Journal of Experimental Medicine

Journal of Experimental Medicine The Journal of Experimental Medicine publishes immunology, cancer, stem cells, microbial pathogenesis, vascular biology, and neurobiology research.
The Journal of Experimental Medicine (JEM) features peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions are made by research-active scientists in conjunction with in-house scientific editors. JEM provides free online access to many article types immediately, with complete archival content freely available online. Established in 1896, JEM is published by The Rockefeller University Press. For more information, visit http://jem.rupress.org. Follow us on Twitter: https://twitter.com/JExpMed
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Since its inception in 1896, the goal of The Journal of Experimental Medicine (JEM) has been to publish outstanding and enduring studies in medical biology. At a time when many leading publishing groups are establishing topic-specific journals, we believe it is critical to complement that approach by offering a distinguished venue for publication of studies that integrate disciplines within the field of pathogenesis. A distinctive editorial system supports this goal with an emphasis on exceptional service to our authors. Two groups of editors work hand-in hand: professional editors with strong scientific backgrounds, and full-time practicing scientists. At least one editor from each group evaluates the merits of each paper prior to external review. The editors convene weekly to discuss all papers with external referee comments, and reach rapid decisions without excessive requests for revision. Within the field of medical biology we focus both on human studies and diverse in vivo experimental models of human disease that address such topics as genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We welcome reports ranging from atomic-level analyses to clinical interventions that illustrate new mechanisms.

This review by Junjie Zhao, Xing Chen, Tomasz Herjan and Xiaoxia Li (https://bit.ly/37imMLi) discusses the growing liter...
11/20/2019
The role of interleukin-17 in tumor development and progression

This review by Junjie Zhao, Xing Chen, Tomasz Herjan and Xiaoxia Li (https://bit.ly/37imMLi) discusses the growing literature on the pathogenic role of IL-17 in cancer, focusing on recent studies that place IL-17 as a nexus linking inflammation, tissue repair, and cancer.

IL-17, a potent proinflammatory cytokine, has been shown to intimately contribute to the formation, growth, and metastasis of a wide range of malignancies. Recent studies implicate IL-17 as a link among inflammation, wound healing, and cancer. While IL-...

Although many chronic inflammatory diseases share the feature of elevated IL-17 production, therapeutic targeting of IL-...
11/19/2019
Targeting interleukin-17 in chronic inflammatory disease: A clinical perspective

Although many chronic inflammatory diseases share the feature of elevated IL-17 production, therapeutic targeting of IL-17 has vastly different clinical outcomes. Here, Pascale Zwicky, Susanne Unger and Burkhard Becher summarize (https://bit.ly/2CT21In) the recent progress in understanding the protective and pathogenic role of the IL-23/IL-17 axis in preclinical models and human inflammatory diseases.

Chronic inflammatory diseases like psoriasis, Crohn’s disease (CD), multiple sclerosis (MS), rheumatoid arthritis (RA), and others are increasingly recognized as disease entities, where dysregulated cytokines contribute substantially to tissue-specific ...

IL-17 plays versatile roles during tumorigenesis. Here, Gerardo A. Vitiello and George Miller (https://bit.ly/35eohbK) s...
11/18/2019
Targeting the interleukin-17 immune axis for cancer immunotherapy

IL-17 plays versatile roles during tumorigenesis. Here, Gerardo A. Vitiello and George Miller (https://bit.ly/35eohbK) summarize current knowledge in harnessing IL-17–producing γδ and Th17 cells for successful cancer immunotherapy.

The role of IL-17 in cancer remains controversial. Emerging evidence suggests that during early oncogenesis IL-17 supports tumor growth, whereas in established tumors IL-17 production by γδ and Th17 cells potentiates antitumor immunity. Consequently, γδ...

Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Xingrong Du, Hongbo Chi, and col...
11/18/2019
Mevalonate metabolism–dependent protein geranylgeranylation regulates thymocyte egress

Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Xingrong Du, Hongbo Chi, and colleagues (https://bit.ly/2OdM1Wl) describe unexpected roles of mevalonate metabolism–fueled protein geranylgeranylation, but not farnesylation, in driving thymocyte egress through modulating Cdc42 and Pak activities

Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Despite the roles of G protein–coupled receptors in thymocyte emigration, the downstream signaling mechanism remains poorly defined. Here, we report the discrete rol...

