bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022–10–02
38 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity.
  2. Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics.
  3. Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function.
  4. Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance.
  5. Tregs in visceral adipose tissue up-regulate circadian-clock expression to promote fitness and enforce a diurnal rhythm of lipolysis.
  6. PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.
  7. Mitochondria controls TH17 cells.
  8. Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration.
  9. BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis.
  10. Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements.
  11. Lipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion.
  12. Targeting neoantigens.
  13. Activation of the human insulin receptor by non-insulin-related peptides.
  14. Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity.
  15. Stroke genetics informs drug discovery and risk prediction across ancestries.
  16. Sugar not fat.
  17. Imprinting tissue immunity.
  18. Regulation of autoimmune disease progression by Pik3ip1 through metabolic reprogramming in T cells and therapeutic implications.
  19. Nexinhib20 Inhibits Neutrophil Adhesion and β2 Integrin Activation by Antagonizing Rac-1-Guanosine 5'-Triphosphate Interaction.
  20. CRISPR screens in Drosophila cells identify Vsg as a Tc toxin receptor.
  21. Metabolite-driven antitumor immunity.
  22. Developmental dynamics of RNA translation in the human brain.
  23. MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis.
  24. The material properties of a bacterial-derived biomolecular condensate tune biological function in natural and synthetic systems.
  25. The transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors.
  26. CBLB Deficiency in Human CD4+ T Cells Results in Resistance to T Regulatory Suppression through Multiple Mechanisms.
  27. TraB family proteins are components of ER-mitochondrial contact sites and regulate ER-mitochondrial interactions and mitophagy.
  28. A competitive precision CRISPR method to identify the fitness effects of transcription factor binding sites.
  29. Therapeutic implications of mitochondrial stress-induced proteasome inhibitor resistance in multiple myeloma.
  30. An LKB1-mitochondria axis controls TH17 effector function.
  31. The role of gravitational body forces in the development of metamorphic core complexes.
  32. Tumor-specific exhaustion.
  33. Transcriptomic Profiling Identifies CD8+ T Cells in the Brain of Aged and Alzheimer's Disease Transgenic Mice as Tissue-Resident Memory T Cells.
  34. cDC1 coordinate innate and adaptive responses in the omentum required for T cell priming and memory.
  35. Tail proteins of phage SU10 reorganize into the nozzle for genome delivery.
  36. Population-level variation in enhancer expression identifies disease mechanisms in the human brain.
  37. Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes.
  38. Autocrine FGF1 signaling promotes glucose uptake in adipocytes.
  1. Nature. 2022 Sep 28.
    LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity.
    Akshay T Krishnamurty, Justin A Shyer, Minh Thai, Vineela Gandham, Matthew B Buechler, Yeqing Angela Yang, Rachana N Pradhan, Amber W Wang, Patricia L Sanchez, Yan Qu, Beatrice Breart, Cécile Chalouni, Debra Dunlap, James Ziai, Justin Elstrott, Neelie Zacharias, Weiguang Mao, Rebecca K Rowntree, Jack Sadowsky, Gail D Lewis, Thomas H Pillow, Barzin Y Nabet, Romain Banchereau, Lucinda Tam, Roger Caothien, Natasha Bacarro, Merone Roose-Girma, Zora Modrusan, Sanjeev Mariathasan, Sören Müller, Shannon J Turley.
      Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)1-3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15-diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-022-05272-1
  2. Nat Genet. 2022 Sep 29.
    Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics.
    Karthik A Jagadeesh, Kushal K Dey, Daniel T Montoro, Rahul Mohan, Steven Gazal, Jesse M Engreitz, Ramnik J Xavier, Alkes L Price, Aviv Regev.
      Genome-wide association studies provide a powerful means of identifying loci and genes contributing to disease, but in many cases, the related cell types/states through which genes confer disease risk remain unknown. Deciphering such relationships is important for identifying pathogenic processes and developing therapeutics. In the present study, we introduce sc-linker, a framework for integrating single-cell RNA-sequencing, epigenomic SNP-to-gene maps and genome-wide association study summary statistics to infer the underlying cell types and processes by which genetic variants influence disease. The inferred disease enrichments recapitulated known biology and highlighted notable cell-disease relationships, including γ-aminobutyric acid-ergic neurons in major depressive disorder, a disease-dependent M-cell program in ulcerative colitis and a disease-specific complement cascade process in multiple sclerosis. In autoimmune disease, both healthy and disease-dependent immune cell-type programs were associated, whereas only disease-dependent epithelial cell programs were prominent, suggesting a role in disease response rather than initiation. Our framework provides a powerful approach for identifying the cell types and cellular processes by which genetic variants influence disease.
    DOI:  https://doi.org/10.1038/s41588-022-01187-9
  3. Science. 2022 Sep 30. 377(6614): 1519-1529
    Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function.
    Giulia Notarangelo, Jessica B Spinelli, Elizabeth M Perez, Gregory J Baker, Kiran Kurmi, Ilaria Elia, Sylwia A Stopka, Gerard Baquer, Jia-Ren Lin, Alexandra J Golby, Shakchhi Joshi, Heide F Baron, Jefte M Drijvers, Peter Georgiev, Alison E Ringel, Elma Zaganjor, Samuel K McBrayer, Peter K Sorger, Arlene H Sharpe, Kai W Wucherpfennig, Sandro Santagata, Nathalie Y R Agar, Mario L Suvà, Marcia C Haigis.
      Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell-intrinsic effects of d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared the oncometabolite d-2HG with its enantiomer, l-2HG, and found that tumor-derived d-2HG was taken up by CD8+ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of d-2HG. d-2HG and inhibition of LDH drive a metabolic program and immune CD8+ T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.
    DOI:  https://doi.org/10.1126/science.abj5104
  4. Nat Commun. 2022 Sep 27. 13(1): 5671
    Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance.
