bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023‒10‒29
forty-nine papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A lesson from failure.
  2. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.
  3. Interferon-γ couples CD8+ T cell avidity and differentiation during infection.
  4. The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.
  5. APOE set the microglia free.
  6. Small and mighty: The hypothalamus.
  7. C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity.
  8. Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.
  9. The challenge of identifying senescent cells.
  10. The functional impact of rare variation across the regulatory cascade.
  11. Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.
  12. Immune synapse formation promotes lipid peroxidation and MHC-I upregulation in licensed dendritic cells for efficient priming of CD8+ T cells.
  13. Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance.
  14. DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts.
  15. Artificial intelligence and interspecific law.
  16. Respiratory mucosal immune memory to SARS-CoV-2 after infection and vaccination.
  17. Organoids transplantation attenuates intestinal ischemia/reperfusion injury in mice through L-Malic acid-mediated M2 macrophage polarization.
  18. Plasma biomarkers predict Alzheimer's disease before clinical onset in Chinese cohorts.
  19. PAPγ associates with PAXT nuclear exosome to control the abundance of PROMPT ncRNAs.
  20. Imaging glycosylated RNAs at the subcellular scale.
  21. Do mammals have menopause?
  22. Ebf3+ niche-derived CXCL12 is required for the localization and maintenance of hematopoietic stem cells.
  23. Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging.
  24. Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura.
  25. The endocannabinoid N-arachidonoyl dopamine is critical for hyperalgesia induced by chronic sleep disruption.
  26. Scientists deliberately gave women Zika - here's why.
  27. Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.
  28. Manganese regulation of COPII condensation controls circulating lipid homeostasis.
  29. Selective control of transposable element expression during T cell exhaustion and anti-PD-1 treatment.
  30. A mitochondrial pentatricopeptide repeat protein enhances cold tolerance by modulating mitochondrial superoxide in rice.
  31. Biomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy.
  32. TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells.
  33. Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis.
  34. Cannabinoid receptor 2 signal promotes type 2 immunity in the lung.
  35. Interconverting mirror-image molecules.
  36. Resident regulatory T cells reflect the immune history of individual lymph nodes.
  37. Telomouse-a mouse model with human-length telomeres generated by a single amino acid change in RTEL1.
  38. Mountain mice break altitude record for mammalian life.
  39. Bach2 Integrates Cytokine Signals to Arbitrate Differentiation Decisions between T Follicular Helper and Th17 Lineages.
  40. Developing synthetic tools to decipher the tumor-immune interactome.
  41. Visualization of accessible cholesterol using a GRAM domain-based biosensor.
  42. Demographic and hormonal evidence for menopause in wild chimpanzees.
  43. SARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors.
  44. Dopamine determines how reward overrides risk.
  45. Domain adapted brain network fusion captures variance related to pubertal brain development and mental health.
  46. A deep population reference panel of tandem repeat variation.
  47. The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer.
  48. Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.
  49. Dengue rates drop after release of modified mosquitoes in Colombia.
  1. Science. 2023 Oct 27. 382(6669): 482
    A lesson from failure.
    Michał Turek.
      
    DOI:  https://doi.org/10.1126/science.adl4907
  2. Nat Commun. 2023 Oct 27. 14(1): 6858
    Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming.
    Hao Wu, Xiufeng Zhao, Sophia M Hochrein, Miriam Eckstein, Gabriela F Gubert, Konrad Knöpper, Ana Maria Mansilla, Arman Öner, Remi Doucet-Ladevèze, Werner Schmitz, Bart Ghesquière, Sebastian Theurich, Jan Dudek, Georg Gasteiger, Alma Zernecke, Sebastian Kobold, Wolfgang Kastenmüller, Martin Vaeth.
      T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-023-42634-3
  3. Nat Commun. 2023 Oct 23. 14(1): 6727
    Interferon-γ couples CD8+ T cell avidity and differentiation during infection.
    Lion F K Uhl, Han Cai, Sophia L Oram, Jagdish N Mahale, Andrew J MacLean, Julie M Mazet, Theo Piccirilli, Alexander J He, Doreen Lau, Tim Elliott, Audrey Gerard.
      Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate.
    DOI:  https://doi.org/10.1038/s41467-023-42455-4
  4. Nat Commun. 2023 Oct 23. 14(1): 6721
    The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.
    Hakjoo Lee, Tae Jin Lee, Chad A Galloway, Wenbo Zhi, Wei Xiao, Karen L de Mesy Bentley, Ashok Sharma, Yong Teng, Hiromi Sesaki, Yisang Yoon.
      Mitochondria are critical for metabolic homeostasis of the liver, and their dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein with a role in cristae shaping. Disruption of OPA1 causes mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we delete OPA1 in the fully developed liver of male mice. Unexpectedly, OPA1 liver knockout (LKO) mice are healthy with unaffected mitochondrial respiration, despite disrupted cristae morphology. OPA1 LKO induces a stress response that establishes a new homeostatic state for sustained liver function. Our data show that OPA1 is required for proper complex V assembly and that OPA1 LKO protects the liver from drug toxicity. Mechanistically, OPA1 LKO decreases toxic drug metabolism and confers resistance to the mitochondrial permeability transition. This study demonstrates that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 LKO prevents liver injury and contributes to liver resiliency.
    DOI:  https://doi.org/10.1038/s41467-023-42564-0
  5. Nat Immunol. 2023 Nov;24(11): 1790-1791
    APOE set the microglia free.
    Emile Wogram, Marco Prinz.
      
    DOI:  https://doi.org/10.1038/s41590-023-01651-6
  6. Science. 2023 Oct 27. 382(6669): 386-387
    Small and mighty: The hypothalamus.
    Mattia Maroso, Peter Stern.
      
    DOI:  https://doi.org/10.1126/science.adl3437
  7. Nat Commun. 2023 Oct 23. 14(1): 6718
    C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity.
    Fan Li, Hui Wang, Yan-Qi Li, Yebo Gu, Xin-Ming Jia.
      Dimerization of C-type lectin receptors (CLRs) or Toll-like receptors (TLRs) can alter their ligand binding ability, thereby modulating immune responses. However, the possibilities and roles of dimerization between CLRs and TLRs remain unclear. Here we show that C-type lectin receptor-2d (CLEC2D) forms homodimers, as well as heterodimers with TLR2. Quantitative ligand binding assays reveal that both CLEC2D homodimers and CLEC2D/TLR2 heterodimers have a higher binding ability to fungi-derived β-glucans than TLR2 homodimers. Moreover, homo- or hetero-dimeric CLEC2D mediates β-glucan-induced ubiquitination and degradation of MyD88 to inhibit the activation of transcription factor IRF5 and subsequent IL-12 production. Clec2d-deficient female mice are resistant to infection with Candida albicans, a human fungal pathogen, owing to the increase of IL-12 production and subsequent generation of IFN-γ-producing NK cells. Together, these data indicate that CLEC2D forms homodimers or heterodimers with TLR2, which negatively regulate antifungal immunity through suppression of IRF5-mediated IL-12 production. These homo- and hetero-dimers of CLEC2D and TLR2 provide an example of receptor dimerization to regulate host innate immunity against microbial infections.
