in human cortex.
  39. Clinical-trial reporting is on the rise.
  40. Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming.
  41. 'Smart' insulin prevents diabetic highs - and deadly lows.
  42. The early days of peer review: five insights from historical reports.
  43. TGF-β-mediated crosstalk between TIGIT+ Tregs and CD226+CD8+ T cells in the progression and remission of type 1 diabetes.
  44. CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation.
  1. Nat Immunol. 2024 Oct 15.
    Weak enhancer allows autoactivation of Irf8 to control cDC1 versus cDC2 lineage commitment.
      
    DOI:  https://doi.org/10.1038/s41590-024-01977-9
  2. Nat Commun. 2024 Oct 19. 15(1): 9027
    Glucose metabolism controls monocyte homeostasis and migration but has no impact on atherosclerosis development in mice.
    Alexandre Gallerand, Bastien Dolfi, Marion I Stunault, Zakariya Caillot, Alexia Castiglione, Axelle Strazzulla, Chuqiao Chen, Gyu Seong Heo, Hannah Luehmann, Flora Batoul, Nathalie Vaillant, Adélie Dumont, Thomas Pilot, Johanna Merlin, Fairouz N Zair, Jerome Gilleron, Adeline Bertola, Peter Carmeliet, Jesse W Williams, Rafael J Arguello, David Masson, David Dombrowicz, Laurent Yvan-Charvet, Denis Doyen, Arvand Haschemi, Yongjian Liu, Rodolphe R Guinamard, Stoyan Ivanov.
      Monocytes directly contribute to atherosclerosis development by their recruitment to plaques in which they differentiate into macrophages. In the present study, we ask how modulating monocyte glucose metabolism could affect their homeostasis and their impact on atherosclerosis. Here we investigate how circulating metabolites control monocyte behavior in blood, bone marrow and peripheral tissues of mice. We find that serum glucose concentrations correlate with monocyte numbers. In diet-restricted mice, monocytes fail to metabolically reprogram from glycolysis to fatty acid oxidation, leading to reduced monocyte numbers in the blood. Mechanistically, Glut1-dependent glucose metabolism helps maintain CD115 membrane expression on monocytes and their progenitors, and regulates monocyte migratory capacity by modulating CCR2 expression. Results from genetic models and pharmacological inhibitors further depict the relative contribution of different metabolic pathways to the regulation of CD115 and CCR2 expression. Meanwhile, Glut1 inhibition does not impact atherosclerotic plaque development in mouse models despite dramatically reducing blood monocyte numbers, potentially due to the remaining monocytes having increased migratory capacity. Together, these data emphasize the role of glucose uptake and intracellular glucose metabolism in controlling monocyte homeostasis and functions.
    DOI:  https://doi.org/10.1038/s41467-024-53267-5
  3. Nature. 2024 Oct 17.
    AlphaFold reveals how sperm and egg hook up in intimate detail.
    Heidi Ledford.
      
    Keywords:  Cell biology; Developmental biology; Proteomics
    DOI:  https://doi.org/10.1038/d41586-024-03319-z
  4. Cell. 2024 Oct 03. pii: S0092-8674(24)01087-0. [Epub ahead of print]
    Structural basis of respiratory complex adaptation to cold temperatures.
    Young-Cheul Shin, Pedro Latorre-Muro, Amina Djurabekova, Oleksii Zdorevskyi, Christopher F Bennett, Nils Burger, Kangkang Song, Chen Xu, Joao A Paulo, Steven P Gygi, Vivek Sharma, Maofu Liao, Pere Puigserver.
      In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain. Yet, the structural basis of respiratory complex adaptation upon cold exposure remains elusive. Herein, we combined thermoregulatory physiology and cryoelectron microscopy (cryo-EM) to study endogenous respiratory supercomplexes from mice exposed to different temperatures. A cold-induced conformation of CI:III2 (termed type 2) supercomplex was identified with a ∼25° rotation of CIII2 around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting catalytic states that favor electron transfer. Large-scale supercomplex simulations in mitochondrial membranes reveal how lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations, and biochemical analyses unveil the thermoregulatory mechanisms and dynamics of increased respiratory capacity in brown fat at the structural and energetic level.
    Keywords:  CIII(2) rotation; brown adipose tissue; cellular adaptation; electron transport chain; membrane lipid remodeling; respiratory complexes
    DOI:  https://doi.org/10.1016/j.cell.2024.09.029
  5. Nat Cell Biol. 2024 Oct 16.
    Now it's getting bloody in cardiac organoids.
    Thomas Brand.
      
    DOI:  https://doi.org/10.1038/s41556-024-01528-2
  6. Nat Immunol. 2024 Oct 16.
    Metabolic-epigenetic rewiring in CD8+ T cells via lactate-dependent histone lactylation.
    Renqiang Sun, Hongbo Chi.
      