    Xu Zhang, Vesselina M Pearsall, Chase M Carver, Elizabeth J Atkinson, Benjamin D S Clarkson, Ethan M Grund, Michelle Baez-Faria, Kevin D Pavelko, Jennifer M Kachergus, Thomas A White, Renee K Johnson, Courtney S Malo, Alan M Gonzalez-Suarez, Katayoun Ayasoufi, Kurt O Johnson, Zachariah P Tritz, Cori E Fain, Roman H Khadka, Mikolaj Ogrodnik, Diana Jurk, Yi Zhu, Tamara Tchkonia, Alexander Revzin, James L Kirkland, Aaron J Johnson, Charles L Howe, E Aubrey Thompson, Nathan K LeBrasseur, Marissa J Schafer.
      Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Activated resident and infiltrating immune cells increase in the aged brain and are partially restored to youthful levels through p16-positive senescent cell clearance in female p16-InkAttac mice, which is associated with preservation of cognitive function. Our study reveals dynamic remodeling of the brain immune cell landscape in aging and suggests senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.
    DOI:  https://doi.org/10.1038/s41467-022-33226-8
  5. Sci Immunol. 2022 Sep 30. 7(75): eabl7641
    Tregs in visceral adipose tissue up-regulate circadian-clock expression to promote fitness and enforce a diurnal rhythm of lipolysis.
    Tianli Xiao, P Kent Langston, Andrés R Muñoz-Rojas, Teshika Jayewickreme, Mitchell A Lazar, Christophe Benoist, Diane Mathis.
      Regulatory T cells (Tregs) in nonlymphoid organs provide critical brakes on inflammation and regulate tissue homeostasis. Although so-called "tissue Tregs" are phenotypically and functionally diverse, serving to optimize their performance and survival, up-regulation of pathways related to circadian rhythms is a feature they share. Yet the diurnal regulation of Tregs and its consequences are controversial and poorly understood. Here, we profiled diurnal variations in visceral adipose tissue (VAT) and splenic Tregs in the presence and absence of core-clock genes. VAT, but not splenic, Tregs up-regulated their cell-intrinsic circadian program and exhibited diurnal variations in their activation and metabolic state. BMAL1 deficiency specifically in Tregs led to constitutive activation and poor oxidative metabolism in VAT, but not splenic, Tregs. Disruption of core-clock components resulted in loss of fitness: BMAL1-deficient VAT Tregs were preferentially lost during competitive transfers and in heterozygous TregBmal1Δ females. After 16 weeks of high-fat diet feeding, VAT inflammation was increased in mice harboring BMAL1-deficient Tregs, and the remaining cells lost the transcriptomic signature of bona fide VAT Tregs. Unexpectedly, VAT Tregs suppressed adipocyte lipolysis, and BMAL1 deficiency specifically in Tregs abrogated the characteristic diurnal variation in adipose tissue lipolysis, resulting in enhanced suppression of lipolysis throughout the day. These findings argue for the importance of the cell-intrinsic clock program in optimizing VAT Treg function and fitness.
    DOI:  https://doi.org/10.1126/sciimmunol.abl7641
  6. Nature. 2022 Sep 28.
    PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.
    Masao Hashimoto, Koichi Araki, Maria A Cardenas, Peng Li, Rohit R Jadhav, Haydn T Kissick, William H Hudson, Donald J McGuire, Rebecca C Obeng, Andreas Wieland, Judong Lee, Daniel T McManus, James L Ross, Se Jin Im, Junghwa Lee, Jian-Xin Lin, Bin Hu, Erin E West, Christopher D Scharer, Gordon J Freeman, Arlene H Sharpe, Suresh S Ramalingam, Alex Pellerin, Volker Teichgräber, William J Greenleaf, Christian Klein, Jorg J Goronzy, Pablo Umaña, Warren J Leonard, Kendall A Smith, Rafi Ahmed.
      Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.
    DOI:  https://doi.org/10.1038/s41586-022-05257-0
  7. Nat Immunol. 2022 Sep 27.
    Mitochondria controls TH17 cells.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-022-01332-w
  8. Sci Adv. 2022 Sep 30. 8(39): eabo4662
    Neurons burdened by DNA double-strand breaks incite microglia activation through antiviral-like signaling in neurodegeneration.
    Gwyneth M Welch, Carles A Boix, Eloi Schmauch, Jose Davila-Velderrain, Matheus B Victor, Vishnu Dileep, P Lorenzo Bozzelli, Qiao Su, Jemmie D Cheng, Audrey Lee, Noelle S Leary, Andreas R Pfenning, Manolis Kellis, Li-Huei Tsai.
      DNA double-strand breaks (DSBs) are linked to neurodegeneration and senescence. However, it is not clear how DSB-bearing neurons influence neuroinflammation associated with neurodegeneration. Here, we characterize DSB-bearing neurons from the CK-p25 mouse model of neurodegeneration using single-nucleus, bulk, and spatial transcriptomic techniques. DSB-bearing neurons enter a late-stage DNA damage response marked by nuclear factor κB (NFκB)-activated senescent and antiviral immune pathways. In humans, Alzheimer's disease pathology is closely associated with immune activation in excitatory neurons. Spatial transcriptomics reveal that regions of CK-p25 brain tissue dense with DSB-bearing neurons harbor signatures of inflammatory microglia, which is ameliorated by NFκB knockdown in neurons. Inhibition of NFκB in DSB-bearing neurons also reduces microglia activation in organotypic mouse brain slice culture. In conclusion, DSBs activate immune pathways in neurons, which in turn adopt a senescence-associated secretory phenotype to elicit microglia activation. These findings highlight a previously unidentified role for neurons in the mechanism of disease-associated neuroinflammation.
    DOI:  https://doi.org/10.1126/sciadv.abo4662
  9. J Exp Med. 2022 Dec 05. pii: e20211476. [Epub ahead of print]219(12):
    BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis.
