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Immunity
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Apr 13, 2021

Volume 54Issue 4p603-844
Open Archive
An effective vaccine against respiratory syncytial virus (RSV) remains an unmet public heath goal. Mukhamedova et al. (769–780) characterized the human antibody responses after vaccination with a prefusion-stabilized RSV fusion (F) protein vaccine, DS-Cav1, and revealed that DS-Cav1 vaccination induces antibody lineages that recognize the prefusion conformation of F and target all known antigenic sites on RSV F. These results support the development and clinical testing of pre-F-based vaccines against RSV. How human antibodies interact with the DS-Cav1 vaccine is illustrated by the missing pieces from the jigsaw puzzle at the interface between two antibodies and DS-Cav1. The structure of DS-Cav1 is shown as molecular surfaces and the two neutralizing antibodies are depicted as uniquely colored ribbons. Cover art by Maryam Mukhamedova....
An effective vaccine against respiratory syncytial virus (RSV) remains an unmet public heath goal. Mukhamedova et al. (769–780) characterized the human antibody responses after vaccination with a prefusion-stabilized RSV fusion (F) protein vaccine, DS-Cav1, and revealed that DS-Cav1 vaccination induces antibody lineages that recognize the prefusion conformation of F and target all known antigenic sites on RSV F. These results support the development and clinical testing of pre-F-based vaccines against RSV. How human antibodies interact with the DS-Cav1 vaccine is illustrated by the missing pieces from the jigsaw puzzle at the interface between two antibodies and DS-Cav1. The structure of DS-Cav1 is shown as molecular surfaces and the two neutralizing antibodies are depicted as uniquely colored ribbons. Cover art by Maryam Mukhamedova.
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  • A “KU” new sensor for cytosolic DNA in T cells

    • Jianjun Wu,
    • Nan Yan
    Adaptive immune cells are usually not equipped with pattern recognition receptors. In this issue of Immunity, Wang et al. revealed an “innate-like” cytosolic DNA-sensing mechanism by the KU complex in aged CD4+ T cells, which exacerbates aging-related autoimmunity.

  • ATAC-ing human tissue Treg cells

    • Maren Köhne,
    • Marc Beyer
    What defines regulatory T (Treg) cells in healthy human tissues? In this issue of Immunity, Delacher et al. describe a human follicular helper T cell-like tissue-repair Treg cell signature governed by BATF based on chromatin accessibility data and link this on a transcriptome and protein level to important functional features like CCR8 expression.

  • Splice it up: Atypical transcripts to boost leukemia immunotherapy

    • Nicoletta Cieri,
    • Catherine J. Wu
    Neoantigens are prime targets for cancer immunotherapy, but their identification in low mutational burden malignancies remains challenging. In this issue of Immunity, Ehx et al. show that atypical transcripts, and particularly retained introns, expand the spectrum of leukemia immunotherapy targets.

  • Immunometabolism the CyTOF way

    • Liujia Qian,
    • Tiannan Guo
    In this issue of Immunity, Levine et al. report a CyTOF-based approach for the analyses of CD8+ T cells metabolic changes at the single-cell level. This approach identified a transition state early in T cell activation that is characterized by high glycolytic and oxidative activity, providing new insight into the metabolic changes that underlie the transition to effector and memory T cell fates.

Spotlight

  • Astrocytes have a license to kill inflammatory T cells

    • Alice H.K. Kwon,
    • Shane A. Liddelow
    Microbiome-induced interferon signaling through gut-derived natural killer cells is integral to minimize peripheral inflammatory responses in the brain and spinal cord. In a recent issue of Nature, Sanmarco, Wheeler, et al. define how interferon signaling induces LAMP1+TRAIL+ astrocytes, which cause death of inflammatory T cells, mitigating degeneration in a mouse model of demyealination.

Review

Articles

  • Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation and aging-related autoimmune inflammation

    • Yan Wang,
    • Zunyun Fu,
    • Xutong Li,
    • Yinming Liang,
    • Siyu Pei,
    • Shumeng Hao,
    • Qingchen Zhu,
    • Tao Yu,
    • Yifei Pei,
    • Jia Yuan,
    • Jialin Ye,
    • Jiemeng Fu,
    • Jing Xu,
    • Jin Hong,
    • Ruirui Yang,
    • Hui Hou,
    • Xinfang Huang,
    • Chao Peng,
    • Mingyue Zheng,
    • Yichuan Xiao
    The KU complex is typically associated with DNA damage repair in the nucleus. Wang et al. now show that, in aging CD4+ T cells, KU complex senses cytoplasmic DNA, promoting T cell activation and proliferation. ZAK, a kinase in this pathway, can be specifically inhibited to ameliorate aging-related autoimmunity.

  • Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasome-driven signaling cascade

    • Stefan Roth,
    • Jiayu Cao,
    • Vikramjeet Singh,
    • Steffen Tiedt,
    • Gabriel Hundeshagen,
    • Ting Li,
    • Julia D. Boehme,
    • Dhruv Chauhan,
    • Jie Zhu,
    • Alessio Ricci,
    • Oliver Gorka,
    • Yaw Asare,
    • Jun Yang,
    • Mary S. Lopez,
    • Markus Rehberg,
    • Dunja Bruder,
    • Shengxiang Zhang,
    • Olaf Groß,
    • Martin Dichgans,
    • Veit Hornung,
    • Arthur Liesz
    Acute tissue injuries result in systemic T cell loss that predisposes individuals to life-threatening infections. Roth et al. uncover a mechanism by which monocytes sense injury-released DNA via the AIM2 inflammasome and induce the extrinsic cell death of T cells.

  • The tissue protective functions of interleukin-22 can be decoupled from pro-inflammatory actions through structure-based design

    • Robert A. Saxton,
    • Lukas T. Henneberg,
    • Marco Calafiore,
    • Leon Su,
    • Kevin M. Jude,
    • Alan M. Hanash,
    • K. Christopher Garcia
    Saxton et al. engineer a high-affinity interleukin-22 (IL-22) super-agonist that enables structure determination of the IL-22-IL-22Rα-IL-10Rβ ternary complex. IL-22 receptor agonists designed based on these structural insights elicit activation of STAT3 but not STAT1 and promote epithelial protection and regeneration without inducing local or systemic inflammation.

  • Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93

    • Jinling Huang,
    • Hae-youn Lee,
    • Xiaohong Zhao,
    • Jinyi Han,
    • Yang Su,
    • Qinli Sun,
    • Jing Shao,
    • Jiwan Ge,
    • Yuxi Zhao,
    • Xue Bai,
    • Yi He,
    • Xinquan Wang,
    • Xiaohu Wang,
    • Chen Dong
    Among IL-17 cytokines, IL-17D is the least studied member. In this study, Dong et al. demonstrate that intestine epithelial cells-derived IL-17D serve as a critical factor in regulating ILC3s function and intestinal homeostasis by binding the receptor CD93.

  • Two sequential activation modules control the differentiation of protective T helper-1 (Th1) cells

    • Peter D. Krueger,
    • Michael F. Goldberg,
    • Sung-Wook Hong,
    • Kevin C. Osum,
    • Ryan A. Langlois,
    • Dmitri I. Kotov,
    • Thamotharampillai Dileepan,
    • Marc K. Jenkins
    CD4+ T cells are critical for protection from phagosomal bacteria but not acute viruses. Krueger et al. find that although both infections drive formation of weakly protective Tfh and IL-12 independent Th1 cells, the phagosomal pathogen stimulated the outgrowth of IL-12 dependent Th1 cells with superior protective capacity.

  • Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells

    • Michael Delacher,
    • Malte Simon,
    • Lieke Sanderink,
    • Agnes Hotz-Wagenblatt,
    • Marina Wuttke,
    • Kathrin Schambeck,
    • Lisa Schmidleithner,
    • Sebastian Bittner,
    • Asmita Pant,
    • Uwe Ritter,
    • Thomas Hehlgans,
    • Dania Riegel,
    • Verena Schneider,
    • Florian Kai Groeber-Becker,
    • Andreas Eigenberger,
    • Claudia Gebhard,
    • Nicholas Strieder,
    • Alexander Fischer,
    • Michael Rehli,
    • Petra Hoffmann,
    • Matthias Edinger,
    • Till Strowig,
    • Jochen Huehn,
    • Christian Schmidl,
    • Jens M. Werner,
    • Lukas Prantl,
    • Benedikt Brors,
    • Charles D. Imbusch,
    • Markus Feuerer
    Delacher et al. identify a conserved transcriptional and epigenetic signature that defines tissue regulatory T (Treg) cells in mice and humans. BATF+CCR8+ Treg cells from healthy human tissue share features with Treg cells found in tumors, suggesting that characteristics associated with tumor-residency may rather reflect the tissue repair functions of these cells.

  • Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery

    • Cristina C. Clement,
    • Padma P. Nanaware,
    • Takahiro Yamazaki,
    • Maria Pia Negroni,
    • Karthik Ramesh,
    • Kateryna Morozova,
    • Sangeetha Thangaswamy,
    • Austin Graves,
    • Hei Jung Kim,
    • Tsai Wanxia Li,
    • Marco Vigano’,
    • Rajesh K. Soni,
    • Massimo Gadina,
    • Harley Y. Tse,
    • Lorenzo Galluzzi,
    • Paul A. Roche,
    • Lisa K. Denzin,
    • Lawrence J. Stern,
    • Laura Santambrogio
    Hyperglycemia and hyperlipidemia during diabetes and metabolic syndrome induce protein oxidative post-translational modifications (PTMs) that affect the MHC class II processing and presentation machinery. Clement et al. reveal that these PTMs are linked to epitope-specific changes in the MHC class II peptidome, with increased presentation of an apolipoprotein B100 peptide, contributing to diabetes-related complications.

  • Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes

    • Grégory Ehx,
    • Jean-David Larouche,
    • Chantal Durette,
    • Jean-Philippe Laverdure,
    • Leslie Hesnard,
    • Krystel Vincent,
    • Marie-Pierre Hardy,
    • Catherine Thériault,
    • Caroline Rulleau,
    • Joël Lanoix,
    • Eric Bonneil,
    • Albert Feghaly,
    • Anca Apavaloaei,
    • Nandita Noronha,
    • Céline M. Laumont,
    • Jean-Sébastien Delisle,
    • Luca Vago,
    • Josée Hébert,
    • Guy Sauvageau,
    • Sébastien Lemieux,
    • Pierre Thibault,
    • Claude Perreault
    The lack of suitable targets is the main obstacle to immunotherapy of acute myeloid leukemia (AML). Ehx et al. reveal the structure and genomic origin of 58 AML-specific antigens. Epigenetic changes and intron retention are instrumental in the biogenesis of these antigens that represent attractive targets for AML immunotherapy.

  • Multi-cohort analysis of host immune response identifies conserved protective and detrimental modules associated with severity across viruses

    • Hong Zheng,
    • Aditya M. Rao,
    • Denis Dermadi,
    • Jiaying Toh,
    • Lara Murphy Jones,
    • Michele Donato,
    • Yiran Liu,
    • Yapeng Su,
    • Cheng L. Dai,
    • Sergey A. Kornilov,
    • Minas Karagiannis,
    • Theodoros Marantos,
    • Yehudit Hasin-Brumshtein,
    • Yudong D. He,
    • Evangelos J. Giamarellos-Bourboulis,
    • James R. Heath,
    • Purvesh Khatri
    Viral infections induce a conserved host response distinct from bacterial infections, but whether this conserved response distinguishes severity is unclear. Zheng et al. analyzed >5000 bulk and single-cell transcriptome profiles from patients infected with one of 16 viruses, including SARS-CoV-2, Ebola, and chikungunya. They identified protective and detrimental host response modules that distinguish patients with mild or severe outcomes.

  • Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein induces genetically and antigenically diverse antibody responses

    • Maryam Mukhamedova,
    • Daniel Wrapp,
    • Chen-Hsiang Shen,
    • Morgan S.A. Gilman,
    • Tracy J. Ruckwardt,
    • Chaim A. Schramm,
    • Larissa Ault,
    • Lauren Chang,
    • Alexandrine Derrien-Colemyn,
    • Sarah A.M. Lucas,
    • Amy Ransier,
    • Samuel Darko,
    • Emily Phung,
    • Lingshu Wang,
    • Yi Zhang,
    • Scott A. Rush,
    • Bharat Madan,
    • Guillaume B.E. Stewart-Jones,
    • Pamela J. Costner,
    • LaSonji A. Holman,
    • Somia P. Hickman,
    • Nina M. Berkowitz,
    • Nicole A. Doria-Rose,
    • Kaitlyn M. Morabito,
    • Brandon J. DeKosky,
    • Martin R. Gaudinski,
    • Grace L. Chen,
    • Michelle C. Crank,
    • John Misasi,
    • Nancy J. Sullivan,
    • Daniel C. Douek,
    • Peter D. Kwong,
    • Barney S. Graham,
    • Jason S. McLellan,
    • John R. Mascola
    A single dose of the prefusion-stabilized fusion (F) glycoprotein subunit vaccine (DS-Cav1) increases serum neutralizing activity in healthy adults. Mukhamedova et al. evaluated RSV F-specific B cell responses before and after vaccination and reveal that DS-Cav1 generates a diverse polyclonal response targeting the antigenic sites on pre-F, supporting the development and advanced testing of pre-F-based vaccines against RSV.

  • Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins

    • Fang Chen,
    • Netanel Tzarum,
    • Xiaohe Lin,
    • Erick Giang,
    • Rodrigo Velázquez-Moctezuma,
    • Elias H. Augestad,
    • Kenna Nagy,
    • Linling He,
    • Mayda Hernandez,
    • Mallorie E. Fouch,
    • Ariadna Grinyó,
    • Deborah Chavez,
    • Benjamin J. Doranz,
    • Jannick Prentoe,
    • Robyn L. Stanfield,
    • Robert Lanford,
    • Jens Bukh,
    • Ian A. Wilson,
    • Jiang Zhu,
    • Mansun Law
    The human IGHV1-69 gene is preferentially utilized in broadly neutralizing antibody (bnAb) responses against HCV infection. Chen et al. discovered that HCV Env immunization of macaques elicited analogous VH1.36 bnAbs on the functional and molecular level. Functional convergence of a corresponding germline-encoded bnAb response within primates has implications for HCV rational vaccine design and testing.

  • Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19

    • Peter A. Szabo,
    • Pranay Dogra,
    • Joshua I. Gray,
    • Steven B. Wells,
    • Thomas J. Connors,
    • Stuart P. Weisberg,
    • Izabela Krupska,
    • Rei Matsumoto,
    • Maya M.L. Poon,
    • Emma Idzikowski,
    • Sinead E. Morris,
    • Chloé Pasin,
    • Andrew J. Yates,
    • Amy Ku,
    • Michael Chait,
    • Julia Davis-Porada,
    • Xinzheng V. Guo,
    • Jing Zhou,
    • Matthew Steinle,
    • Sean Mackay,
    • Anjali Saqi,
    • Matthew R. Baldwin,
    • Peter A. Sims,
    • Donna L. Farber
    Through longitudinal profiling of paired airways and blood from patients with severe COVID-19, Szabo et al. reveal airway immune responses that correlate with age and outcome. They further identify coordinate roles for T and myeloid cells in the respiratory tract and circulation in perpetuating lung pathology and disease pathogenesis.

Resources

  • A Fc engineering approach to define functional humoral correlates of immunity against Ebola virus

    • Bronwyn M. Gunn,
    • Richard Lu,
    • Matthew D. Slein,
    • Philipp A. Ilinykh,
    • Kai Huang,
    • Caroline Atyeo,
    • Sharon L. Schendel,
    • Jiyoung Kim,
    • Caitlin Cain,
    • Vicky Roy,
    • Todd J. Suscovich,
    • Ayato Takada,
    • Peter J. Halfmann,
    • Yoshihiro Kawaoka,
    • Matthias G. Pauthner,
    • Mambu Momoh,
    • Augustine Goba,
    • Lansana Kanneh,
    • Kristian G. Andersen,
    • John S. Schieffelin,
    • Donald Grant,
    • Robert F. Garry,
    • Erica Ollmann Saphire,
    • Alexander Bukreyev,
    • Galit Alter
    Gunn et al. profile Ebola virus disease survivors and apply a platform for engineering antibody Fc domains to define protective profiles. Fc variants with complement deposition yet moderate NK cell activity completely protected infected mice from disease. This experimental platform can be used for identifying correlates of immunity to other pathogens and to guide therapeutic antibody design.

  • Single-cell analysis by mass cytometry reveals metabolic states of early-activated CD8+ T cells during the primary immune response

    • Lauren S. Levine,
    • Kamir J. Hiam-Galvez,
    • Diana M. Marquez,
    • Iliana Tenvooren,
    • Matthew Z. Madden,
    • Diana C. Contreras,
    • Debolanle O. Dahunsi,
    • Jonathan M. Irish,
    • Olalekan O. Oluwole,
    • Jeffrey C. Rathmell,
    • Matthew H. Spitzer
    Levine, Hiam-Galvez, et al. develop a mass-cytometry-based approach to quantify metabolic protein expression in single cells in vivo, revealing a distinct metabolic state early after CD8+ T cell activation characterized by simultaneous expression of glycolytic and oxidative proteins. This approach provides a resource for the study of metabolic regulation across a variety of applications.
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