    DOI:  https://doi.org/10.1038/s41590-024-01991-x
  7. Nat Neurosci. 2024 Oct 15.
    The hippocampal CA2 region discriminates social threat from social safety.
    Pegah Kassraian, Shivani K Bigler, Diana M Gilly Suarez, Neilesh Shrotri, Anastasia Barnett, Heon-Jin Lee, W Scott Young, Steven A Siegelbaum.
      The dorsal cornu ammonis 2 (dCA2) region of the hippocampus enables the discrimination of novel from familiar conspecifics. However, the neural bases for more complex social-spatial episodic memories are unknown. Here we report that the spatial and social contents of an aversive social experience require distinct hippocampal regions. While dorsal CA1 (dCA1) pyramidal neurons mediate the memory of an aversive location, dCA2 pyramidal neurons enable the discrimination of threat-associated (CS+) from safety-associated (CS-) conspecifics in both female and male mice. Silencing dCA2 during encoding or recall trials disrupted social fear discrimination memory, resulting in fear responses toward both the CS+ and CS- mice. Calcium imaging revealed that the aversive experience strengthened and stabilized dCA2 representations of both the CS+ and CS- mice, with the incorporation of an abstract representation of social valence into representations of social identity. Thus, dCA2 contributes to both social novelty detection and the adaptive discrimination of threat-associated from safety-associated individuals during an aversive social episodic experience.
    DOI:  https://doi.org/10.1038/s41593-024-01771-8
  8. Mol Cell. 2024 Oct 14. pii: S1097-2765(24)00782-2. [Epub ahead of print]
    Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma.
    Sadaaki Nishimura, Juan F Linares, Antoine L'Hermitte, Angeles Duran, Tania Cid-Diaz, Anxo Martinez-Ordoñez, Marc Ruiz-Martinez, Yotaro Kudo, Antonio Marzio, Mathias Heikenwalder, Lewis R Roberts, Maria T Diaz-Meco, Jorge Moscat.
      Hepatocellular carcinoma (HCC) emerges from chronic inflammation, to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation. Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Of functional relevance, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs by rescuing the inhibited STING-IFN pathway, thus enhancing anti-tumor responses mediated by CD8+ T cells. Therefore, NBR1 emerges as a synthetic vulnerability of p62 deficiency in HSCs by promoting the STING/IFN pathway, which boosts anti-tumor CD8+ T cell responses to restrain HCC progression.
    Keywords:  CD8(+) T cells; NBR1; STING; TRIM32; hepatic stellate cells; hepatocellular carcinoma; interferon; microenvironment; p62
    DOI:  https://doi.org/10.1016/j.molcel.2024.09.026
  9. Nat Immunol. 2024 Oct 16.
    Spatial cytokine microniches direct T helper cell pathways that drive allergic asthma.
      
    DOI:  https://doi.org/10.1038/s41590-024-01987-7
  10. Nat Metab. 2024 Oct 14.
    Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
    Ekaterina D Korobkina, Camila Martinez Calejman, John A Haley, Miranda E Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R Green, Paula Vo, Clay F Semenkovich, Jason R Pitarresi, Jessica B Spinelli, Ozkan Aydemir, Christian M Metallo, Matthew D Lynes, Cholsoon Jang, Nathaniel W Snyder, Kathryn E Wellen, David A Guertin.
      Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.
    DOI:  https://doi.org/10.1038/s42255-024-01143-3
  11. Cell. 2024 Oct 03. pii: S0092-8674(24)01068-7. [Epub ahead of print]
    Genome integrity sensing by the broad-spectrum Hachiman antiphage defense complex.
    Owen T Tuck, Benjamin A Adler, Emily G Armbruster, Arushi Lahiri, Jason J Hu, Julia Zhou, Joe Pogliano, Jennifer A Doudna.
      Hachiman is a broad-spectrum antiphage defense system of unknown function. We show here that Hachiman is a heterodimeric nuclease-helicase complex, HamAB. HamA, previously a protein of unknown function, is the effector nuclease. HamB is the sensor helicase. HamB constrains HamA activity during surveillance of intact double-stranded DNA (dsDNA). When the HamAB complex detects DNA damage, HamB helicase activity activates HamA, unleashing nuclease activity. Hachiman activation degrades all DNA in the cell, creating "phantom" cells devoid of both phage and host DNA. We demonstrate Hachiman activation in the absence of phage by treatment with DNA-damaging agents, suggesting that Hachiman responds to aberrant DNA states. Phylogenetic similarities between the Hachiman helicase and enzymes from eukaryotes and archaea suggest deep functional symmetries with other important helicases across domains of life.
    Keywords:  cryo-EM; genome integrity; helicase; immunity; phage defense
    DOI:  https://doi.org/10.1016/j.cell.2024.09.020
  12. Cell. 2024 Oct 17. pii: S0092-8674(24)01037-7. [Epub ahead of print]187(21): 5871-5876
    Pioneering discovery and therapeutics at the brain-vascular-immune interface.
    Katerina Akassoglou, Dimitrios Davalos, Andrew S Mendiola, Mark A Petersen, Jae Kyu Ryu, Christian Schachtrup, Zhaoqi Yan.
      The brain-vascular-immune interface has emerged as a dynamic player in brain physiology and disease. We propose integrating vascular risk factors with genetic susceptibility as the nexus for the discovery of mechanisms and therapies for neuroinflammation, neurodegeneration, and neurorepair across polygenic neurologic diseases.
    DOI:  https://doi.org/10.1016/j.cell.2024.09.018
  13. EMBO J. 2024 Oct 18.
    The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.
    Wandi Xiong, Kaiyu Xu, Jacquelyne Ka-Li Sun, Siling Liu, Baizhen Zhao, Jie Shi, Karl Herrup, Hei-Man Chow, Lin Lu, Jiali Li.
      Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis.
    Keywords:   lncMtDloop ; Alzheimer’s Disease; Mitochondrial Homeostasis; TFAM; mtDNA
    DOI:  https://doi.org/10.1038/s44318-024-00270-7
  14. Nature. 2024 Oct;634(8034): 528-531
    Your diet can change your immune system - here's how.
    Nic Fleming.
      