    Charlotte J Imianowski, Sarah K Whiteside, Teresa Lozano, Alexander C Evans, Jayme D Benson, Christina J F Courreges, Firas Sadiyah, Colleen M Lau, Nordin D Zandhuis, Francis M Grant, Martijn J Schuijs, Panagiota Vardaka, Paula Kuo, Elizabeth J Soilleux, Jie Yang, Joseph C Sun, Tomohiro Kurosaki, Klaus Okkenhaug, Timotheus Y F Halim, Rahul Roychoudhuri.
      Natural killer (NK) cells are critical to immune surveillance against infections and cancer. Their role in immune surveillance requires that NK cells are present within tissues in a quiescent state. Mechanisms by which NK cells remain quiescent in tissues are incompletely elucidated. The transcriptional repressor BACH2 plays a critical role within the adaptive immune system, but its function within innate lymphocytes has been unclear. Here, we show that BACH2 acts as an intrinsic negative regulator of NK cell maturation and function. BACH2 is expressed within developing and mature NK cells and promotes the maintenance of immature NK cells by restricting their maturation in the presence of weak stimulatory signals. Loss of BACH2 within NK cells results in accumulation of activated NK cells with unrestrained cytotoxic function within tissues, which mediate augmented immune surveillance to pulmonary cancer metastasis. These findings establish a critical function of BACH2 as a global negative regulator of innate cytotoxic function and tumor immune surveillance by NK cells.
    DOI:  https://doi.org/10.1084/jem.20211476
  10. Nat Genet. 2022 Sep 26.
    Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements.
    Lovelace J Luquette, Michael B Miller, Zinan Zhou, Craig L Bohrson, Yifan Zhao, Hu Jin, Doga Gulhan, Javier Ganz, Sara Bizzotto, Samantha Kirkham, Tino Hochepied, Claude Libert, Alon Galor, Junho Kim, Michael A Lodato, Juan I Garaycoechea, Charles Gawad, Jay West, Christopher A Walsh, Peter J Park.
      Accurate somatic mutation detection from single-cell DNA sequencing is challenging due to amplification-related artifacts. To reduce this artifact burden, an improved amplification technique, primary template-directed amplification (PTA), was recently introduced. We analyzed whole-genome sequencing data from 52 PTA-amplified single neurons using SCAN2, a new genotyper we developed to leverage mutation signatures and allele balance in identifying somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) in PTA data. Our analysis confirms an increase in nonclonal somatic mutation in single neurons with age, but revises the estimated rate of this accumulation to 16 SNVs per year. We also identify artifacts in other amplification methods. Most importantly, we show that somatic indels increase by at least three per year per neuron and are enriched in functional regions of the genome such as enhancers and promoters. Our data suggest that indels in gene-regulatory elements have a considerable effect on genome integrity in human neurons.
    DOI:  https://doi.org/10.1038/s41588-022-01180-2
  11. Nat Commun. 2022 Sep 30. 13(1): 5761
    Lipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion.
    Anastasiya Strembitska, Gwenaël Labouèbe, Alexandre Picard, Xavier P Berney, David Tarussio, Maxime Jan, Bernard Thorens.
      The counterregulatory response to hypoglycemia that restores normal blood glucose levels is an essential physiological function. It is initiated, in large part, by incompletely characterized brain hypoglycemia sensing neurons that trigger the secretion of counterregulatory hormones, in particular glucagon, to stimulate hepatic glucose production. In a genetic screen of recombinant inbred BXD mice we previously identified Agpat5 as a candidate regulator of hypoglycemia-induced glucagon secretion. Here, using genetic mouse models, we demonstrate that Agpat5 expressed in agouti-related peptide neurons is required for their activation by hypoglycemia, for hypoglycemia-induced vagal nerve activity, and glucagon secretion. We find that inactivation of Agpat5 leads to increased fatty acid oxidation and ATP production and that suppressing Cpt1a-dependent fatty acid import into mitochondria restores hypoglycemia sensing. Collectively, our data show that AgRP neurons are involved in the control of glucagon secretion and that Agpat5, by partitioning fatty acyl-CoAs away from mitochondrial fatty acid oxidation and ATP generation, ensures that the fall in intracellular ATP, which triggers neuronal firing, faithfully reflects changes in glycemia.
    DOI:  https://doi.org/10.1038/s41467-022-33484-6
  12. Nat Immunol. 2022 Sep 27.
    Targeting neoantigens.
    Nick Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-022-01334-8
  13. Nat Commun. 2022 Sep 28. 13(1): 5695
    Activation of the human insulin receptor by non-insulin-related peptides.
    Nicholas S Kirk, Qi Chen, Yingzhe Ginger Wu, Anastasia L Asante, Haitao Hu, Juan F Espinosa, Francisco Martínez-Olid, Mai B Margetts, Faiz A Mohammed, Vladislav V Kiselyov, David G Barrett, Michael C Lawrence.
      The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in turn effects trans-activation of the intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether insulin receptor signalling can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures that show how a 33-mer polypeptide unrelated to insulin can cross-link two sites on the receptor surface and direct the receptor into a signalling-active conformation. The 33-mer polypeptide engages the receptor by two helical binding motifs that are each potentially mimicable by small molecules. The resultant conformation of the receptor is distinct from-but related to-those in extant three-dimensional structures of the insulin-complexed receptor. Our findings thus illuminate unexplored pathways for controlling the signalling of the insulin receptor as well as opportunities for development of insulin mimetics.
    DOI:  https://doi.org/10.1038/s41467-022-33315-8
  14. Nat Commun. 2022 Sep 24. 13(1): 5606
    Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity.
    David Bradley, Alan J Smith, Alecia Blaszczak, Dharti Shantaram, Stephen M Bergin, Anahita Jalilvand, Valerie Wright, Kathleen L Wyne, Revati S Dewal, Lisa A Baer, Katherine R Wright, Kristin I Stanford, Bradley Needleman, Stacy Brethauer, Sabrena Noria, David Renton, Joshua J Joseph, Amy Lovett-Racke, Joey Liu, Willa A Hsueh.
      Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance.
    DOI:  https://doi.org/10.1038/s41467-022-33067-5
  15. Nature. 2022 Sep 30.
    Stroke genetics informs drug discovery and risk prediction across ancestries.
    COMPASS Consortium
      Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
    DOI:  https://doi.org/10.1038/s41586-022-05165-3
  16. Nat Immunol. 2022 Sep 27.
    Sugar not fat.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-022-01333-9
  17. Nat Immunol. 2022 Sep 27.
    Imprinting tissue immunity.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-022-01331-x
  18. Sci Adv. 2022 Sep 30. 8(39): eabo4250
    Regulation of autoimmune disease progression by Pik3ip1 through metabolic reprogramming in T cells and therapeutic implications.
    Wenqiang Xie, Juan Fang, Zhongyan Shan, Junyi Guo, Yuan Liao, Zhaolei Zou, Jun Wang, Shuqiong Wen, Lisa Yang, Yanshu Zhang, Huanzi Lu, Hang Zhao, Dong-Ming Kuang, Peng Huang, Qianming Chen, Zhi Wang.
      Metabolic alterations could profoundly affect immune functions and influence the progression and outcome of autoimmune diseases. However, the detailed mechanisms and their therapeutic potential remain to be defined. Here, we show that phosphatidylinositide 3-kinase interacting protein 1 (Pik3ip1), a newly identified negative immune regulator, is notably down-regulated in several major autoimmune diseases through a previously unidentified mechanism mediated by interleukin-21/p38 mitogen-activated protein kinase/a disintegrin and metalloprotease-17 (ADAM17) pathway. Down-regulation of Pik3ip1 in T cells causes a major metabolic shift from oxidative phosphorylation toward aerobic glycolysis, leading to their overactivation and aggressive disease progression in experimental autoimmune encephalomyelitis (EAE) mouse model. Suppression of hypoxia-inducible factor 1α (Hif1α) or pharmacologic inhibition of glycolysis could reverse these phenotypes and largely mitigate EAE severity. Our study reveals a previously unrecognized role of Pik3ip1 in metabolic regulation that substantially affects the inflammatory loop in the autoimmune setting and identifies the Pik3ip1/Hif1α/glycolysis axis as a potential therapeutic target for treatment of autoimmune diseases.
    DOI:  https://doi.org/10.1126/sciadv.abo4250
  19. J Immunol. 2022 Sep 07. pii: ji2101112. [Epub ahead of print]
    Nexinhib20 Inhibits Neutrophil Adhesion and β2 Integrin Activation by Antagonizing Rac-1-Guanosine 5'-Triphosphate Interaction.
    Wei Liu, Chunxia G Cronin, Ziming Cao, Chengliang Wang, Jianbin Ruan, Sunitha Pulikkot, Alexxus Hall, Hao Sun, Alex Groisman, Yunfeng Chen, Anthony T Vella, Liang Hu, Bruce T Liang, Zhichao Fan.
      Nutrophils are critical for mediating inflammatory responses. Inhibiting neutrophil recruitment is an attractive approach for preventing inflammatory injuries, including myocardial ischemia-reperfusion (I/R) injury, which exacerbates cardiomyocyte death after primary percutaneous coronary intervention in acute myocardial infarction. In this study, we found out that a neutrophil exocytosis inhibitor Nexinhib20 inhibits not only exocytosis but also neutrophil adhesion by limiting β2 integrin activation. Using a microfluidic chamber, we found that Nexinhib20 inhibited IL-8-induced β2 integrin-dependent human neutrophil adhesion under flow. Using a dynamic flow cytometry assay, we discovered that Nexinhib20 suppresses intracellular calcium flux and β2 integrin activation after IL-8 stimulation. Western blots of Ras-related C3 botulinum toxin substrate 1 (Rac-1)-GTP pull-down assays confirmed that Nexinhib20 inhibited Rac-1 activation in leukocytes. An in vitro competition assay showed that Nexinhib20 antagonized the binding of Rac-1 and GTP. Using a mouse model of myocardial I/R injury, Nexinhib20 administration after ischemia and before reperfusion significantly decreased neutrophil recruitment and infarct size. Our results highlight the translational potential of Nexinhib20 as a dual-functional neutrophil inhibitory drug to prevent myocardial I/R injury.
    DOI:  https://doi.org/10.4049/jimmunol.2101112
  20. Nature. 2022 Sep 28.
    CRISPR screens in Drosophila cells identify Vsg as a Tc toxin receptor.
    Ying Xu, Raghuvir Viswanatha, Oleg Sitsel, Daniel Roderer, Haifang Zhao, Christopher Ashwood, Cecilia Voelcker, Songhai Tian, Stefan Raunser, Norbert Perrimon, Min Dong.
      Entomopathogenic nematodes are widely used as biopesticides1,2. Their insecticidal activity depends on symbiotic bacteria such as Photorhabdus luminescens, which produces toxin complex (Tc) toxins as major virulence factors3-6. No protein receptors are known for any Tc toxins, which limits our understanding of their specificity and pathogenesis. Here we use genome-wide CRISPR-Cas9-mediated knockout screening in Drosophila melanogaster S2R+ cells and identify Visgun (Vsg) as a receptor for an archetypal P. luminescens Tc toxin (pTc). The toxin recognizes the extracellular O-glycosylated mucin-like domain of Vsg that contains high-density repeats of proline, threonine and serine (HD-PTS). Vsg orthologues in mosquitoes and beetles contain HD-PTS and can function as pTc receptors, whereas orthologues without HD-PTS, such as moth and human versions, are not pTc receptors. Vsg is expressed in immune cells, including haemocytes and fat body cells. Haemocytes from Vsg knockout Drosophila are resistant to pTc and maintain phagocytosis in the presence of pTc, and their sensitivity to pTc is restored through the transgenic expression of mosquito Vsg. Last, Vsg knockout Drosophila show reduced bacterial loads and lethality from P. luminescens infection. Our findings identify a proteinaceous Tc toxin receptor, reveal how Tc toxins contribute to P. luminescens pathogenesis, and establish a genome-wide CRISPR screening approach for investigating insecticidal toxins and pathogens.