This review by Immo Prinz, Inga Sandrock and Ulrich Mrowietz (https://bit.ly/3760HQ6) summarizes the steps from basic re...
11/15/2019
Interleukin-17 cytokines: Effectors and targets in psoriasis—A breakthrough in understanding and treatment

This review by Immo Prinz, Inga Sandrock and Ulrich Mrowietz (https://bit.ly/3760HQ6) summarizes the steps from basic research on IL-17 family cytokines to understanding their role in psoriasis pathogenesis to the approval of a number of monoclonal antibodies targeting IL-17 pathways as first line treatment of psoriasis and psoriatic arthritis.

The IL-17 cytokine family comprising IL-17A to IL-17F and receptor subunits IL-17RA to IL-17RE represents a genetically ancient intercellular network regulating local tissue homeostasis. Its pivotal role in antifungal defense and its central position in...

HIV-1 is an exceptionally difficult vaccine target, and only certain types of antibodies are effective. Vaccination indu...
11/15/2019
Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses

HIV-1 is an exceptionally difficult vaccine target, and only certain types of antibodies are effective. Vaccination induces antibodies that bind the virus with different efficiencies. This study by Ganesh E. Phad, Gunilla B. Karlsson Hedestam, and colleagues (https://bit.ly/2NKDbAH) investigates this process and reveals how the immune system works to improve the binding capacity of each antibody.

Well-ordered HIV-1 envelope glycoprotein (Env) trimers are prioritized for clinical evaluation, and there is a need for an improved understanding about how elicited B cell responses evolve following immunization. To accomplish this, we prime-boosted rhe...

Atsushi Tanaka, Shimon Sakaguchi, and colleagues (https://bit.ly/2Kk4srj) show that as a novel type of anticancer reagen...
11/14/2019
Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells

Atsushi Tanaka, Shimon Sakaguchi, and colleagues (https://bit.ly/2Kk4srj) show that as a novel type of anticancer reagent, imatinib inhibits not only BCR-ABL oncogenic protein but also LCK in T cells as an off-target, being able to selectively deplete mature regulatory T cells and thereby evoke effective immune responses to various cancers.

This report addresses whether small molecules can deplete FoxP3-expressing regulatory T (T reg) cells, thereby augmenting antitumor immunity. Imatinib, a tyrosine kinase inhibitor of oncogenic BCR-ABL protein expressed by chronic myelogenous leukemia (C...

Xiu-xiu Liu, Ying-mei Lu, and colleagues (https://bit.ly/2O4Jm1b) reveal a key mechanism mediating the transition from c...
11/14/2019
Endothelial Cdk5 deficit leads to the development of spontaneous epilepsy through CXCL1/CXCR2-mediated reactive astrogliosis

Xiu-xiu Liu, Ying-mei Lu, and colleagues (https://bit.ly/2O4Jm1b) reveal a key mechanism mediating the transition from cerebrovascular damage to epilepsy. They reveal that the endothelial cyclin-dependent kinase 5 (CDK5) regulates astrocytic glutamate reuptake and increased glutamate synaptic function through CXCL1/CXCR2-mediated astrogliosis.

Blood–brain barrier (BBB) dysfunction has been suggested to play an important role in epilepsy. However, the mechanism mediating the transition from cerebrovascular damage to epilepsy remains unknown. Here, we report that endothelial cyclin-dependent kinase 5 (CDK5) is a central regulator of neuro...

This study by Jennifer K. Bando, Marco Colonna, and colleagues  (https://bit.ly/2O21LMa) shows that the regulatory innat...
11/13/2019
ILC2s are the predominant source of intestinal ILC-derived IL-10

This study by Jennifer K. Bando, Marco Colonna, and colleagues (https://bit.ly/2O21LMa) shows that the regulatory innate lymphoid cell (ILCreg), a recently described IL-10–producing innate lymphocyte, is not present in mice bred in four different facilities. Instead, group 2 ILCs provide an inducible source of IL-10 in the intestine.