    Keywords:  Immunology; Nutrition; Personalized medicine
    DOI:  https://doi.org/10.1038/d41586-024-03334-0
  15. Nat Commun. 2024 Oct 17. 15(1): 8980
    Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome.
    Maiko Matsui, Lauren E Lynch, Isabella Distefano, Allison Galante, Aravind R Gade, Hong-Gang Wang, Nicolas Gómez-Banoy, Patrick Towers, Daniel S Sinden, Eric Q Wei, Adam S Barnett, Kenneth Johnson, Renan Lima, Alfonso Rubio-Navarro, Ang K Li, Steven O Marx, Timothy E McGraw, Paul S Thornton, Katherine W Timothy, James C Lo, Geoffrey S Pitt.
      The canonical G406R mutation that increases Ca2+ influx through the CACNA1C-encoded CaV1.2 Ca2+ channel underlies the multisystem disorder Timothy syndrome (TS), characterized by life-threatening arrhythmias. Severe episodic hypoglycemia is among the poorly characterized non-cardiac TS pathologies. While hypothesized from increased Ca2+ influx in pancreatic beta cells and consequent hyperinsulinism, this hypoglycemia mechanism is undemonstrated because of limited clinical data and lack of animal models. We generated a CaV1.2 G406R knockin mouse model that recapitulates key TS features, including hypoglycemia. Unexpectedly, these mice do not show hyperactive beta cells or hyperinsulinism in the setting of normal intrinsic beta cell function, suggesting dysregulated glucose homeostasis. Patient data confirm the absence of hyperinsulinism. We discover multiple alternative contributors, including perturbed counterregulatory hormone responses with defects in glucagon secretion and abnormal hypothalamic control of glucose homeostasis. These data provide new insights into contributions of CaV1.2 channels and reveal integrated consequences of the mutant channels driving life-threatening events in TS.
    DOI:  https://doi.org/10.1038/s41467-024-52885-3
  16. Nat Commun. 2024 Oct 19. 15(1): 9030
    Depletion of loss-of-function germline mutations in centenarians reveals longevity genes.
    Kejun Ying, José P Castro, Anastasia V Shindyapina, Alexander Tyshkovskiy, Mahdi Moqri, Ludger J E Goeminne, Sofiya Milman, Zhengdong D Zhang, Nir Barzilai, Vadim N Gladyshev.
      While previous studies identified common genetic variants associated with longevity in centenarians, the role of the rare loss-of-function (LOF) mutation burden remains largely unexplored. Here, we investigated the burden of rare LOF mutations in Ashkenazi Jewish individuals from the Longevity Genes Project and LonGenity study cohorts using whole-exome sequencing data. We found that centenarians had a significantly lower burden (11-22%) of LOF mutations compared to controls. Similar effects were also observed in their offspring. Gene-level burden analysis identified 35 genes with depleted LOF mutations in centenarians, with 14 of these validated in the UK Biobank. Mendelian randomization and multi-omic analyses on these genes identified RGP1, PCNX2, and ANO9 as longevity genes with consistent causal effects on multiple aging-related traits and altered expression during aging. Our findings suggest that a protective genetic background, characterized by a reduced burden of damaging variants, contributes to exceptional longevity, likely acting in concert with specific protective variants to promote healthy aging.
    DOI:  https://doi.org/10.1038/s41467-024-52967-2
  17. Nat Commun. 2024 Oct 18. 15(1): 9008
    Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.
    Sunita Maharjan, Howard Gamper, Yuka Yamaki, Thomas Christian, Robert Y Henley, Nan-Sheng Li, Takeo Suzuki, Tsutomu Suzuki, Joseph A Piccirilli, Meni Wanunu, Erin Seifert, Douglas C Wallace, Ya-Ming Hou.
      Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA would also stabilize its pathogenic variants is unknown. Here we show that the N1-methylation of guanosine at position 9 (m1G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has a destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated, as removal of the m1G9 methylation, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving the structure and activity of the variant. These results have therapeutic implications, suggesting that the N1-methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-53318-x
  18. Nat Commun. 2024 Oct 16. 15(1): 8918
    Spatial transcriptomics of a parasitic flatworm provides a molecular map of drug targets and drug resistance genes.
    Svenja Gramberg, Oliver Puckelwaldt, Tobias Schmitt, Zhigang Lu, Simone Haeberlein.
      The spatial organization of gene expression dictates tissue functions in multicellular parasites. Here, we present the spatial transcriptome of a parasitic flatworm, the common liver fluke Fasciola hepatica. We identify gene expression profiles and marker genes for eight distinct tissues and validate the latter by in situ hybridization. To demonstrate the power of our spatial atlas, we focus on genes with substantial medical importance, including vaccine candidates (Ly6 proteins) and drug resistance genes (glutathione S-transferases, ABC transporters). Several of these genes exhibit unique expression patterns, indicating tissue-specific biological functions. Notably, the prioritization of tegumental protein kinases identifies a PKCβ, for which small-molecule targeting causes parasite death. Our comprehensive gene expression map provides unprecedented molecular insights into the organ systems of this complex parasitic organism, serving as a valuable tool for both basic and applied research.
    DOI:  https://doi.org/10.1038/s41467-024-53215-3
  19. Nat Metab. 2024 Oct 15.
    Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
      