    DOI:  https://doi.org/10.1038/s41586-022-05250-7
  21. Science. 2022 Sep 30. 377(6614): 1488-1489
    Metabolite-driven antitumor immunity.
    James A Nathan.
      An oncometabolite blocks T cell killing by inhibiting glycolysis.
    DOI:  https://doi.org/10.1126/science.ade3697
  22. Nat Neurosci. 2022 Sep 28.
    Developmental dynamics of RNA translation in the human brain.
    Erin E Duffy, Benjamin Finander, GiHun Choi, Ava C Carter, Iva Pritisanac, Aqsa Alam, Victor Luria, Amir Karger, William Phu, Maxwell A Sherman, Elena G Assad, Naomi Pajarillo, Alexandra Khitun, Elizabeth E Crouch, Sanika Ganesh, Jin Chen, Bonnie Berger, Nenad Sestan, Anne O'Donnell-Luria, Eric J Huang, Eric C Griffith, Julie D Forman-Kay, Alan M Moses, Brian T Kalish, Michael E Greenberg.
      The precise regulation of gene expression is fundamental to neurodevelopment, plasticity and cognitive function. Although several studies have profiled transcription in the developing human brain, there is a gap in understanding of accompanying translational regulation. In this study, we performed ribosome profiling on 73 human prenatal and adult cortex samples. We characterized the translational regulation of annotated open reading frames (ORFs) and identified thousands of previously unknown translation events, including small ORFs that give rise to human-specific and/or brain-specific microproteins, many of which we independently verified using proteomics. Ribosome profiling in stem-cell-derived human neuronal cultures corroborated these findings and revealed that several neuronal activity-induced non-coding RNAs encode previously undescribed microproteins. Physicochemical analysis of brain microproteins identified a class of proteins that contain arginine-glycine-glycine (RGG) repeats and, thus, may be regulators of RNA metabolism. This resource expands the known translational landscape of the human brain and illuminates previously unknown brain-specific protein products.
    DOI:  https://doi.org/10.1038/s41593-022-01164-9
  23. Nat Commun. 2022 Sep 29. 13(1): 5733
    MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis.
    Mary P LaPierre, Katherine Lawler, Svenja Godbersen, I Sadaf Farooqi, Markus Stoffel.
      MicroRNAs (miRNAs) modulate physiological responses by repressing the expression of gene networks. We found that global deletion of microRNA-7 (miR-7), the most enriched miRNA in the hypothalamus, causes obesity in mice. Targeted deletion of miR-7 in Single-minded homolog 1 (Sim1) neurons, a critical component of the hypothalamic melanocortin pathway, causes hyperphagia, obesity and increased linear growth, mirroring Sim1 and Melanocortin-4 receptor (MC4R) haplo-insufficiency in mice and humans. We identified Snca (α-Synuclein) and Igsf8 (Immunoglobulin Superfamily Member 8) as miR-7 target genes that act in Sim1 neurons to regulate body weight and endocrine axes. In humans, MIR-7-1 is located in the last intron of HNRNPK, whose promoter drives the expression of both genes. Genetic variants at the HNRNPK locus that reduce its expression are associated with increased height and truncal fat mass. These findings demonstrate that miR-7 suppresses gene networks involved in the hypothalamic melanocortin pathway to regulate mammalian energy homeostasis.
    DOI:  https://doi.org/10.1038/s41467-022-33367-w
  24. Nat Commun. 2022 Sep 26. 13(1): 5643
    The material properties of a bacterial-derived biomolecular condensate tune biological function in natural and synthetic systems.
    Keren Lasker, Steven Boeynaems, Vinson Lam, Daniel Scholl, Emma Stainton, Adam Briner, Maarten Jacquemyn, Dirk Daelemans, Ashok Deniz, Elizabeth Villa, Alex S Holehouse, Aaron D Gitler, Lucy Shapiro.
      Intracellular phase separation is emerging as a universal principle for organizing biochemical reactions in time and space. It remains incompletely resolved how biological function is encoded in these assemblies and whether this depends on their material state. The conserved intrinsically disordered protein PopZ forms condensates at the poles of the bacterium Caulobacter crescentus, which in turn orchestrate cell-cycle regulating signaling cascades. Here we show that the material properties of these condensates are determined by a balance between attractive and repulsive forces mediated by a helical oligomerization domain and an expanded disordered region, respectively. A series of PopZ mutants disrupting this balance results in condensates that span the material properties spectrum, from liquid to solid. A narrow range of condensate material properties supports proper cell division, linking emergent properties to organismal fitness. We use these insights to repurpose PopZ as a modular platform for generating tunable synthetic condensates in human cells.
    DOI:  https://doi.org/10.1038/s41467-022-33221-z
  25. Nat Commun. 2022 Sep 28. 13(1): 5703
    The transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors.
    Hui Wang, Boyuan Li, Linyu Zuo, Bo Wang, Yan Yan, Kai Tian, Rong Zhou, Chenlu Wang, Xizi Chen, Yongpeng Jiang, Haonan Zheng, Fangfei Qin, Bin Zhang, Yang Yu, Chao-Pei Liu, Yanhui Xu, Juntao Gao, Zhi Qi, Wulan Deng, Xiong Ji.