    DOI:  https://doi.org/10.1038/s41467-023-42216-3
  8. Cell. 2023 Oct 18. pii: S0092-8674(23)01078-4. [Epub ahead of print]
    Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.
    Jonathan Bohlen, Qinhua Zhou, Quentin Philippot, Masato Ogishi, Darawan Rinchai, Tea Nieminen, Simin Seyedpour, Nima Parvaneh, Nima Rezaei, Niloufar Yazdanpanah, Mana Momenilandi, Clément Conil, Anna-Lena Neehus, Carltin Schmidt, Carlos A Arango-Franco, Tom Le Voyer, Taushif Khan, Rui Yang, Julia Puchan, Lucia Erazo, Mykola Roiuk, Taja Vatovec, Zarah Janda, Ivan Bagarić, Marie Materna, Adrian Gervais, Hailun Li, Jérémie Rosain, Jessica N Peel, Yoann Seeleuthner, Ji Eun Han, Anne-Sophie L'Honneur, Marcela Moncada-Vélez, Marta Martin-Fernandez, Michael E Horesh, Tatiana Kochetkov, Monika Schmidt, Mohammed A AlShehri, Eeva Salo, Harri Saxen, Gehad ElGhazali, Ahmad Yatim, Camille Soudée, Federica Sallusto, Armin Ensser, Nico Marr, Peng Zhang, Dusan Bogunovic, Aurélie Cobat, Mohammad Shahrooei, Vivien Béziat, Laurent Abel, Xiaochuan Wang, Stéphanie Boisson-Dupuis, Aurelio A Teleman, Jacinta Bustamante, Qian Zhang, Jean-Laurent Casanova.
      Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.
    Keywords:  IL-23; JAK2; MCTS1; MSMD; X-linked disease; inborn error of immunity; mycobacterium; translation re-initiation
    DOI:  https://doi.org/10.1016/j.cell.2023.09.024
  9. Nat Cell Biol. 2023 Oct 26.
    The challenge of identifying senescent cells.
    Jesús Gil.
      
    DOI:  https://doi.org/10.1038/s41556-023-01267-w
  10. Cell Genom. 2023 Oct 11. 3(10): 100401
    The functional impact of rare variation across the regulatory cascade.
    Taibo Li, Nicole Ferraro, Benjamin J Strober, Francois Aguet, Silva Kasela, Marios Arvanitis, Bohan Ni, Laurens Wiel, Elliot Hershberg, Kristin Ardlie, Dan E Arking, Rebecca L Beer, Jennifer Brody, Thomas W Blackwell, Clary Clish, Stacey Gabriel, Robert Gerszten, Xiuqing Guo, Namrata Gupta, W Craig Johnson, Tuuli Lappalainen, Henry J Lin, Yongmei Liu, Deborah A Nickerson, George Papanicolaou, Jonathan K Pritchard, Pankaj Qasba, Ali Shojaie, Josh Smith, Nona Sotoodehnia, Kent D Taylor, Russell P Tracy, David Van Den Berg, Matthew T Wheeler, Stephen S Rich, Jerome I Rotter, Alexis Battle, Stephen B Montgomery.
      Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease.
    Keywords:  functional genomics; machine learning; methylome; multi-omics; proteome; rare variants; transcriptome
    DOI:  https://doi.org/10.1016/j.xgen.2023.100401
  11. Nat Commun. 2023 Oct 23. 14(1): 6729
    Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.
    Hongming Su, Hong Guo, Xiaoxue Qiu, Te-Yueh Lin, Chao Qin, Gail Celio, Peter Yong, Mark Senders, Xianlin Han, David A Bernlohr, Xiaoli Chen.
      Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.
    DOI:  https://doi.org/10.1038/s41467-023-42473-2
  12. Nat Commun. 2023 Oct 25. 14(1): 6772
    Immune synapse formation promotes lipid peroxidation and MHC-I upregulation in licensed dendritic cells for efficient priming of CD8+ T cells.
    Diego Calzada-Fraile, Salvador Iborra, Marta Ramírez-Huesca, Inmaculada Jorge, Enrico Dotta, Elena Hernández-García, Noa Martín-Cófreces, Estanislao Nistal-Villán, Esteban Veiga, Jesús Vázquez, Giulia Pasqual, Francisco Sánchez-Madrid.
      Antigen cognate dendritic cell (DC)-T cell synaptic interactions drive activation of T cells and instruct DCs. Upon receiving CD4+ T cell help, post-synaptic DCs (psDCs) are licensed to generate CD8+ T cell responses. However, the cellular and molecular mechanisms that enable psDCs licensing remain unclear. Here, we describe that antigen presentation induces an upregulation of MHC-I protein molecules and increased lipid peroxidation on psDCs in vitro and in vivo. We also show that these events mediate DC licensing. In addition, psDC adoptive transfer enhances pathogen-specific CD8+ T responses and protects mice from infection in a CD8+ T cell-dependent manner. Conversely, depletion of psDCs in vivo abrogates antigen-specific CD8+ T cell responses during immunization. Together, our data show that psDCs enable CD8+ T cell responses in vivo during vaccination and reveal crucial molecular events underlying psDC licensing.
    DOI:  https://doi.org/10.1038/s41467-023-42480-3
  13. Sci Immunol. 2023 Oct 27. 8(88): eabq3109
    Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance.
    Jun Hyung Sin, Juliana Sucharov, Sujit Kashyap, Yi Wang, Irina Proekt, Xian Liu, Audrey V Parent, Alexander Gupta, Philippe Kastner, Susan Chan, James M Gardner, Vasilis Ntranos, Corey N Miller, Mark S Anderson, Hilde Schjerven, Michael R Waterfield.
      Mutations in the gene encoding the zinc-finger transcription factor Ikaros (IKZF1) are found in patients with immunodeficiency, leukemia, and autoimmunity. Although Ikaros has a well-established function in modulating gene expression programs important for hematopoietic development, its role in other cell types is less well defined. Here, we uncover functions for Ikaros in thymic epithelial lineage development in mice and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both autoimmune regulator-positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity, and its deletion results in a marked expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals that Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
    DOI:  https://doi.org/10.1126/sciimmunol.abq3109
  14. Nat Commun. 2023 Oct 23. 14(1): 6731
    DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts.
    Ashish Goyal, Jens Bauer, Joschka Hey, Dimitris N Papageorgiou, Ekaterina Stepanova, Michael Daskalakis, Jonas Scheid, Marissa Dubbelaar, Boris Klimovich, Dominic Schwarz, Melanie Märklin, Malte Roerden, Yu-Yu Lin, Tobias Ma, Oliver Mücke, Hans-Georg Rammensee, Michael Lübbert, Fabricio Loayza-Puch, Jeroen Krijgsveld, Juliane S Walz, Christoph Plass.