    DOI:  https://doi.org/10.1038/s42255-024-01152-2
  20. Nature. 2024 Oct 17.
    Scientific papers that mention AI get a citation boost.
    Mariana Lenharo.
      
    Keywords:  Computer science; Machine learning; Publishing; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03355-9
  21. Nat Metab. 2024 Oct 17.
    Genetic architecture of oral glucose-stimulated insulin release provides biological insights into type 2 diabetes aetiology.
    A L Madsen, S Bonàs-Guarch, S Gheibi, R Prasad, J Vangipurapu, V Ahuja, L R Cataldo, O Dwivedi, G Hatem, G Atla, M Guindo-Martínez, A M Jørgensen, A E Jonsson, I Miguel-Escalada, S Hassan, A Linneberg, Tarunveer S Ahluwalia, T Drivsholm, O Pedersen, T I A Sørensen, A Astrup, D Witte, P Damm, T D Clausen, E Mathiesen, T H Pers, R J F Loos, L Hakaste, M Fex, N Grarup, T Tuomi, M Laakso, H Mulder, J Ferrer, T Hansen.
      The genetics of β-cell function (BCF) offer valuable insights into the aetiology of type 2 diabetes (T2D)1,2. Previous studies have expanded the catalogue of BCF genetic associations through candidate gene studies3-7, large-scale genome-wide association studies (GWAS) of fasting BCF8,9 or functional islet studies on T2D risk variants10-14. Nonetheless, GWAS focused on BCF traits derived from oral glucose tolerance test (OGTT) data have been limited in sample size15,16 and have often overlooked the potential for related traits to capture distinct genetic features of insulin-producing β-cells17,18. We reasoned that investigating the genetic basis of multiple BCF estimates could provide a broader understanding of β-cell physiology. Here, we aggregate GWAS data of eight OGTT-based BCF traits from ~26,000 individuals of European descent, identifying 55 independent genetic associations at 44 loci. By examining the effects of BCF genetic signals on related phenotypes, we uncover diverse disease mechanisms whereby genetic regulation of BCF may influence T2D risk. Integrating BCF-GWAS data with pancreatic islet transcriptomic and epigenomic datasets reveals 92 candidate effector genes. Gene silencing in β-cell models highlights ACSL1 and FAM46C as key regulators of insulin secretion. Overall, our findings yield insights into the biology of insulin release and the molecular processes linking BCF to T2D risk, shedding light on the heterogeneity of T2D pathophysiology.
    DOI:  https://doi.org/10.1038/s42255-024-01140-6
  22. Nat Biotechnol. 2024 Oct 16.
    Lung and liver editing by lipid nanoparticle delivery of a stable CRISPR-Cas9 ribonucleoprotein.
    Kai Chen, Hesong Han, Sheng Zhao, Bryant Xu, Boyan Yin, Atip Lawanprasert, Marena Trinidad, Benjamin W Burgstone, Niren Murthy, Jennifer A Doudna.
      Lipid nanoparticle (LNP) delivery of clustered regularly interspaced short palindromic repeat (CRISPR) ribonucleoproteins (RNPs) could enable high-efficiency, low-toxicity and scalable in vivo genome editing if efficacious RNP-LNP complexes can be reliably produced. Here we engineer a thermostable Cas9 from Geobacillus stearothermophilus (GeoCas9) to generate iGeoCas9 variants capable of >100× more genome editing of cells and organs compared with the native GeoCas9 enzyme. Furthermore, iGeoCas9 RNP-LNP complexes edit a variety of cell types and induce homology-directed repair in cells receiving codelivered single-stranded DNA templates. Using tissue-selective LNP formulations, we observe genome-editing levels of 16‒37% in the liver and lungs of reporter mice that receive single intravenous injections of iGeoCas9 RNP-LNPs. In addition, iGeoCas9 RNPs complexed to biodegradable LNPs edit the disease-causing SFTPC gene in lung tissue with 19% average efficiency, representing a major improvement over genome-editing levels observed previously using viral or nonviral delivery strategies. These results show that thermostable Cas9 RNP-LNP complexes can expand the therapeutic potential of genome editing.
    DOI:  https://doi.org/10.1038/s41587-024-02437-3
  23. Nature. 2024 Oct 16.
    A sequence of memories.
    Eva Papasoulioti.
      