      RNA polymerase II (Pol II) apparatuses are compartmentalized into transcriptional clusters. Whether protein factors control these clusters remains unknown. In this study, we find that the ATPase-associated with diverse cellular activities (AAA + ) ATPase RUVBL2 co-occupies promoters with Pol II and various transcription factors. RUVBL2 interacts with unphosphorylated Pol II in chromatin to promote RPB1 carboxy-terminal domain (CTD) clustering and transcription initiation. Rapid depletion of RUVBL2 leads to a decrease in the number of Pol II clusters and inhibits nascent RNA synthesis, and tethering RUVBL2 to an active promoter enhances Pol II clustering at the promoter. We also identify target genes that are directly linked to the RUVBL2-Pol II axis. Many of these genes are hallmarks of cancers and encode proteins with diverse cellular functions. Our results demonstrate an emerging activity for RUVBL2 in regulating Pol II cluster formation in the nucleus.
    DOI:  https://doi.org/10.1038/s41467-022-33433-3
  26. J Immunol. 2022 Oct 01. 209(7): 1260-1271
    CBLB Deficiency in Human CD4+ T Cells Results in Resistance to T Regulatory Suppression through Multiple Mechanisms.
    Jing Song, Warren Anderson, Alex Hu, Kazushige Obata-Ninomiya, Steven F Ziegler, David J Rawlings, Jane H Buckner.
      Cbl-b is a negative regulator of T cell activation, and in murine models, a lack of Cblb results in resistance of T effector (Teff) cells to T regulatory (Treg) cells, a feature of T cells in many autoimmune diseases. Here, we used trackable gene editing approaches to knock out CBLB in primary human CD4+ T cells. We found that CBLB-knockout (CBLB-KO) CD4+ T cells were hyperproliferative and produced excessive amounts of IL-2. CBLB-KO CD4+ T cells were resistant to Treg suppression in vitro, which was partially reversed by blockade of IL-2. RNA-sequencing and puromycin incorporation assays demonstrated that CBLB-KO CD4+ T cells can overcome Treg suppression on the transcriptional and translational levels, resulting in the overproduction of cytokines to drive the proliferation and activation of Teff cells. These findings highlight a potential mechanism of Teff resistance in human autoimmune disease and the power of gene editing primary T cells to explore disease mechanisms.
    DOI:  https://doi.org/10.4049/jimmunol.2200219
  27. Nat Commun. 2022 Sep 26. 13(1): 5658
    TraB family proteins are components of ER-mitochondrial contact sites and regulate ER-mitochondrial interactions and mitophagy.
    Chengyang Li, Patrick Duckney, Tong Zhang, Yanshu Fu, Xin Li, Johan Kroon, Geert De Jaeger, Yunjiang Cheng, Patrick J Hussey, Pengwei Wang.
      ER-mitochondrial contact sites (EMCSs) are important for mitochondrial function. Here, we have identified a EMCS complex, comprising a family of uncharacterised mitochondrial outer membrane proteins, TRB1, TRB2, and the ER protein, VAP27-1. In Arabidopsis, there are three TraB family isoforms and the trb1/trb2 double mutant exhibits abnormal mitochondrial morphology, strong starch accumulation, and impaired energy metabolism, indicating that these proteins are essential for normal mitochondrial function. Moreover, TRB1 and TRB2 proteins also interact with ATG8 in order to regulate mitochondrial degradation (mitophagy). The turnover of depolarised mitochondria is significantly reduced in both trb1/trb2 and VAP27 mutants (vap27-1,3,4,6) under mitochondrial stress conditions, with an increased population of dysfunctional mitochondria present in the cytoplasm. Consequently, plant recovery after stress is significantly perturbed, suggesting that TRB1-regulated mitophagy and ER-mitochondrial interaction are two closely related processes. Taken together, we ascribe a dual role to TraB family proteins which are component of the EMCS complex in eukaryotes, regulating both interaction of the mitochondria to the ER and mitophagy.
    DOI:  https://doi.org/10.1038/s41467-022-33402-w
  28. Nat Biotechnol. 2022 Sep 26.
    A competitive precision CRISPR method to identify the fitness effects of transcription factor binding sites.
    Päivi Pihlajamaa, Otto Kauko, Biswajyoti Sahu, Teemu Kivioja, Jussi Taipale.
      Here we describe a competitive genome editing method that measures the effect of mutations on molecular functions, based on precision CRISPR editing using template libraries with either the original or altered sequence, and a sequence tag, enabling direct comparison between original and mutated cells. Using the example of the MYC oncogene, we identify important transcriptional targets and show that E-box mutations at MYC target gene promoters reduce cellular fitness.
    DOI:  https://doi.org/10.1038/s41587-022-01444-6
  29. Sci Adv. 2022 Sep 30. 8(39): eabq5575
    Therapeutic implications of mitochondrial stress-induced proteasome inhibitor resistance in multiple myeloma.
    Aditi Sharma, Remya Nair, Abhinav Achreja, Anjali Mittal, Pulkit Gupta, Kamakshi Balakrishnan, Claudia L Edgar, Olamide Animasahun, Bhakti Dwivedi, Benjamin G Barwick, Vikas A Gupta, Shannon M Matulis, Manoj Bhasin, Sagar Lonial, Ajay K Nooka, Arun P Wiita, Lawrence H Boise, Deepak Nagrath, Mala Shanmugam.
      The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show that ETC suppression promotes resistance to proteasome inhibitors (PIs). Interrogation of ETC-suppressed MM reveals integrated stress response-dependent suppression of protein translation and ubiquitination, leading to PI resistance. ETC and protein translation gene expression signatures from the CoMMpass trial are down-regulated in patients with poor outcome and relapse, corroborating our in vitro findings. ETC-suppressed MM exhibits up-regulation of the cystine-glutamate antiporter SLC7A11, and analysis of patient single-cell RNA-seq shows that clusters with low ETC gene expression correlate with higher SLC7A11 expression. Furthermore, erastin or venetoclax treatment diminishes mitochondrial stress-induced PI resistance. In sum, our work demonstrates that mitochondrial stress promotes PI resistance and underscores the need for implementing combinatorial regimens in MM cognizant of mitochondrial metabolic state.