      Immunotherapies targeting cancer-specific neoantigens have revolutionized the treatment of cancer patients. Recent evidence suggests that epigenetic therapies synergize with immunotherapies, mediated by the de-repression of endogenous retroviral element (ERV)-encoded promoters, and the initiation of transcription. Here, we use deep RNA sequencing from cancer cell lines treated with DNA methyltransferase inhibitor (DNMTi) and/or Histone deacetylase inhibitor (HDACi), to assemble a de novo transcriptome and identify several thousand ERV-derived, treatment-induced novel polyadenylated transcripts (TINPATs). Using immunopeptidomics, we demonstrate the human leukocyte antigen (HLA) presentation of 45 spectra-validated treatment-induced neopeptides (t-neopeptides) arising from TINPATs. We illustrate the potential of the identified t-neopeptides to elicit a T-cell response to effectively target cancer cells. We further verify the presence of t-neopeptides in AML patient samples after in vivo treatment with the DNMT inhibitor Decitabine. Our findings highlight the potential of ERV-derived neoantigens in epigenetic and immune therapies.
    DOI:  https://doi.org/10.1038/s41467-023-42417-w
  15. Science. 2023 Oct 27. 382(6669): 376-378
    Artificial intelligence and interspecific law.
    Daniel J Gervais, John J Nay.
      Law could recognize nonhuman AI-led corporate entities.
    DOI:  https://doi.org/10.1126/science.adi8678
  16. Nat Commun. 2023 Oct 26. 14(1): 6815
    Respiratory mucosal immune memory to SARS-CoV-2 after infection and vaccination.
    Elena Mitsi, Mariana O Diniz, Jesús Reiné, Andrea M Collins, Ryan E Robinson, Angela Hyder-Wright, Madlen Farrar, Konstantinos Liatsikos, Josh Hamilton, Onyia Onyema, Britta C Urban, Carla Solórzano, Sandra Belij-Rammerstorfer, Emma Sheehan, Teresa Lambe, Simon J Draper, Daniela Weiskopf, Alessandro Sette, Mala K Maini, Daniela M Ferreira.
      Respiratory mucosal immunity induced by vaccination is vital for protection from coronavirus infection in animal models. In humans, the capacity of peripheral vaccination to generate sustained immunity in the lung mucosa, and how this is influenced by prior SARS-CoV-2 infection, is unknown. Here we show using bronchoalveolar lavage samples that donors with history of both infection and vaccination have more airway mucosal SARS-CoV-2 antibodies and memory B cells than those only vaccinated. Infection also induces populations of airway spike-specific memory CD4+ and CD8+ T cells that are not expanded by vaccination alone. Airway mucosal T cells induced by infection have a distinct hierarchy of antigen specificity compared to the periphery. Spike-specific T cells persist in the lung mucosa for 7 months after the last immunising event. Thus, peripheral vaccination alone does not appear to induce durable lung mucosal immunity against SARS-CoV-2, supporting an argument for the need for vaccines targeting the airways.
    DOI:  https://doi.org/10.1038/s41467-023-42433-w
  17. Nat Commun. 2023 Oct 25. 14(1): 6779
    Organoids transplantation attenuates intestinal ischemia/reperfusion injury in mice through L-Malic acid-mediated M2 macrophage polarization.
    Fang-Ling Zhang, Zhen Hu, Yi-Fan Wang, Wen-Juan Zhang, Bo-Wei Zhou, Qi-Shun Sun, Ze-Bin Lin, Ke-Xuan Liu.
      Intestinal organoid transplantation is a promising therapy for the treatment of mucosal injury. However, how the transplanted organoids regulate the immune microenvironment of recipient mice and their role in treating intestinal ischemia-reperfusion (I/R) injury remains unclear. Here, we establish a method for transplanting intestinal organoids into intestinal I/R mice. We find that transplantation improve mouse survival, promote self-renewal of intestinal stem cells and regulate the immune microenvironment after intestinal I/R, depending on the enhanced ability of macrophages polarized to an anti-inflammatory M2 phenotype. Specifically, we report that L-Malic acid (MA) is highly expressed and enriched in the organoids-derived conditioned medium and cecal contents of transplanted mice, demonstrating that organoids secrete MA during engraftment. Both in vivo and in vitro experiments demonstrate that MA induces M2 macrophage polarization and restores interleukin-10 levels in a SOCS2-dependent manner. This study provides a therapeutic strategy for intestinal I/R injury.
    DOI:  https://doi.org/10.1038/s41467-023-42502-0
  18. Nat Commun. 2023 10 24. 14(1): 6747
    Plasma biomarkers predict Alzheimer's disease before clinical onset in Chinese cohorts.
    Huimin Cai, Yana Pang, Xiaofeng Fu, Ziye Ren, Longfei Jia.
      Plasma amyloid-β (Aβ)42, phosphorylated tau (p-tau)181, and neurofilament light chain (NfL) are promising biomarkers of Alzheimer's disease (AD). However, whether these biomarkers can predict AD in Chinese populations is yet to be fully explored. We therefore tested the performance of these plasma biomarkers in 126 participants with preclinical AD and 123 controls with 8-10 years of follow-up from the China Cognition and Aging Study. Plasma Aβ42, p-tau181, and NfL were significantly correlated with cerebrospinal fluid counterparts and significantly altered in participants with preclinical AD. Combining plasma Aβ42, p-tau181, and NfL successfully discriminated preclinical AD from controls. These findings were validated in a replication cohort including 51 familial AD mutation carriers and 52 non-carriers from the Chinese Familial Alzheimer's Disease Network. Here we show that plasma Aβ42, p-tau181, and NfL may be useful for predicting AD 8 years before clinical onset in Chinese populations.
    DOI:  https://doi.org/10.1038/s41467-023-42596-6
  19. Nat Commun. 2023 Oct 24. 14(1): 6745
    PAPγ associates with PAXT nuclear exosome to control the abundance of PROMPT ncRNAs.
    Xavier Contreras, David Depierre, Charbel Akkawi, Marina Srbic, Marion Helsmoortel, Maguelone Nogaret, Matthieu LeHars, Kader Salifou, Alexandre Heurteau, Olivier Cuvier, Rosemary Kiernan.
      Pervasive transcription of the human genome generates an abundance of RNAs that must be processed and degraded. The nuclear RNA exosome is the main RNA degradation machinery in the nucleus. However, nuclear exosome must be recruited to its substrates by targeting complexes, such as NEXT or PAXT. By proteomic analysis, we identify additional subunits of PAXT, including many orthologs of MTREC found in S. pombe. In particular, we show that polyA polymerase gamma (PAPγ) associates with PAXT. Genome-wide mapping of the binding sites of ZFC3H1, RBM27 and PAPγ shows that PAXT is recruited to the TSS of hundreds of genes. Loss of ZFC3H1 abolishes recruitment of PAXT subunits including PAPγ to TSSs and concomitantly increases the abundance of PROMPTs at the same sites. Moreover, PAPγ, as well as MTR4 and ZFC3H1, is implicated in the polyadenylation of PROMPTs. Our results thus provide key insights into the direct targeting of PROMPT ncRNAs by PAXT at their genomic sites.