    Keywords:  Arts; Culture
    DOI:  https://doi.org/10.1038/d41586-024-03297-2
  24. Nat Metab. 2024 Oct 18.
    Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling.
    Xiaomin Zhang, Yali Chen, Geng Sun, Yankang Fei, Ha Zhu, Yanfang Liu, Junyan Dan, Chunzhen Li, Xuetao Cao, Juan Liu.
      Cellular metabolism modulates dendritic cell (DC) maturation and activation. Migratory dendritic cells (mig-DCs) travelling from the tissues to draining lymph nodes (dLNs) are critical for instructing adaptive immune responses. However, how lipid metabolites influence mig-DCs in autoimmunity remains elusive. Here, we demonstrate that farnesyl pyrophosphate (FPP), an intermediate of the mevalonate pathway, accumulates in mig-DCs derived from mice with systemic lupus erythematosus (SLE). FPP promotes mig-DC survival and germinal centre responses in the dLNs by coordinating protein geranylgeranylation and mitochondrial remodelling. Mechanistically, FPP-dependent RhoA geranylgeranylation promotes mitochondrial fusion and oxidative respiration through mitochondrial RhoA-MFN interaction, which subsequently facilitates the resolution of endoplasmic reticulum stress in mig-DCs. Simvastatin, a chemical inhibitor of the mevalonate pathway, restores mitochondrial function in mig-DCs and ameliorates systemic pathogenesis in SLE mice. Our study reveals a critical role for FPP in dictating mig-DC survival by reprogramming mitochondrial structure and metabolism, providing new insights into the pathogenesis of DC-dependent autoimmune diseases.
    DOI:  https://doi.org/10.1038/s42255-024-01149-x
  25. Nat Cell Biol. 2024 Oct 16.
    Waste management and cell death in T cells.
    Douglas R Green.
      
