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Takaki Asano, Joëlle Khourieh, Peng Zhang, Franck Rapaport, András N. Spaan, Juan Li, Wei-Te Lei, Simon J. Pelham, David Hum, Maya Chrabieh, Ji Eun Han, Antoine Guérin, Joseph Mackie, Sudhir Gupta, Biman Saikia, Jamila E.I. Baghdadi, Ilham Fadil, Aziz Bousfiha, Tanwir Habib, Nico Marr, Luckshman Ganeshanandan, Jane Peake, Luke Droney, Andrew Williams, Fatih Celmeli, Nevin Hatipoglu, Tayfun Ozcelik, Capucine Picard, Laurent Abel, Stuart G. Tangye, Stéphanie Boisson-Dupuis, Qian Zhang, Anne Puel, Vivien Béziat, Jean-Laurent Casanova, Bertrand Boisson
Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) are heterozygous for rare STAT3 variants. The mechanism of dominance was recently questioned. The authors show that both in-frame and out-of-frame STAT3 variants underlie AD-HIES by negative dominance and not haploinsufficiency.
Technical Advances and Resources
Lindsay M. Milich, James S. Choi, Christine Ryan, Susana R. Cerqueira, Sofia Benavides, Stephanie L. Yahn, Pantelis Tsoulfas, Jae K. Lee
This study uses single-cell RNA sequencing to investigate the transcriptional heterogeneity of all cell types known to comprise the acutely injured spinal cord in mice. The authors investigate both cell subtype heterogeneity and potential signaling interactions between myeloid, vascular, and macroglia cells.
Article
Aaron J. Wilk, Madeline J. Lee, Bei Wei, Benjamin Parks, Ruoxi Pi, Giovanny J. Martínez-Colón, Thanmayi Ranganath, Nancy Q. Zhao, Shalina Taylor, Winston Becker, Stanford COVID-19 Biobank, David Jimenez-Morales, Andra L. Blomkalns, Ruth O’Hara, Euan A. Ashley, Kari C. Nadeau, Samuel Yang, Susan Holmes, Marlene Rabinovitch, Angela J. Rogers, William J. Greenleaf, Catherine A. Blish
Single-cell profiling demonstrates multifarious dysregulation of innate immune phenotype associated with COVID-19 severity. Severe COVID-19 is associated with hyperactivation of neutrophils and NK cells, while monocytes take on tolerogenic phenotypes. Meanwhile, mild COVID-19 is associated with limited, or rapidly resolved, immune perturbation.
Article
Nagarjuna R. Cheemarla, Timothy A. Watkins, Valia T. Mihaylova, Bao Wang, Dejian Zhao, Guilin Wang, Marie L. Landry, Ellen F. Foxman
SARS-CoV-2 replication in the upper respiratory tract initiates infection and leads to viral transmission. Cheemarla et al. show that a dynamic innate immune response can curtail viral replication early in infection, and that recent exposure to rhinovirus accelerates innate defenses and blocks viral replication.
Brief Definitive Report
Jeremy T. Warshauer, Julia A. Belk, Alice Y. Chan, Jiaxi Wang, Alexander R. Gupta, Quanming Shi, Nikolaos Skartsis, Yani Peng, Jonah D. Phipps, Dante Acenas, Jennifer A. Smith, Stanley J. Tamaki, Qizhi Tang, James M. Gardner, Ansuman T. Satpathy, Mark S. Anderson
Human STAT3 gain-of-function (GOF) mutations are linked to type 1 diabetes (T1D). This study establishes a STAT3-GOF mouse model that recapitulates the human T1D phenotype. STAT3-GOF drives cytotoxic CD8+ T cells that are resistant to terminal exhaustion, epigenetically distinct, and sufficient to accelerate T1D development.
Brief Definitive Report
Bryan M. Rogers, Laura Smith, Zoltan Dezso, Xu Shi, Enrico DiGiammarino, Denny Nguyen, Sunantha Sethuraman, Pingping Zheng, Donghee Choi, Dong Zhang, Andrew Nguyen, Kathleen McGuire, Wei Liu, Namjin Chung, Debra T. Chao, Shiming Ye, Gabriel R. Starbeck-Miller
VISTA biology has yet to be fully resolved despite much enthusiasm to define it as an immune checkpoint protein. Here, we show that VISTA antibodies can singly activate human monocytes and provide evidence that Syndecan-2 can regulate VISTA interactions.
Article
Charlotte Viant, Tobias Wirthmiller, Mohamed A. ElTanbouly, Spencer T. Chen, Melissa Cipolla, Victor Ramos, Thiago Y. Oliveira, Leonidas Stamatatos, Michel C. Nussenzweig
Memory B cells comprise a heterogenous group of cells. Viant et al. report on the use of an unbiased lineage-tracking approach to explore the origins and properties of memory B cell subsets in mice with an intact immune system.

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Issue Cover
Current Issue
Volume 218,
Issue 6,
June 7, 2021
Reviews & Opinions
Insights
Moujtaba Y. Kasmani, Weiguo Cui
BRD4 is a bromodomain-containing protein that binds acetylated histones to regulate transcription. In this issue of JEM, Milner et al. show that BRD4 plays a critical role in the effector function of CD8 T cells responding to infection and cancer.
Review | Hematopoietic Stem Cells Focus
Tobias Kull, Timm Schroeder
Cells constantly sense their environment to adapt their behavior to changing needs. Kull and Schroeder discuss the requirements, potential, and limitations of current technologies for quantification and manipulation of cellular signaling in the context of inflammatory signaling in hematopoietic cells.
Review | Hematopoietic Stem Cells Focus
Francisco Caiado, Eric M. Pietras, Markus G. Manz
This review summarizes and integrates current views on the contribution of inflammatory signals derived from multiple sources to hematopoietic stem cell function and its long-term implications on mutational selection and clonal expansion during aging.

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