    DOI:  https://doi.org/10.1038/s41467-023-42620-9
  20. Nat Biotechnol. 2023 Oct 23.
    Imaging glycosylated RNAs at the subcellular scale.
    Petar Hristov, Ryan A Flynn.
      
    DOI:  https://doi.org/10.1038/s41587-023-02021-1
  21. Cell. 2023 Oct 26. pii: S0092-8674(23)01080-2. [Epub ahead of print]186(22): 4729-4733
    Do mammals have menopause?
    Ivana Winkler, Angela Goncalves.
      Semantics and lack of data have clouded our understanding about menopause in non-human mammals. The traditional definition of menopause based on the last menstrual bleed is limited and hinders cross-species comparison. Here, we redefine it as the permanent cessation of ovulation and show menopause to be widespread across mammalian orders.
    DOI:  https://doi.org/10.1016/j.cell.2023.09.026
  22. Nat Commun. 2023 Oct 25. 14(1): 6402
    Ebf3+ niche-derived CXCL12 is required for the localization and maintenance of hematopoietic stem cells.
    Taichi Nakatani, Tatsuki Sugiyama, Yoshiki Omatsu, Hitomi Watanabe, Gen Kondoh, Takashi Nagasawa.
      Lympho-hematopoiesis is regulated by cytokines; however, it remains unclear how cytokines regulate hematopoietic stem cells (HSCs) to induce production of lymphoid progenitors. Here, we show that in mice whose CXC chemokine ligand 12 (CXCL12) is deleted from half HSC niche cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells, HSCs migrate from CXCL12-deficient niches to CXCL12-intact niches. In mice whose CXCL12 is deleted from all Ebf3+/leptin receptor (LepR)+ CAR cells, HSCs are markedly reduced and their ability to generate B cell progenitors is reduced compared with that to generate myeloid progenitors even when transplanted into wild-type mice. Additionally, CXCL12 enables the maintenance of B lineage repopulating ability of HSCs in vitro. These results demonstrate that CAR cell-derived CXCL12 attracts HSCs to CAR cells within bone marrow and plays a critical role in the maintenance of HSCs, especially lymphoid-biased or balanced HSCs. This study suggests an additional mechanism by which cytokines act on HSCs to produce B cells.
    DOI:  https://doi.org/10.1038/s41467-023-42047-2
  23. Nat Commun. 2023 Oct 27. 14(1): 6598
    Lactate biosensors for spectrally and spatially multiplexed fluorescence imaging.
    Yusuke Nasu, Abhi Aggarwal, Giang N T Le, Camilla Trang Vo, Yuki Kambe, Xinxing Wang, Felix R M Beinlich, Ashley Bomin Lee, Tina R Ram, Fangying Wang, Kelsea A Gorzo, Yuki Kamijo, Marc Boisvert, Suguru Nishinami, Genki Kawamura, Takeaki Ozawa, Hirofumi Toda, Grant R Gordon, Shaoyu Ge, Hajime Hirase, Maiken Nedergaard, Marie-Eve Paquet, Mikhail Drobizhev, Kaspar Podgorski, Robert E Campbell.
      L-Lactate is increasingly appreciated as a key metabolite and signaling molecule in mammals. However, investigations of the inter- and intra-cellular dynamics of L-lactate are currently hampered by the limited selection and performance of L-lactate-specific genetically encoded biosensors. Here we now report a spectrally and functionally orthogonal pair of high-performance genetically encoded biosensors: a green fluorescent extracellular L-lactate biosensor, designated eLACCO2.1, and a red fluorescent intracellular L-lactate biosensor, designated R-iLACCO1. eLACCO2.1 exhibits excellent membrane localization and robust fluorescence response. To the best of our knowledge, R-iLACCO1 and its affinity variants exhibit larger fluorescence responses than any previously reported intracellular L-lactate biosensor. We demonstrate spectrally and spatially multiplexed imaging of L-lactate dynamics by coexpression of eLACCO2.1 and R-iLACCO1 in cultured cells, and in vivo imaging of extracellular and intracellular L-lactate dynamics in mice.
    DOI:  https://doi.org/10.1038/s41467-023-42230-5
  24. Nat Genet. 2023 Oct 26.
    Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura.
    DBDS Genetic Consortium
      Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.
    DOI:  https://doi.org/10.1038/s41588-023-01538-0
  25. Nat Commun. 2023 Oct 25. 14(1): 6696
    The endocannabinoid N-arachidonoyl dopamine is critical for hyperalgesia induced by chronic sleep disruption.
    Weihua Ding, Liuyue Yang, Eleanor Shi, Bowon Kim, Sarah Low, Kun Hu, Lei Gao, Ping Chen, Wei Ding, David Borsook, Andrew Luo, Jee Hyun Choi, Changning Wang, Oluwaseun Akeju, Jun Yang, Chongzhao Ran, Kristin L Schreiber, Jianren Mao, Qian Chen, Guoping Feng, Shiqian Shen.
      Chronic pain is highly prevalent and is linked to a broad range of comorbidities, including sleep disorders. Epidemiological and clinical evidence suggests that chronic sleep disruption (CSD) leads to heightened pain sensitivity, referred to as CSD-induced hyperalgesia. However, the underlying mechanisms are unclear. The thalamic reticular nucleus (TRN) has unique integrative functions in sensory processing, attention/arousal and sleep spindle generation. We report that the TRN played an important role in CSD-induced hyperalgesia in mice, through its projections to the ventroposterior region of the thalamus. Metabolomics revealed that the level of N-arachidonoyl dopamine (NADA), an endocannabinoid, was decreased in the TRN after CSD. Using a recently developed CB1 receptor (cannabinoid receptor 1) activity sensor with spatiotemporal resolution, CB1 receptor activity in the TRN was found to be decreased after CSD. Moreover, CSD-induced hyperalgesia was attenuated by local NADA administration to the TRN. Taken together, these results suggest that TRN NADA signaling is critical for CSD-induced hyperalgesia.
    DOI:  https://doi.org/10.1038/s41467-023-42283-6
  26. Nature. 2023 Oct 21.
    Scientists deliberately gave women Zika - here's why.
    Mariana Lenharo.
      
    Keywords:  Public health; Vaccines; Virology
    DOI:  https://doi.org/10.1038/d41586-023-03289-8
  27. Nat Commun. 2023 Oct 21. 14(1): 6670
    Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's disease.
    Xingyu Zhang, Li Tang, Jiaolong Yang, Lanxia Meng, Jiehui Chen, Lingyan Zhou, Jiangyu Wang, Min Xiong, Zhentao Zhang.
      Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identified transgelin-2 (TG2) expressed on neurons as the receptor for sTREM2. The microglia-derived sTREM2 binds to TG2, induces RhoA phosphorylation at S188, and deactivates the RhoA-ROCK-GSK3β pathway, ameliorating tau phosphorylation. The sTREM2 (77-89) fragment, which is the minimal active sequence of sTREM2 to activate TG2, mimics the inhibitory effect of sTREM2 on tau phosphorylation. Overexpression of sTREM2 or administration of the active peptide rescues tau pathology and behavioral defects in the tau P301S transgenic mice. Together, these findings demonstrate that the sTREM2-TG2 interaction mediates the cross-talk between microglia and neurons. sTREM2 and its active peptide may be a potential therapeutic intervention for tauopathies including AD.