    DOI:  https://doi.org/10.1038/s41556-024-01538-0
  26. Nat Commun. 2024 Oct 15. 15(1): 8890
    Centrioles are frequently amplified in early B cell development but dispensable for humoral immunity.
    Marina A Schapfl, Gina M LoMastro, Vincent Z Braun, Maretoshi Hirai, Michelle S Levine, Eva Kiermaier, Verena Labi, Andrew J Holland, Andreas Villunger.
      Centrioles define centrosome structure and function. Deregulation of centriole numbers can cause developmental defects and cancer. The p53 tumor suppressor limits the growth of cells lacking or harboring additional centrosomes and can be engaged by the "mitotic surveillance" or the "PIDDosome pathway", respectively. Here, we show that early B cell progenitors frequently present extra centrioles, ensuing their high proliferative activity and related DNA damage. Extra centrioles are efficiently cleared during B cell maturation. In contrast, centriole loss upon Polo-like kinase 4 (Plk4) deletion causes apoptosis and arrests B cell development. This defect can be rescued by co-deletion of Usp28, a critical component of the mitotic surveillance pathway, that restores cell survival and maturation. Centriole-deficient mature B cells are proliferation competent and mount a humoral immune response. Our findings imply that progenitor B cells are intolerant to centriole loss but permissive to centriole amplification, a feature potentially facilitating their malignant transformation.
    DOI:  https://doi.org/10.1038/s41467-024-53222-4
  27. Nat Commun. 2024 Oct 18. 15(1): 9009
    Prosocial preferences can escalate intergroup conflicts by countering selfish motivations to leave.
    Luuk L Snijder, Jörg Gross, Mirre Stallen, Carsten K W De Dreu.
      When defending against hostile enemies, individual group members can benefit from others staying in the group and fighting. However, individuals themselves may be better off by leaving the group and avoiding the personal risks associated with fighting. While fleeing is indeed commonly observed, when and why defenders fight or flee remains poorly understood and is addressed here with three incentivized and preregistered experiments (total n = 602). In stylized attacker-defender contest games in which defenders could stay and fight or leave, we show that the less costly leaving is, the more likely individuals are to abandon their group. In addition, more risk-averse individuals are more likely to leave. Conversely, individuals more likely stay and fight when they have pro-social preferences and when fellow group members cannot leave. However, those who stay not always contribute fully to group defense, to some degree free-riding on the efforts of other group members. Nonetheless, staying increased intergroup conflict and its associated costs.
    DOI:  https://doi.org/10.1038/s41467-024-53409-9
  28. Nat Metab. 2024 Oct 15.
    Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
    Shane M O'Carroll, Christian G Peace, Juliana E Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J O'Sullivan, Aline Zoller, Anne F Mcgettrick, Emily A Day, Maria Simarro, Neali Armstrong, Justin P Annes, Luke A J O'Neill.
      Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.
    DOI:  https://doi.org/10.1038/s42255-024-01145-1
  29. J Exp Med. 2024 Nov 04. pii: e20240992. [Epub ahead of print]221(11):
    Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity.
    Hanson Tam, Ying Xu, Jinping An, Torsten Schöneberg, Angela Schulz, Jagan R Muppidi, Jason G Cyster.
      The peritoneal cavity (PerC) is an important site for immune responses to infection and cancer metastasis. Yet few ligand-receptor axes are known to preferentially govern immune cell accumulation in this compartment. GPR34 is a lysophosphatidylserine (lysoPS)-responsive receptor that frequently harbors gain-of-function mutations in mucosa-associated B cell lymphoma. Here, we set out to test the impact of a GPR34 knock-in (KI) allele in the B-lineage. We report that GPR34 KI promotes the PerC accumulation of plasma cells (PC) and memory B cells (MemB). These KI cells migrate robustly to lysoPS ex vivo, and the KI allele synergizes with a Bcl2 transgene to promote MemB but not PC accumulation. Gene expression and labeling studies reveal that GPR34 KI enhances PerC MemB proliferation. Both KI PC and MemB are specifically enriched at the omentum, a visceral adipose tissue containing fibroblasts that express the lysoPS-generating PLA1A enzyme. Adoptive transfer and chimera experiments revealed that KI PC and MemB maintenance in the PerC is dependent on stromal PLA1A. These findings provide in vivo evidence that PLA1A produces lysoPS that can regulate GPR34-mediated immune cell accumulation at the omentum.
    DOI:  https://doi.org/10.1084/jem.20240992
  30. Nature. 2024 Oct 18.
    The huge protein database that spawned AlphaFold and biology's AI revolution.
    Ewen Callaway.
      