Although innate lymphoid cells (ILCs) functionally analogous to T helper type 1 (Th1), Th2, and Th17 cells are well characterized, an ILC subset strictly equivalent to IL-10–secreting regulatory T cells has only recently been proposed. Here, we report t...

On the cover of JEM—Albright et al. describe the previously unknown function of TGFβ in promoting the transition of GCB ...
11/13/2019

On the cover of JEM—Albright et al. describe the previously unknown function of TGFβ in promoting the transition of GCB cells from LZ to DZ. The cover shows staining for phosphorylated Smad2 (red) in a Peyer’s patch from a wild-type mouse. The image was provided by Albright et al. https://bit.ly/2WWEuiJ

The latest issue of JEM features new research on APOE-dependent neurodegeneration, autoimmune encephalomyelitis, regulat...
11/12/2019

The latest issue of JEM features new research on APOE-dependent neurodegeneration, autoimmune encephalomyelitis, regulatory T cell generation, and more: https://bit.ly/36TorqC

Zhen Xiong, Zusen Fan, and colleagues (https://bit.ly/2pTkD8e) show that CCP3 performs deglutamylation of BAP1 to stabil...
11/12/2019
Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis

Zhen Xiong, Zusen Fan, and colleagues (https://bit.ly/2pTkD8e) show that CCP3 performs deglutamylation of BAP1 to stabilize BAP1, which eliminates H2AK119Ub from Hoxa1 promoter and initiates Hoxa1 expression, leading to enhanced HSC self-renewal.

All hematopoietic lineages are derived from a limited pool of hematopoietic stem cells (HSCs). Although the mechanisms underlying HSC self-renewal have been extensively studied, little is known about the role of protein glutamylation and deglutamylation...

On the cover of JEM—Albright et al. describe the previously unknown function of TGFβ in promoting the transition of GCB ...
11/11/2019

On the cover of JEM—Albright et al. describe the previously unknown function of TGFβ in promoting the transition of GCB cells from LZ to DZ. The cover shows staining for phosphorylated Smad2 (red) in a Peyer’s patch from a wild-type mouse. The image was provided by Albright et al. https://bit.ly/2WWEuiJ

Using a polyclonal regulatory T (pTreg) cell replacement system, Alvin Pratama, Christophe Benoist, and colleagues (http...
11/08/2019
Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells

Using a polyclonal regulatory T (pTreg) cell replacement system, Alvin Pratama, Christophe Benoist, and colleagues (https://bit.ly/2pKbfDS) show that naive conventional CD4+ cells (Tconv) have the capacity to convert into both RORγ+ and Helios+ Treg cells in the colon. The developmental maturity (or cell states) of the starting Tconv cells determines the phenotype of the resulting pTreg cells.

RORγ+ and Helios+ Treg cells in the colon are phenotypically and functionally distinct, but their origins and relationships are poorly understood. In monocolonized and normal mice, single-cell RNA-seq revealed sharing of TCR clonotypes between these Tre...

In this study, Dehong Yan, Youhai H. Chen, Xiaochun Wan, and colleagues (https://bit.ly/36BtWdu) demonstrate that TIPE2,...
11/07/2019
TIPE2 specifies the functional polarization of myeloid-derived suppressor cells during tumorigenesis

In this study, Dehong Yan, Youhai H. Chen, Xiaochun Wan, and colleagues (https://bit.ly/36BtWdu) demonstrate that TIPE2, which is induced by tumor-derived ROS, promotes the functional polarization of protumoral myeloid-derived suppressor cells (MDSCs) during tumorigenesis by specifying the expression of MDSC signature genes such as Cebpb.

Myeloid-derived suppressor cells (MDSCs) are “polarized” myeloid cells that effectively promote tumorigenesis by inhibiting antitumor immunity. How myeloid cells acquire the protumoral properties during tumorigenesis is poorly understood. We report here...

Using mice modeling patients’ variant, this study by Beibei Zhang, Qinghua Shi, and colleagues (https://bit.ly/34ra9LR) ...
11/06/2019
A DNAH17 missense variant causes flagella destabilization and asthenozoospermia

Using mice modeling patients’ variant, this study by Beibei Zhang, Qinghua Shi, and colleagues (https://bit.ly/34ra9LR) demonstrates that a homozygous DNAH17 missense variant causes asthenozoospermia and specifically destabilizes microtubule doublets 4–7 in flagella, which could be largely due to the storage of sperm in epididymis.