    DOI:  https://doi.org/10.1038/s41467-023-42505-x
  28. Nat Cell Biol. 2023 Oct 26.
    Manganese regulation of COPII condensation controls circulating lipid homeostasis.
    Xiao Wang, Runze Huang, Yawei Wang, Wenjing Zhou, Yating Hu, Yuanhang Yao, Kunlun Cheng, Xin Li, Bolin Xu, Jie Zhang, Yaowen Xu, Fanxin Zeng, Yuangang Zhu, Xiao-Wei Chen.
      Precise control of circulating lipids is instrumental in health and disease. Bulk lipids, carried by specialized lipoproteins, are secreted into the circulation, initially via the coat protein complex II (COPII). How the universal COPII machinery accommodates the abundant yet unconventional lipoproteins remains unclear, let alone its therapeutic translation. Here we report that COPII uses manganese-tuning, self-constrained condensation to selectively drive lipoprotein delivery and set lipid homeostasis in vivo. Serendipitously, adenovirus hijacks the condensation-based transport mechanism, thus enabling the identification of cytosolic manganese as an unexpected control signal. Manganese directly binds the inner COPII coat and enhances its condensation, thereby shifting the assembly-versus-dynamics balance of the transport machinery. Manganese can be mobilized from mitochondria stores to signal COPII, and selectively controls lipoprotein secretion with a distinctive, bell-shaped function. Consequently, dietary titration of manganese enables tailored lipid management that counters pathological dyslipidaemia and atherosclerosis, implicating a condensation-targeting strategy with broad therapeutic potential for cardio-metabolic health.
    DOI:  https://doi.org/10.1038/s41556-023-01260-3
  29. Sci Immunol. 2023 Oct 27. 8(88): eadf8838
    Selective control of transposable element expression during T cell exhaustion and anti-PD-1 treatment.
    Pierre-Emmanuel Bonté, Christina Metoikidou, Sandrine Heurtebise-Chretien, Yago A Arribas, Aurélien Sutra Del Galy, Mengliang Ye, Leticia Laura Niborski, Elina Zueva, Eliane Piaggio, Agathe Seguin-Givelet, Nicolas Girard, Cécile Alanio, Marianne Burbage, Christel Goudot, Sebastian Amigorena.
      In chronic infections and cancer, T cells are exposed to prolonged antigen stimulation, resulting in loss of function (or exhaustion) and impairment of effective immunological protection. Exhausted T cells are heterogeneous and include early progenitors (Tpex) and terminally exhausted cells (Tex). Here, we used bulk and single-cell transcriptomics to analyze expression of transposable elements (TEs) in subpopulations of mouse and human CD8+ tumor-infiltrating T lymphocytes (TILs). We show that in mice, members of the virus-like murine VL30 TE family (mostly intact, evolutionary young ERV1s) are strongly repressed in terminally exhausted CD8+ T cells in both tumor and viral models of exhaustion. Tpex expression of these VL30s, which are mainly intergenic and transcribed independently of their closest gene neighbors, was driven by Fli1, a transcription factor involved in progression from Tpex to Tex. Immune checkpoint blockade (ICB) in both mice and patients with cancer increased TE expression (including VL30 in mice), demonstrating that TEs may be applicable as ICB response biomarkers. We conclude that expression of TEs is tightly regulated in TILs during establishment of exhaustion and reprogramming by ICB. Analyses of TE expression on single cells and bulk populations open opportunities for understanding immune cell identity and heterogeneity, as well as for defining cellular gene expression signatures and disease biomarkers.
    DOI:  https://doi.org/10.1126/sciimmunol.adf8838
  30. Nat Commun. 2023 Oct 25. 14(1): 6789
    A mitochondrial pentatricopeptide repeat protein enhances cold tolerance by modulating mitochondrial superoxide in rice.
    Xiaofeng Zu, Lilan Luo, Zhen Wang, Jie Gong, Chao Yang, Yong Wang, Chunhui Xu, Xinhua Qiao, Xian Deng, Xianwei Song, Chang Chen, Bao-Cai Tan, Xiaofeng Cao.
      Cold stress affects rice growth and productivity. Defects in the plastid-localized pseudouridine synthase OsPUS1 affect chloroplast ribosome biogenesis, leading to low-temperature albino seedlings and accumulation of reactive oxygen species (ROS). Here, we report an ospus1-1 suppressor, sop10. SOP10 encodes a mitochondria-localized pentatricopeptide repeat protein. Mutations in SOP10 impair intron splicing of the nad4 and nad5 transcripts and decrease RNA editing efficiency of the nad2, nad6, and rps4 transcripts, resulting in deficiencies in mitochondrial complex I, thus decrease ROS generation and rescuing the albino phenotype. Overexpression of different compartment-localized superoxide dismutases (SOD) genes in ospus1-1 reverses the ROS over-accumulation and albino phenotypes to various degrees, with Mn-SOD reversing the best. Mutation of SOP10 in indica rice varieties enhances cold tolerance with lower ROS levels. We find that the mitochondrial superoxide plays a key role in rice cold responses, and identify a mitochondrial superoxide modulating factor, informing efforts to improve rice cold tolerance.
    DOI:  https://doi.org/10.1038/s41467-023-42269-4
  31. Nat Commun. 2023 10 24. 14(1): 6748
    Biomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy.
    Kaiyuan Wang, Xuanbo Zhang, Hao Ye, Xia Wang, Zhijin Fan, Qi Lu, Songhao Li, Jian Zhao, Shunzhe Zheng, Zhonggui He, Qianqian Ni, Xiaoyuan Chen, Jin Sun.
      Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects.
    DOI:  https://doi.org/10.1038/s41467-023-42155-z
  32. Nat Aging. 2023 Oct 26.
    TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells.
    Tingting Hong, Jia Li, Lei Guo, Maryn Cavalier, Tianlu Wang, Yaling Dou, Aaron DeLaFuente, Shaohai Fang, Anna Guzman, Katherina Wohlan, Chiraag Kapadia, Carina Rosas, Yaling Yang, C Cameron Yin, Shaoying Li, M James You, Xiaodong Cheng, Margaret A Goodell, Yubin Zhou, Yun Huang.