    DOI:  https://doi.org/10.1126/sciadv.abq5575
  30. Nature. 2022 Sep 28.
    An LKB1-mitochondria axis controls TH17 effector function.
    Francesc Baixauli, Klara Piletic, Daniel J Puleston, Matteo Villa, Cameron S Field, Lea J Flachsmann, Andrea Quintana, Nisha Rana, Joy Edwards-Hicks, Mai Matsushita, Michal A Stanczak, Katarzyna M Grzes, Agnieszka M Kabat, Mario Fabri, George Caputa, Beth Kelly, Mauro Corrado, Yaarub Musa, Katarzyna J Duda, Gerhard Mittler, David O'Sullivan, Hiromi Sesaki, Thomas Jenuwein, Joerg M Buescher, Edward J Pearce, David E Sanin, Erika L Pearce.
      CD4+ T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes1-3. Mitochondrial membrane dynamics sustains mitochondrial processes4, including respiration and tricarboxylic acid (TCA) cycle metabolism5, but whether mitochondrial membrane remodelling orchestrates CD4+ T cell differentiation remains unclear. Here we show that unlike other CD4+ T cell subsets, T helper 17 (TH17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology6, revealed that TH17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD+ balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate-a metabolite that influences the epigenetic landscape5,7. Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+ and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of TH17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in TH17 cells.
    DOI:  https://doi.org/10.1038/s41586-022-05264-1
  31. Nat Commun. 2022 Sep 26. 13(1): 5646
    The role of gravitational body forces in the development of metamorphic core complexes.
    Alireza Bahadori, William E Holt, Jacqueline Austermann, Lajhon Campbell, E Troy Rasbury, Daniel M Davis, Christopher M Calvelage, Lucy M Flesch.
      Within extreme continental extension areas, ductile middle crust is exhumed at the surface as metamorphic core complexes. Sophisticated quantitative models of extreme extension predicted upward transport of ductile middle-lower crust through time. Here we develop a general model for metamorphic core complexes formation and demonstrate that they result from the collapse of a mountain belt supported by a thickened crustal root. We show that gravitational body forces generated by topography and crustal root cause an upward flow pattern of the ductile lower-middle crust, facilitated by a detachment surface evolving into low-angle normal fault. This detachment surface acquires large amounts of finite strain, consistent with thick mylonite zones found in metamorphic core complexes. Isostatic rebound exposes the detachment in a domed upwarp, while the final Moho discontinuity across the extended region relaxes to a flat geometry. This work suggests that belts of metamorphic core complexes are a fossil signature of collapsed highlands.
    DOI:  https://doi.org/10.1038/s41467-022-33361-2
  32. Nat Immunol. 2022 Sep 27.
    Tumor-specific exhaustion.
    Ioana Visan.
      
    DOI:  https://doi.org/10.1038/s41590-022-01330-y
  33. J Immunol. 2022 Oct 01. 209(7): 1272-1285
    Transcriptomic Profiling Identifies CD8+ T Cells in the Brain of Aged and Alzheimer's Disease Transgenic Mice as Tissue-Resident Memory T Cells.
    Barbara Altendorfer, Michael Stefan Unger, Rodolphe Poupardin, Anna Hoog, Daniela Asslaber, Iris Karina Gratz, Heike Mrowetz, Ariane Benedetti, Diana Marisa Bessa de Sousa, Richard Greil, Alexander Egle, David Gate, Tony Wyss-Coray, Ludwig Aigner.
      Peripheral immune cell infiltration into the brain is a prominent feature in aging and various neurodegenerative diseases such as Alzheimer's disease (AD). As AD progresses, CD8+ T cells infiltrate into the brain parenchyma, where they tightly associate with neurons and microglia. The functional properties of CD8+ T cells in the brain are largely unknown. To gain further insights into the putative functions of CD8+ T cells in the brain, we explored and compared the transcriptomic profile of CD8+ T cells isolated from the brain and blood of transgenic AD (APPswe/PSEN1dE9, line 85 [APP-PS1]) and age-matched wild-type (WT) mice. Brain CD8+ T cells of APP-PS1 and WT animals had similar transcriptomic profiles and substantially differed from blood circulating CD8+ T cells. The gene signature of brain CD8+ T cells identified them as tissue-resident memory (Trm) T cells. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis on the significantly upregulated genes revealed overrepresentation of biological processes involved in IFN-β signaling and the response to viral infections. Furthermore, brain CD8+ T cells of APP-PS1 and aged WT mice showed similar differentially regulated genes as brain Trm CD8+ T cells in mouse models with acute virus infection, chronic parasite infection, and tumor growth. In conclusion, our profiling of brain CD8+ T cells suggests that in AD, these cells exhibit similar adaptive immune responses as in other inflammatory diseases of the CNS, potentially opening the door for immunotherapy in AD.
    DOI:  https://doi.org/10.4049/jimmunol.2100737
  34. Sci Immunol. 2022 Sep 30. 7(75): eabq7432
    cDC1 coordinate innate and adaptive responses in the omentum required for T cell priming and memory.
    David A Christian, Thomas A Adams, Lindsey A Shallberg, Anthony T Phan, Tony E Smith, Mosana Abraha, Joseph Perry, Gordon Ruthel, Joseph T Clark, Gretchen Harms Pritchard, Lillian R Aronson, Selamawit Gossa, Dorian B McGavern, Ross M Kedl, Christopher A Hunter.
      In the peritoneal cavity, the omentum contains fat-associated lymphoid clusters (FALCs) whose role in response to infection is poorly understood. After intraperitoneal immunization with Toxoplasma gondii, conventional type 1 dendritic cells (cDC1s) were critical to induce innate sources of IFN-γ and cellular changes in the FALCs. Unexpectedly, infected peritoneal macrophages that migrated into the FALCs primed CD8+ T cells. Although T cell priming was cDC1 independent, these DCs were required for maximal CD8+ T cell expansion. An agent-based computational model and experimental data highlighted that cDC1s affected the magnitude of the proliferative burst and promoted CD8+ T cell expression of nutrient uptake receptors and cell survival. Thus, although FALCs lack the organization of secondary lymphoid organs, cDC1s resident in this tissue coordinate innate responses to microbial challenge and provide secondary signals required for T cell expansion and memory formation.