Asthenozoospermia is a common cause of male infertility, but its etiology remains incompletely understood. We recruited three Pakistani infertile brothers, born to first-cousin parents, displaying idiopathic asthenozoospermia but no ciliary-related symp...

Jing Yang, Erol Fikrig, and colleagues at Yale University (https://bit.ly/36zIYjS) show that CRISPR-mediated disruption ...
11/05/2019
Disruption of mosGILT in Anopheles gambiae impairs ovarian development and Plasmodium infection

Jing Yang, Erol Fikrig, and colleagues at Yale University (https://bit.ly/36zIYjS) show that CRISPR-mediated disruption of a mosquito gene, mosGILT, impairs ovarian development and vitellogenesis, resulting in enhanced anti-Plasmodium immunity in the malaria vector Anopheles gambiae.

Plasmodium infection in Anopheles is influenced by mosquito-derived factors. We previously showed that a protein in saliva from infected Anopheles , mosquito gamma-interferon–inducible lysosomal thiol reductase (mosGILT), inhibits the ability of sporozo...

This work by Anna Haeger, Peter Friedl, and colleagues (https://bit.ly/2JQA8Ev) identifies an integrin-dependent tissue ...
11/05/2019
Collective cancer invasion forms an integrin-dependent radioresistant niche

This work by Anna Haeger, Peter Friedl, and colleagues (https://bit.ly/2JQA8Ev) identifies an integrin-dependent tissue niche that supports both collective invasion and radiation resistance and can be eradicated by joint targeting of β1 and αV integrins, but neither alone. The additive effect of multiple-integrin interference indicates that clinical efficacy of integrin-based therapy will depend on multi-integrin-targeted strategies.

Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrat...

Masashi Yukawa, Artem Barski, and colleagues (https://bit.ly/2qYosJf) show that the AP-1 transcription factor is recruit...
11/01/2019
AP-1 activity induced by co-stimulation is required for chromatin opening during T cell activation

Masashi Yukawa, Artem Barski, and colleagues (https://bit.ly/2qYosJf) show that the AP-1 transcription factor is recruited to the majority of chromatin remodeling sites during T cell activation. The activity of AP-1 is induced by co-stimulation and is required for chromatin opening. The sites of remodeling overlap with risk loci of immunological diseases.

Activation of T cells is dependent on the organized and timely opening and closing of chromatin. Herein, we identify AP-1 as the transcription factor that directs most of this remodeling. Chromatin accessibility profiling showed quick opening of closed ...

Hiroyuki Hosokawa, Ellen Rothenberg, and colleagues https://bit.ly/34fmuTa find that Bcl11b binds to distinctive genomic...
10/31/2019
Cell type–specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells

Hiroyuki Hosokawa, Ellen Rothenberg, and colleagues https://bit.ly/34fmuTa find that Bcl11b binds to distinctive genomic regions with different partners and regulates completely different target genes in pro-T and ILC2 cells. Despite these divergences in Bcl11b function, a shared enhancer supports initial Bcl11b locus opening in both pro-T and ILC2 lineages.

The zinc finger transcription factor, Bcl11b, is expressed in T cells and group 2 innate lymphoid cells (ILC2s) among hematopoietic cells. In early T-lineage cells, Bcl11b directly binds and represses the gene encoding the E protein antagonist, Id2 , pr...

Shahrnaz Kemal and Robert Vassar (https://bit.ly/2BUvYqK) highlight work by Yang Shi, David Holtzman, and colleagues (ht...
10/30/2019
Death by microglia

Shahrnaz Kemal and Robert Vassar (https://bit.ly/2BUvYqK) highlight work by Yang Shi, David Holtzman, and colleagues (https://bit.ly/32406LQ) demonstrating that microglia-mediated innate immunity collaborates with ApoE to drive neurodegeneration and disease progression in a mouse model of tauopathy.

The roles of microglia and ApoE in tauopathies, such as Alzheimer’s disease, remain elusive. In this issue, Shi et al. () demonstrate that microglia-mediated innate immunity collaborates with ApoE to drive neurodege...