      DNA methylation deregulation at partially methylated domains (PMDs) represents an epigenetic signature of aging and cancer, yet the underlying molecular basis and resulting biological consequences remain unresolved. We report herein a mechanistic link between disrupted DNA methylation at PMDs and the spatial relocalization of H3K9me3-marked heterochromatin in aged hematopoietic stem and progenitor cells (HSPCs) or those with impaired DNA methylation. We uncover that TET2 modulates the spatial redistribution of H3K9me3-marked heterochromatin to mediate the upregulation of endogenous retroviruses (ERVs) and interferon-stimulated genes (ISGs), hence contributing to functional decline of aged HSPCs. TET2-deficient HSPCs retain perinuclear distribution of heterochromatin and exhibit age-related clonal expansion. Reverse transcriptase inhibitors suppress ERVs and ISGs expression, thereby restoring age-related defects in aged HSPCs. Collectively, our findings deepen the understanding of the functional interplay between DNA methylation and histone modifications, which is vital for maintaining heterochromatin function and safeguarding genome stability in stem cells.
    DOI:  https://doi.org/10.1038/s43587-023-00505-y
  33. Nat Commun. 2023 Oct 23. 14(1): 6719
    Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis.
    Jonathan W Lo, Domenico Cozzetto, James L Alexander, Nathan P Danckert, Matthew Madgwick, Naomi Knox, Jillian Yong Xin Sieh, Marton Olbei, Zhigang Liu, Hajir Ibraheim, Jesus Miguens Blanco, Hiromi Kudo, Rocio Castro Seoane, Lucia A Possamai, Robert Goldin, Julian Marchesi, Tamas Korcsmaros, Graham M Lord, Nick Powell.
      Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make a once previously untreatable disease now amenable to a potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homoeostasis, mice are challenged with anti-CTLA4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. The immune profile of the colon of these mice with CPI-colitis is analysed using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis in mice is dependent on the composition of the intestinal microbiota and by the induction of lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. This pre-clinical model of CPI-colitis could be attenuated following blockade of the IL23/IFNγ axis. Therapeutic targeting of IFNγ-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis.
    DOI:  https://doi.org/10.1038/s41467-023-41798-2
  34. Cell Insight. 2023 Oct;2(5): 100124
    Cannabinoid receptor 2 signal promotes type 2 immunity in the lung.
    Tingting Liu, Jiaqi Liu, Hongjie Chen, Xin Zhou, Wei Fu, Ying Cao, Jing Yang.
      Type 2 immunity in the lung protects against pathogenic infection and facilitates tissue repair, but its dysregulation may lead to severe human diseases. Notably, cannabis usage for medical or recreational purposes has increased globally. However, the potential impact of the cannabinoid signal on lung immunity is incompletely understood. Here, we report that cannabinoid receptor 2 (CB2) is highly expressed in group 2 innate lymphoid cells (ILC2s) of mouse and human lung tissues. Of importance, the CB2 signal enhances the IL-33-elicited immune response of ILC2s. In addition, the chemogenetic manipulation of inhibitory G proteins (Gi) downstream of CB2 produces a similarly promotive effect. Conversely, the genetic deletion of CB2 mitigates the IL-33-elicited type 2 immunity in the lung. Also, such ablation of the CB2 signal ameliorates papain-induced tissue inflammation. Together, these results have elucidated a critical aspect of the CB2 signal in lung immunity, implicating its potential involvement in pulmonary diseases.
    Keywords:  3D imaging; Cannabinoid receptor 2 (CB2); Group 2 innate lymphoid cells (ILC2s); Lung; Type 2 immunity
    DOI:  https://doi.org/10.1016/j.cellin.2023.100124
  35. Science. 2023 Oct 27. 382(6669): 373-374
    Interconverting mirror-image molecules.
    Sojung F Kim, Richmond Sarpong.
      A light-driven multitasking catalyst enhances chirality in molecular mixtures.
    DOI:  https://doi.org/10.1126/science.adk7116
  36. Sci Immunol. 2023 Oct 24. eadj5789
    Resident regulatory T cells reflect the immune history of individual lymph nodes.
    Anne Kaminski, Fabian Tobias Hager, Lydia Kopplin, Fabio Ticconi, Andrea Leufgen, Emilia Vendelova, Lennart Rüttger, Georg Gasteiger, Vuk Cerovic, Wolfgang Kastenmüller, Oliver Pabst, Milas Ugur.
      Regulatory T cells (Treg) are present in lymphoid and non-lymphoid tissues where they restrict immune activation, prevent autoimmunity and regulate inflammation. Treg in non-lymphoid tissues are typically resident, while those in lymph nodes (LNs) are considered to recirculate. However, Treg in LNs are not a homogenous population and circulation kinetics of different Treg subsets are poorly characterized. Furthermore, whether Treg can acquire memory T cell properties and persist for extended periods after their activation in LNs is unclear. Here, we used in situ labeling with a stabilized photoconvertible protein to uncover turnover rates of Treg in LNs in vivo. We found that while the majority of Treg in LNs recirculate, 10-20% are memory-like resident cells that remain in their respective LNs for weeks to months. Single cell RNA sequencing revealed that LN-resident cells are a functionally and ontogenetically heterogeneous population and share the same core residency gene signature with conventional CD4+ and CD8+ T cells. Resident cells in LNs did not actively proliferate and did not require continuous TCR signaling for their residency. Yet, resident and circulating Treg had distinct TCR repertoires, and each LN contained exclusive clonal subpopulations of resident Treg. Our results demonstrate that, similar to conventional T cells, Treg can form resident memory-like populations in LNs after adaptive immune responses. Specific and local suppression of immune responses by resident Treg in draining LNs might provide new therapeutic opportunities for the treatment of local chronic inflammatory conditions.
    DOI:  https://doi.org/10.1126/sciimmunol.adj5789
  37. Nat Commun. 2023 Oct 23. 14(1): 6708
    Telomouse-a mouse model with human-length telomeres generated by a single amino acid change in RTEL1.
    Riham Smoom, Catherine Lee May, Vivian Ortiz, Mark Tigue, Hannah M Kolev, Melissa Rowe, Yitzhak Reizel, Ashleigh Morgan, Nachshon Egyes, Dan Lichtental, Emmanuel Skordalakes, Klaus H Kaestner, Yehuda Tzfati.
      Telomeres, the ends of eukaryotic chromosomes, protect genome integrity and enable cell proliferation. Maintaining optimal telomere length in the germline and throughout life limits the risk of cancer and enables healthy aging. Telomeres in the house mouse, Mus musculus, are about five times longer than human telomeres, limiting the use of this common laboratory animal for studying the contribution of telomere biology to aging and cancer. We identified a key amino acid variation in the helicase RTEL1, naturally occurring in the short-telomere mouse species M. spretus. Introducing this variation into M. musculus is sufficient to reduce the telomere length set point in the germline and generate mice with human-length telomeres. While these mice are fertile and appear healthy, the regenerative capacity of their colonic epithelium is compromised. The engineered Telomouse reported here demonstrates a dominant role of RTEL1 in telomere length regulation and provides a unique model for aging and cancer.
    DOI:  https://doi.org/10.1038/s41467-023-42534-6
  38. Science. 2023 Oct 27. 382(6669): 360
    Mountain mice break altitude record for mammalian life.
    Elizabeth Pennisi.
      How rodents survive on summits is a mystery.
    DOI:  https://doi.org/10.1126/science.adl5524
  39. J Immunol. 2023 Oct 27. pii: ji2300354. [Epub ahead of print]
    Bach2 Integrates Cytokine Signals to Arbitrate Differentiation Decisions between T Follicular Helper and Th17 Lineages.