    Keywords:  Databases
    DOI:  https://doi.org/10.1038/d41586-024-03423-0
  31. Nature. 2024 Oct 16.
    Quantifying constraint in the human mitochondrial genome.
    Nicole J Lake, Kaiyue Ma, Wei Liu, Stephanie L Battle, Kristen M Laricchia, Grace Tiao, Daniela Puiu, Kenneth K Ng, Justin Cohen, Alison G Compton, Shannon Cowie, John Christodoulou, David R Thorburn, Hongyu Zhao, Dan E Arking, Shamil R Sunyaev, Monkol Lek.
      Mitochondrial DNA (mtDNA) has an important yet often overlooked role in health and disease. Constraint models quantify the removal of deleterious variation from the population by selection and represent powerful tools for identifying genetic variation that underlies human phenotypes1-4. However, nuclear constraint models are not applicable to mtDNA, owing to its distinct features. Here we describe the development of a mitochondrial genome constraint model and its application to the Genome Aggregation Database (gnomAD), a large-scale population dataset that reports mtDNA variation across 56,434 human participants5. Specifically, we analyse constraint by comparing the observed variation in gnomAD to that expected under neutrality, which was calculated using a mtDNA mutational model and observed maximum heteroplasmy-level data. Our results highlight strong depletion of expected variation, which suggests that many deleterious mtDNA variants remain undetected. To aid their discovery, we compute constraint metrics for every mitochondrial protein, tRNA and rRNA gene, which revealed a range of intolerance to variation. We further characterize the most constrained regions within genes through regional constraint and identify the most constrained sites within the entire mitochondrial genome through local constraint, which showed enrichment of pathogenic variation. Constraint also clustered in three-dimensional structures, which provided insight into functionally important domains and their disease relevance. Notably, we identify constraint at often overlooked sites, including in rRNA and noncoding regions. Last, we demonstrate that these metrics can improve the discovery of deleterious variation that underlies rare and common phenotypes.
    DOI:  https://doi.org/10.1038/s41586-024-08048-x
  32. Nat Commun. 2024 Oct 17. 15(1): 8969
    Dynamic patterns of functional connectivity in the human brain underlie individual memory formation.
    Audrey T Phan, Weizhen Xie, Julio I Chapeton, Sara K Inati, Kareem A Zaghloul.
      Remembering our everyday experiences involves dynamically coordinating information distributed across different brain regions. Investigating how momentary fluctuations in connectivity in the brain are relevant for episodic memory formation, however, has been challenging. Here we leverage the high temporal precision of intracranial EEG to examine sub-second changes in functional connectivity in the human brain as 20 participants perform a paired associates verbal memory task. We first identify potential functional connections by selecting electrode pairs across the neocortex that exhibit strong correlations with a consistent time delay across random recording segments. We then find that successful memory formation during the task involves dynamic sub-second changes in functional connectivity that are specific to each word pair. These patterns of dynamic changes are reinstated when participants successfully retrieve the word pairs from memory. Therefore, our data provide direct evidence that specific patterns of dynamic changes in human brain connectivity are associated with successful memory formation.
    DOI:  https://doi.org/10.1038/s41467-024-52744-1
  33. J Exp Med. 2024 Nov 04. pii: e20220867. [Epub ahead of print]221(11):
    The lifespan and kinetics of human dendritic cell subsets and their precursors in health and inflammation.
    Ruth Lubin, Amit A Patel, Jonas Mackerodt, Yan Zhang, Rotem Gvili, Kevin Mulder, Charles-Antoine Dutertre, Parinaaz Jalali, James R W Glanville, Idit Hazan, Nikhila Sridharan, Gurion Rivkin, Ayse Akarca, Teresa Marafioti, Derek W Gilroy, Leonid Kandel, Alexander Mildner, Asaf Wilensky, Becca Asquith, Florent Ginhoux, Derek Macallan, Simon Yona.
      Dendritic cells (DC) are specialized mononuclear phagocytes that link innate and adaptive immunity. They comprise two principal subsets: plasmacytoid DC (pDC) and conventional DC (cDC). Understanding the generation, differentiation, and migration of cDC is critical for immune homeostasis. Through human in vivo deuterium-glucose labeling, we observed the rapid appearance of AXL+ Siglec6+ DC (ASDC) in the bloodstream. ASDC circulate for ∼2.16 days, while cDC1 and DC2 circulate for ∼1.32 and ∼2.20 days, respectively, upon release from the bone marrow. Interestingly, DC3, a cDC subset that shares several similarities with monocytes, exhibits a labeling profile closely resembling that of DC2. In a human in vivo model of cutaneous inflammation, ASDC were recruited to the inflammatory site, displaying a distinctive effector signature. Taken together, these results quantify the ephemeral circulating lifespan of human cDC and propose functions of cDC and their precursors that are rapidly recruited to sites of inflammation.
    DOI:  https://doi.org/10.1084/jem.20220867
  34. Nature. 2024 Oct 14.
    No bandage needed: electrical impulses to major nerve help stop bleeding.
    Max Kozlov.
      
    Keywords:  Immunology; Medical research; Neuroscience; Technology
    DOI:  https://doi.org/10.1038/d41586-024-03330-4
  35. Nature. 2024 Oct 17.
    Season's mis-greetings: why timing matters in global academia.
    Melissa Hart, Negin Nazarian.
      
    Keywords:  Careers; Climate sciences; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-03245-0
  36. Cell. 2024 Oct 17. pii: S0092-8674(24)01018-3. [Epub ahead of print]187(21): 5838-5857
    Unraveling mechanisms of human brain evolution.
    Madeline A Lancaster.
      Evolutionary changes in human brain structure and function have enabled our specialized cognitive abilities. How these changes have come about genetically and functionally has remained an open question. However, new methods are providing a wealth of information about the genetic, epigenetic, and transcriptomic differences that set the human brain apart. Combined with in vitro models that allow access to developing brain tissue and the cells of our closest living relatives, the puzzle pieces are now coming together to yield a much more complete picture of what is actually unique about the human brain. The challenge now will be linking these observations and making the jump from correlation to causation. However, elegant genetic manipulations are now possible and, when combined with model systems such as organoids, will uncover a mechanistic understanding of how evolutionary changes at the genetic level have led to key differences in development and function that enable human cognition.
    Keywords:  brain; development; evolution; human evolution; neuroscience; organoids
    DOI:  https://doi.org/10.1016/j.cell.2024.08.052
  37. Nat Aging. 2024 Oct;4(10): 1331-1334
    SEA-AD is a multimodal cellular atlas and resource for Alzheimer's disease.
    Michael Hawrylycz, Eitan S Kaplan, Kyle J Travaglini, Mariano I Gabitto, Jeremy A Miller, Lydia Ng, Jennie L Close, Rebecca D Hodge, Brian Long, Tyler Mollenkopf, Shoaib Mufti, Nicole M Gatto, Eric B Larson, Paul K Crane, Thomas J Grabowski, C Dirk Keene, Ed S Lein.
      