Mucin-type O-glycans (O-glycans) are a major component of gastric mucus with an unclear function. Fei Liu, Lijun Xia, an...
10/30/2019
Core 1–derived mucin-type O-glycosylation protects against spontaneous gastritis and gastric cancer

Mucin-type O-glycans (O-glycans) are a major component of gastric mucus with an unclear function. Fei Liu, Lijun Xia, and colleagues (https://bit.ly/2MVcs3U) report that O-glycans protect gastric mucosa from inflammation and cancer mediated by activation of caspases 1 and 11–dependent inflammasome.

Core 1–derived mucin-type O-glycans (O-glycans) are a major component of gastric mucus with an unclear role. To address this, we generated mice lacking gastric epithelial O-glycans (GEC C1galt1 −/− ). GEC C1galt1−/− mice exhibited spontaneous gastritis ...

Regulation of Bcl6 expression during follicular helper T cell differentiation remains incompletely understood. Here, Xue...
10/29/2019
Nutrient mTORC1 signaling underpins regulatory T cell control of immune tolerance

Regulation of Bcl6 expression during follicular helper T cell differentiation remains incompletely understood. Here, Xuehui Long, Xiaoming Wang, and colleagues (https://bit.ly/2BH8Hso) show that T cell activation induces H3K36me2 methyltransferase Nsd2, in a CD28- and ICOS-dependent manner, to promote Bcl6 expression and Tfh differentiation.

Foxp3+ regulatory T (T reg) cells are pivotal regulators of immune tolerance, with T cell receptor (TCR)–driven activated T reg (aT reg) cells playing a central role; yet how TCR signaling propagates to control aT reg cell responses remains poorly under...

Arkaitz Carracedo is a principal investigator at the Association for Cooperative Research in Biosciences (CIC bioGUNE) i...
10/28/2019
Arkaitz Carracedo: If the scientific question is good, the result will be interesting

Arkaitz Carracedo is a principal investigator at the Association for Cooperative Research in Biosciences (CIC bioGUNE) in Spain; his laboratory focuses on signaling and metabolic alterations in cancer. Read more in the latest People & Ideas: https://bit.ly/364y1Xp

Arkaitz Carracedo is a principal investigator at the Association for Cooperative Research in Biosciences (CIC bioGUNE) in Spain; his laboratory focuses on signaling and metabolic alterations in cancer. Arkaitz has investigated the regulation of fatty ac...

Specific IL-1 family cytokines are initially expressed as inactive, cytosolic pro-forms. Amy H. Chan and Kate Schroder (...
10/28/2019
Inflammasome signaling and regulation of interleukin-1 family cytokines

Specific IL-1 family cytokines are initially expressed as inactive, cytosolic pro-forms. Amy H. Chan and Kate Schroder (https://bit.ly/2o72H92) review inflammasome signaling and cell death decisions, mechanisms underpinning IL-1α, IL-1β, IL-18, and IL-37 maturation and release, and the functions of these cytokines in protective and pathological inflammation.

Specific IL-1 family cytokines are expressed by cells as cytosolic pro-forms that require cleavage for their activity and cellular release. IL-1β, IL-18, and IL-37 maturation and secretion is governed by inflammatory caspases within signaling platforms ...

GM-CSF is a potential therapeutic target in inflammation and autoimmunity. This study by John A. Hamilton (https://bit.l...
10/25/2019
GM-CSF in inflammation

GM-CSF is a potential therapeutic target in inflammation and autoimmunity. This study by John A. Hamilton (https://bit.ly/2JfiB8H) reviews the literature on the biology of GM-CSF, in particular that describing the research leading to clinical trials targeting GM-CSF and its receptor in numerous inflammatory/autoimmune conditions, such as rheumatoid arthritis.

Granulocyte–macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells. Key features of GM-CSF biology need to be defined ...

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The Journal of Experimental Medicine (JEM) features peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions are made by research-active scientists in conjunction with in-house scientific editors. JEM provides free online access to many article types from the date of publication and to all archival content. Established in 1896, JEM is published by The Rockefeller University Press. For more information, visit http://jem.rupress.org. Follow us on Twitter: https://twitter.com/JExpMed

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