    Andrew R Schroeder, Xianyou Xia, Kim Nguyen, Fangming Zhu, Jianlin Geng, Diego O Sialer, Hui Hu.
      CXCR5 is a hallmark of T follicular helper (Tfh) cells. The mechanism of CXCR5 induction, however, is still incompletely understood. In this study, we report that in mice with the absence of transcription factor Bach2, the Th17-inducing cytokines IL-6 and TGF-β together induced CXCR5 expression in vitro. Mechanistically, IL-6/STAT3 drove Cxcr5 promoter activity via the upstream site 1 regulatory element, whereas TGF-β enhanced permissive histone modifications, and the STAT3 binding to the site 1 regulatory element was higher in the absence of Bach2. Subsequently, despite previous studies showing enhanced Th17 cell differentiation in the absence of Bach2 in vitro, we found that in vivo, the Bach2 deficiency led to an enhanced Tfh cell response at the expense of the Th17 cell response. These findings suggest that Bach2 helps integrate cytokine signals to arbitrate differentiation decisions between Tfh and Th17 lineages.
    DOI:  https://doi.org/10.4049/jimmunol.2300354
  40. Proc Natl Acad Sci U S A. 2023 Oct 31. 120(44): e2306632120
    Developing synthetic tools to decipher the tumor-immune interactome.
    Orr-El Weizman, Sophia Luyten, Peiwen Lu, Eric Song, Kai Qin, Darius Mostaghimi, Aaron M Ring, Akiko Iwasaki.
      The ability of immune cells to directly interact with transformed cells is an essential component of immune surveillance and critical for optimal tissue function. The tumor-immune interactome (the collective cellular interactions between oncogenic cells and immune cells) is distinct and varied based on the tissue location and immunogenicity of tumor subtypes. However, comprehensive landscape and the consequences of tumor-interacting immune cells in the tumor microenvironment are not well understood. Current tools are limited in their ability to identify and record interactors in vivo or be utilized for downstream analysis. Here, we describe the development and validation of a technology leveraging synthetic Notch receptors reporting physical tumor cell-immune cell contact in vivo in order to decipher the tumor-immune interactome. We call this approach, Tumor-Immune Interactome Non-biased Discovery Retroviral Reporter or TIINDRR. Using TIINDRR, we identify the tumor-immune interactomes that define immunological refractory and sensitive tumors and how different immunotherapies alter these interactions. Thus, TIINDRR provides a flexible and versatile tool for studying in-vivo tumor-immune cell interactions, aiding in the identification of biologically relevant information needed for the rational design of immune-based therapies.
    Keywords:  T cells; cancer immunology; immunotherapy; myeloid cells; surveillance
    DOI:  https://doi.org/10.1073/pnas.2306632120
  41. Nat Commun. 2023 Oct 25. 14(1): 6773
    Visualization of accessible cholesterol using a GRAM domain-based biosensor.
    Dylan Hong Zheng Koh, Tomoki Naito, Minyoung Na, Yee Jie Yeap, Pritisha Rozario, Franklin L Zhong, Kah-Leong Lim, Yasunori Saheki.
      Cholesterol is important for membrane integrity and cell signaling, and dysregulation of the distribution of cellular cholesterol is associated with numerous diseases, including neurodegenerative disorders. While regulated transport of a specific pool of cholesterol, known as "accessible cholesterol", contributes to the maintenance of cellular cholesterol distribution and homeostasis, tools to monitor accessible cholesterol in live cells remain limited. Here, we engineer a highly sensitive accessible cholesterol biosensor by taking advantage of the cholesterol-sensing element (the GRAM domain) of an evolutionarily conserved lipid transfer protein, GRAMD1b. Using this cholesterol biosensor, which we call GRAM-W, we successfully visualize in real time the distribution of accessible cholesterol in many different cell types, including human keratinocytes and iPSC-derived neurons, and show differential dependencies on cholesterol biosynthesis and uptake for maintaining levels of accessible cholesterol. Furthermore, we combine GRAM-W with a dimerization-dependent fluorescent protein (ddFP) and establish a strategy for the ultrasensitive detection of accessible plasma membrane cholesterol. These tools will allow us to obtain important insights into the molecular mechanisms by which the distribution of cellular cholesterol is regulated.
    DOI:  https://doi.org/10.1038/s41467-023-42498-7
  42. Science. 2023 10 27. 382(6669): eadd5473
    Demographic and hormonal evidence for menopause in wild chimpanzees.
    Brian M Wood, Jacob D Negrey, Janine L Brown, Tobias Deschner, Melissa Emery Thompson, Sholly Gunter, John C Mitani, David P Watts, Kevin E Langergraber.
      Among mammals, post-reproductive life spans are currently documented only in humans and a few species of toothed whales. Here we show that a post-reproductive life span exists among wild chimpanzees in the Ngogo community of Kibale National Park, Uganda. Post-reproductive representation was 0.195, indicating that a female who reached adulthood could expect to live about one-fifth of her adult life in a post-reproductive state, around half as long as human hunter-gatherers. Post-reproductive females exhibited hormonal signatures of menopause, including sharply increasing gonadotropins after age 50. We discuss whether post-reproductive life spans in wild chimpanzees occur only rarely, as a short-term response to favorable ecological conditions, or instead are an evolved species-typical trait as well as the implications of these alternatives for our understanding of the evolution of post-reproductive life spans.
    DOI:  https://doi.org/10.1126/science.add5473
  43. Nat Commun. 2023 10 23. 14(1): 6725
    SARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors.
    Cecily Choy, Joseph Chen, Jiangyuan Li, D Travis Gallagher, Jian Lu, Daichao Wu, Ainslee Zou, Humza Hemani, Beverly A Baptiste, Emily Wichmann, Qian Yang, Jeffrey Ciffelo, Rui Yin, Julia McKelvy, Denise Melvin, Tonya Wallace, Christopher Dunn, Cuong Nguyen, Chee W Chia, Jinshui Fan, Jeannie Ruffolo, Linda Zukley, Guixin Shi, Tomokazu Amano, Yang An, Osorio Meirelles, Wells W Wu, Chao-Kai Chou, Rong-Fong Shen, Richard A Willis, Minoru S H Ko, Yu-Tsueng Liu, Supriyo De, Brian G Pierce, Luigi Ferrucci, Josephine Egan, Roy Mariuzza, Nan-Ping Weng.