    DOI:  https://doi.org/10.1126/sciimmunol.abq7432
  35. Nat Commun. 2022 Sep 24. 13(1): 5622
    Tail proteins of phage SU10 reorganize into the nozzle for genome delivery.
    Marta Šiborová, Tibor Füzik, Michaela Procházková, Jiří Nováček, Martin Benešík, Anders S Nilsson, Pavel Plevka.
      Escherichia coli phage SU10 belongs to the genus Kuravirus from the class Caudoviricetes of phages with short non-contractile tails. In contrast to other short-tailed phages, the tails of Kuraviruses elongate upon cell attachment. Here we show that the virion of SU10 has a prolate head, containing genome and ejection proteins, and a tail, which is formed of portal, adaptor, nozzle, and tail needle proteins and decorated with long and short fibers. The binding of the long tail fibers to the receptors in the outer bacterial membrane induces the straightening of nozzle proteins and rotation of short tail fibers. After the re-arrangement, the nozzle proteins and short tail fibers alternate to form a nozzle that extends the tail by 28 nm. Subsequently, the tail needle detaches from the nozzle proteins and five types of ejection proteins are released from the SU10 head. The nozzle with the putative extension formed by the ejection proteins enables the delivery of the SU10 genome into the bacterial cytoplasm. It is likely that this mechanism of genome delivery, involving the formation of the tail nozzle, is employed by all Kuraviruses.
    DOI:  https://doi.org/10.1038/s41467-022-33305-w
  36. Nat Genet. 2022 Sep 26.
    Population-level variation in enhancer expression identifies disease mechanisms in the human brain.
    CommonMind Consortium
      Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding population-level variation in enhancer function in the human brain. Besides regulating tissue-specific and cell-type-specific transcription of target genes, enhancers themselves can be transcribed. By jointly analyzing large-scale cell-type-specific transcriptome and regulome data, we cataloged 30,795 neuronal and 23,265 non-neuronal candidate transcribed enhancers. Examination of the transcriptome in 1,382 brain samples identified robust expression of transcribed enhancers. We explored gene-enhancer coordination and found that enhancer-linked genes are strongly implicated in neuropsychiatric disease. We identified expression quantitative trait loci (eQTLs) for both genes and enhancers and found that enhancer eQTLs mediate a substantial fraction of neuropsychiatric trait heritability. Inclusion of enhancer eQTLs in transcriptome-wide association studies enhanced functional interpretation of disease loci. Overall, our study characterizes the gene-enhancer regulome and genetic mechanisms in the human cortex in both healthy and diseased states.
    DOI:  https://doi.org/10.1038/s41588-022-01170-4
  37. Cell. 2022 Sep 29. pii: S0092-8674(22)01128-X. [Epub ahead of print]185(20): 3689-3704.e21
    Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes.
    Alessa R Ringel, Quentin Szabo, Andrea M Chiariello, Konrad Chudzik, Robert Schöpflin, Patricia Rothe, Alexandra L Mattei, Tobias Zehnder, Dermot Harnett, Verena Laupert, Simona Bianco, Sara Hetzel, Juliane Glaser, Mai H Q Phan, Magdalena Schindler, Daniel M Ibrahim, Christina Paliou, Andrea Esposito, Cesar A Prada-Medina, Stefan A Haas, Peter Giere, Martin Vingron, Lars Wittler, Alexander Meissner, Mario Nicodemi, Giacomo Cavalli, Frédéric Bantignies, Stefan Mundlos, Michael I Robson.
      Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1's intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42's unresponsiveness. Rather, Zfp42's promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome wide, most TADs contain multiple independently expressed genes.
    Keywords:  3D genome organization; CTCF; DNA methylation; cohesin; developmental gene regulation; enhancer-promoter specificity; evolution; lamina-associated domain; loop extrusion; topologically associating domains
    DOI:  https://doi.org/10.1016/j.cell.2022.09.006
  38. Proc Natl Acad Sci U S A. 2022 Oct 04. 119(40): e2122382119
    Autocrine FGF1 signaling promotes glucose uptake in adipocytes.
    Vera J M Nies, Dicky Struik, Sihao Liu, Weilin Liu, Janine K Kruit, Michael Downes, Tim van Zutphen, Henkjan J Verkade, Ronald M Evans, Johan W Jonker.
      Fibroblast growth factor 1 (FGF1) is an autocrine growth factor released from adipose tissue during over-nutrition or fasting to feeding transition. While local actions underlie the majority of FGF1's anti-diabetic functions, the molecular mechanisms downstream of adipose FGF receptor signaling are unclear. We investigated the effects of FGF1 on glucose uptake and its underlying mechanism in murine 3T3-L1 adipocytes and in ex vivo adipose explants from mice. FGF1 increased glucose uptake in 3T3-L1 adipocytes and epididymal WAT (eWAT) and inguinal WAT (iWAT). Conversely, glucose uptake was reduced in eWAT and iWAT of FGF1 knockout mice. We show that FGF1 acutely increased adipocyte glucose uptake via activation of the insulin-sensitive glucose transporter GLUT4, involving dynamic crosstalk between the MEK1/2 and Akt signaling proteins. Prolonged exposure to FGF1 stimulated adipocyte glucose uptake by MEK1/2-dependent transcription of the basal glucose transporter GLUT1. We have thus identified an alternative pathway to stimulate glucose uptake in adipocytes, independent from insulin, which could open new avenues for treating patients with type 2 diabetes.
    Keywords:  FGF1; adipocytes; fibroblast growth factors; glucose metabolism; insulin
    DOI:  https://doi.org/10.1073/pnas.2122382119
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