    DOI:  https://doi.org/10.1038/s43587-024-00719-8
  38. Nature. 2024 Oct 16.
    Neuronal sequences in population bursts encode information in human cortex.
    Weizhen Xie, John H Wittig, Julio I Chapeton, Mostafa El-Kalliny, Samantha N Jackson, Sara K Inati, Kareem A Zaghloul.
      Neural coding has traditionally been examined through changes in firing rates and latencies in response to different stimuli1-5. However, populations of neurons can also exhibit transient bursts of spiking activity, wherein neurons fire in a specific temporal order or sequence6-8. The human brain may utilize these neuronal sequences within population bursts to efficiently represent information9-12, thereby complementing the well-known neural code based on spike rate or latency. Here we examined this possibility by recording the spiking activity of populations of single units in the human anterior temporal lobe as eight participants performed a visual categorization task. We find that population spiking activity organizes into bursts during the task. The temporal order of spiking across the activated units within each burst varies across stimulus categories, creating unique stereotypical sequences for individual categories as well as for individual exemplars within a category. The information conveyed by the temporal order of spiking activity is separable from and complements the information conveyed by the units' spike rates or latencies following stimulus onset. Collectively, our data provide evidence that the human brain contains a complementary code based on the neuronal sequence within bursts of population spiking to represent information.
    DOI:  https://doi.org/10.1038/s41586-024-08075-8
  39. Nature. 2024 Oct;634(8034): S21-S23
    Clinical-trial reporting is on the rise.
    Inga Vesper.
      
    Keywords:  Health care; Medical research; Public health
    DOI:  https://doi.org/10.1038/d41586-024-03317-1
  40. Nat Commun. 2024 Oct 18. 15(1): 9000
    Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming.
    Dinesh K Deochand, Marija Dacic, Michael J Bale, Andrew W Daman, Vidyanath Chaudhary, Steven Z Josefowicz, David Oliver, Yurii Chinenov, Inez Rogatsky.
      Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids (GC), widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics that M2IL4 and M2GC transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the glucocorticoid receptor, whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, many of the M2IL4:M2GC-shared transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated phagocytic activity of both populations in vitro and macrophage tissue-repair properties in the murine colitis model in vivo. These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform anti-inflammatory drug design.
    DOI:  https://doi.org/10.1038/s41467-024-52942-x
  41. Nature. 2024 Oct 16.
    'Smart' insulin prevents diabetic highs - and deadly lows.
    Diana Kwon.
      
    Keywords:  Chemical biology; Diabetes; Drug discovery
    DOI:  https://doi.org/10.1038/d41586-024-03357-7
  42. Nature. 2024 Oct 15.
    The early days of peer review: five insights from historical reports.
    David Adam.
      
    Keywords:  History; Scientific community
    DOI:  https://doi.org/10.1038/d41586-024-03287-4
  43. Nat Commun. 2024 Oct 15. 15(1): 8894
    TGF-β-mediated crosstalk between TIGIT+ Tregs and CD226+CD8+ T cells in the progression and remission of type 1 diabetes.
    Ting Zhong, Xinyu Li, Kang Lei, Rong Tang, Qiaolin Deng, Paul E Love, Zhiguang Zhou, Bin Zhao, Xia Li.
      Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGIT+CCR7- Tregs and CD226+CCR7-CD8+ cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGIT+CCR7- Tregs and CD226+CD8+ T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGIT+CCR7- Tregs may inhibit CD226+CCR7-CD8+ T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D.
    DOI:  https://doi.org/10.1038/s41467-024-53264-8
  44. Immunity. 2024 Oct 09. pii: S1074-7613(24)00457-6. [Epub ahead of print]
    CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation.
    Jana L Raynor, Nicholas Collins, Hao Shi, Cliff Guy, Jordy Saravia, Seon Ah Lim, Nicole M Chapman, Peipei Zhou, Yan Wang, Yu Sun, Isabel Risch, Haoran Hu, Anil Kc, Renqiang Sun, Sharad Shrestha, Hongling Huang, Jon P Connelly, Shondra M Pruett-Miller, Miguel Reina-Campos, Ananda W Goldrath, Yasmine Belkaid, Hongbo Chi.
      Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using in vivo CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8+ tissue-resident memory T (TRM) cell development. TRM cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes-Flcn, Ragulator, and Rag GTPases-inhibited intestinal TRM cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to TRM programming. Further, Flcn deficiency promoted protective TRM cell responses in the small intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor β (TGF-β)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early TRM cell formation, while Acss1 controlled TRM cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity.
    Keywords:  CD8 T cell; adaptive immunity; dietary intervention; immunometabolism; lysosome; mitochondria; tissue-resident memory
    DOI:  https://doi.org/10.1016/j.immuni.2024.09.013
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