      The resolution of SARS-CoV-2 replication hinges on cell-mediated immunity, wherein CD8+ T cells play a vital role. Nonetheless, the characterization of the specificity and TCR composition of CD8+ T cells targeting non-spike protein of SARS-CoV-2 before and after infection remains incomplete. Here, we analyzed CD8+ T cells recognizing six epitopes from the SARS-CoV-2 nucleocapsid (N) protein and found that SARS-CoV-2 infection slightly increased the frequencies of N-recognizing CD8+ T cells but significantly enhanced activation-induced proliferation compared to that of the uninfected donors. The frequencies of N-specific CD8+ T cells and their proliferative response to stimulation did not decrease over one year. We identified the N222-230 peptide (LLLDRLNQL, referred to as LLL thereafter) as a dominant epitope that elicited the greatest proliferative response from both convalescent and uninfected donors. Single-cell sequencing of T cell receptors (TCR) from LLL-specific CD8+ T cells revealed highly restricted Vα gene usage (TRAV12-2) with limited CDR3α motifs, supported by structural characterization of the TCR-LLL-HLA-A2 complex. Lastly, transcriptome analysis of LLL-specific CD8+ T cells from donors who had expansion (expanders) or no expansion (non-expanders) after in vitro stimulation identified increased chromatin modification and innate immune functions of CD8+ T cells in non-expanders. These results suggests that SARS-CoV-2 infection induces LLL-specific CD8+ T cell responses with a restricted TCR repertoire.
    DOI:  https://doi.org/10.1038/s41467-023-42430-z
  44. Nature. 2023 Oct 25.
    Dopamine determines how reward overrides risk.
    Kristin M Scaplen, Karla R Kaun.
      
    Keywords:  Animal behaviour; Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-03085-4
  45. Nat Commun. 2023 Oct 23. 14(1): 6698
    Domain adapted brain network fusion captures variance related to pubertal brain development and mental health.
    Dominik Kraft, Dag Alnæs, Tobias Kaufmann.
      Puberty demarks a period of profound brain dynamics that orchestrates changes to a multitude of neuroimaging-derived phenotypes. This complexity poses a dimensionality problem when attempting to chart an individual's brain development over time. Here, we illustrate that shifts in subject similarity of brain imaging data relate to pubertal maturation in the longitudinal ABCD study. Given that puberty depicts a critical window for emerging mental health issues, we additionally show that our model is capable of capturing variance in the adolescent brain related to psychopathology in a population-based and a clinical cohort. These results suggest that low-dimensional reference spaces based on subject similarities render useful to chart variance in brain development in youths.
    DOI:  https://doi.org/10.1038/s41467-023-41839-w
  46. Nat Commun. 2023 Oct 23. 14(1): 6711
    A deep population reference panel of tandem repeat variation.
    Helyaneh Ziaei Jam, Yang Li, Ross DeVito, Nima Mousavi, Nichole Ma, Ibra Lujumba, Yagoub Adam, Mikhail Maksimov, Bonnie Huang, Egor Dolzhenko, Yunjiang Qiu, Fredrick Elishama Kakembo, Habi Joseph, Blessing Onyido, Jumoke Adeyemi, Mehrdad Bakhtiari, Jonghun Park, Sara Javadzadeh, Daudi Jjingo, Ezekiel Adebiyi, Vineet Bafna, Melissa Gymrek.
      Tandem repeats (TRs) represent one of the largest sources of genetic variation in humans and are implicated in a range of phenotypes. Here we present a deep characterization of TR variation based on high coverage whole genome sequencing from 3550 diverse individuals from the 1000 Genomes Project and H3Africa cohorts. We develop a method, EnsembleTR, to integrate genotypes from four separate methods resulting in high-quality genotypes at more than 1.7 million TR loci. Our catalog reveals novel sequence features influencing TR heterozygosity, identifies population-specific trinucleotide expansions, and finds hundreds of novel eQTL signals. Finally, we generate a phased haplotype panel which can be used to impute most TRs from nearby single nucleotide polymorphisms (SNPs) with high accuracy. Overall, the TR genotypes and reference haplotype panel generated here will serve as valuable resources for future genome-wide and population-wide studies of TRs and their role in human phenotypes.
    DOI:  https://doi.org/10.1038/s41467-023-42278-3
  47. Nat Commun. 2023 Oct 23. 14(1): 6690
    The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer.
    Jia-Jun Li, Jin-Hong Wang, Tian Tian, Jia Liu, Yong-Qiang Zheng, Hai-Yu Mo, Hui Sheng, Yan-Xing Chen, Qi-Nian Wu, Yi Han, Kun Liao, Yi-Qian Pan, Zhao-Lei Zeng, Ze-Xian Liu, Wei Yang, Rui-Hua Xu, Huai-Qiang Ju.
      Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we identify that fibrinogen-like protein 1 (FGL1), secreted from cancer cells and hepatocytes, facilitates the progression of CRC in an intraportal injection model by reducing the infiltration of T cells. Mechanistically, tumor-associated macrophages (TAMs) activate NF-ĸB by secreting TNFα/IL-1β in the liver microenvironment and transcriptionally upregulate OTU deubiquitinase 1 (OTUD1) expression, which enhances FGL1 stability via deubiquitination. Disrupting the TAM-OTUD1-FGL1 axis inhibits metastatic tumor progression and synergizes with immune checkpoint blockade (ICB) therapy. Clinically, high plasma FGL1 levels predict poor outcomes and reduced ICB therapy benefits. Benzethonium chloride, an FDA-approved antiseptics, curbs FGL1 secretion, thereby inhibiting liver metastatic tumor growth. Overall, this study uncovers the critical roles and posttranslational regulatory mechanism of FGL1 in promoting metastatic tumor progression, highlighting the TAM-OTUD1-FGL1 axis as a potential target for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-023-42332-0
  48. FASEB J. 2023 11;37(11): e23265
    Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.
    Qianqian Yang, Lulu Wang, Yuehong Liang, Qingyu He, Qi Sun, Jing Luo, Hongdi Cao, Yi Fang, Yang Zhou, Junwei Yang, Ping Wen, Lei Jiang.
      Mitochondrial dysfunction plays an important role in the onset and progression of podocyte injury and proteinuria. However, the process by which the change in the podocyte mitochondria occurs is not well understood. Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which is located in the mitochondrial inner membrane. Here, we reported that mice with podocyte-specific Ucp2 deficiency developed podocytopathy with proteinuria with aging. Furthermore, those mice exhibited increased proteinuria in experimental models evoked by Adriamycin. Our findings suggest that UCP2 mediates mitochondrial dysfunction by regulating mitochondrial dynamic balance. Ucp2-deleted podocytes exhibited increased mitochondrial fission and deficient in ATP production. Mechanistically, opacity protein 1 (OPA1), a key protein in fusion of mitochondrial inner membrane, was regulated by UCP2. Ucp2 deficiency promoted proteolysis of OPA1 by activation OMA1 which belongs to mitochondrial inner membrane zinc metalloprotease. Those finding demonstrate the role of UCP2 in mitochondrial dynamics in podocytes and provide new insights into pathogenesis associated with podocyte injury and proteinuria.
    Keywords:  OMA1; OPA1; UCP2; mitochondria; podocyte injury
    DOI:  https://doi.org/10.1096/fj.202301055R
  49. Nature. 2023 Oct 27.
    Dengue rates drop after release of modified mosquitoes in Colombia.
    Mariana Lenharo.
      
    Keywords:  Diseases; Public health
    DOI:  https://doi.org/10.1038/d41586-023-03346-2
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