Journal of Experimental Medicine

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ISSN / EISSN : 0022-1007 / 1540-9538
Published by: Rockefeller University Press (10.1084)
Total articles ≅ 25,283
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Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.20201314

Abstract:
The intracellular parasite Toxoplasma gondii has long provided a tractable experimental system to investigate how the immune system deals with intracellular infections. This review highlights the advances in defining how this organism was first detected and the studies with T. gondii that contribute to our understanding of how the cytokine IFN-γ promotes control of vacuolar pathogens. In addition, the genetic tractability of this eukaryote organism has provided the foundation for studies into the diverse strategies that pathogens use to evade antimicrobial responses and now provides the opportunity to study the basis for latency. Thus, T. gondii remains a clinically relevant organism whose evolving interactions with the host immune system continue to teach lessons broadly relevant to host–pathogen interactions.
Correction
Zhen Zhuang, Xiaomin Lai, Jing Sun, Zhao Chen, Zhaoyong Zhang, Jun Dai, Donglan Liu, Yuming Li, Fang Li, Yanqun Wang, et al.
Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.2020218710052021c

Xiuyuan Lu, Yuki Hosono, , Shigenari Ishizuka, Eri Ishikawa, Daisuke Motooka, Yuki Ozaki, Nicolas Sax, , , et al.
Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.20211327

Abstract:
Adaptive immunity is a fundamental component in controlling COVID-19. In this process, follicular helper T (Tfh) cells are a subset of CD4+ T cells that mediate the production of protective antibodies; however, the SARS-CoV-2 epitopes activating Tfh cells are not well characterized. Here, we identified and crystallized TCRs of public circulating Tfh (cTfh) clonotypes that are expanded in patients who have recovered from mild symptoms. These public clonotypes recognized the SARS-CoV-2 spike (S) epitopes conserved across emerging variants. The epitope of the most prevalent cTfh clonotype, S864–882, was presented by multiple HLAs and activated T cells in most healthy donors, suggesting that this S region is a universal T cell epitope useful for booster antigen. SARS-CoV-2–specific public cTfh clonotypes also cross-reacted with specific commensal bacteria. In this study, we identified conserved SARS-CoV-2 S epitopes that activate public cTfh clonotypes associated with mild symptoms.
, Laura Marie Gail, Lisa Kleissl, , Valerie Smejkal, Julian Huber, Viktoria Puxkandl, Luisa Unterluggauer, Ruth Dingelmaier-Hovorka, Denise Atzmüller, et al.
Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.20210417

Abstract:
Emigration of tissue-resident memory T cells (TRMs) was recently introduced in mouse models and may drive systemic inflammation. Skin TRMs of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) can coexist beside donor T cells, offering a unique human model system to study T cell migration. By genotyping, mathematical modeling, single-cell transcriptomics, and functional analysis of patient blood and skin T cells, we detected a small consistent population of circulating skin-derived T cells with a TRM phenotype (cTRMs) in the blood and unveil their skin origin and striking resemblance to skin TRMs. Blood from patients with active graft-versus-host disease (GVHD) contains elevated numbers of host cTRMs producing pro-inflammatory Th2/Th17 cytokines and mediating keratinocyte damage. Expression of gut-homing receptors and the occurrence of cTRMs in gastrointestinal GVHD lesions emphasize their potential to reseed and propagate inflammation in distant organs. Collectively, we describe a distinct circulating T cell population mirroring skin inflammation, which could serve as a biomarker or therapeutic target in GVHD.
Robert A. Lindquist,
Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.20211605

Abstract:
In this issue of JEM, Zhang et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20202669) identify a dependency of glioma stem cells on tyrosine phosphatase activity of EYA2 and a new role for this phosphatase at the centrosome, offering a new therapeutic approach to target mitotic activity.
Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.20211427

Abstract:
Latent intact HIV-1 proviruses persist in a small subset of long-lived CD4+ T cells that can undergo clonal expansion in vivo. Expanded clones of CD4+ T cells dominate latent reservoirs in individuals on long-term antiretroviral therapy (ART) and represent a major barrier to HIV-1 cure. To determine how integration landscape might contribute to latency, we analyzed integration sites of near full length HIV-1 genomes from individuals on long-term ART, focusing on individuals whose reservoirs are highly clonal. We find that intact proviruses in expanded CD4+ T cell clones are preferentially integrated within Krüppel-associated box (KRAB) domain–containing zinc finger (ZNF) genes. ZNF genes are associated with heterochromatin in memory CD4+ T cells; nevertheless, they are expressed in these cells under steady-state conditions. In contrast to genes carrying unique integrations, ZNF genes carrying clonal intact integrations are down-regulated upon cellular activation. Together, the data suggest selected genomic sites, including ZNF genes, can be especially permissive for maintaining HIV-1 latency during memory CD4+ T cell expansion.
Ryo Shinnakasu, , Hiromi Yamamoto, Po-Hung Wang, Saya Moriyama, Nicolas Sax, Chikako Ono, Atsushi Yamanaka, Yu Adachi, Taishi Onodera, et al.
Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.20211003

Abstract:
Broadly protective vaccines against SARS-related coronaviruses that may cause future outbreaks are urgently needed. The SARS-CoV-2 spike receptor-binding domain (RBD) comprises two regions, the core-RBD and the receptor-binding motif (RBM); the former is structurally conserved between SARS-CoV-2 and SARS-CoV. Here, in order to elicit humoral responses to the more conserved core-RBD, we introduced N-linked glycans onto RBM surfaces of the SARS-CoV-2 RBD and used them as immunogens in a mouse model. We found that glycan addition elicited higher proportions of the core-RBD–specific germinal center (GC) B cells and antibody responses, thereby manifesting significant neutralizing activity for SARS-CoV, SARS-CoV-2, and the bat WIV1-CoV. These results have implications for the design of SARS-like virus vaccines.
Guoxin Zhang, Zhen Dong, Ryan C. Gimple, Arthur Wolin, Qiulian Wu, , Lisa M. Wood, , Li Jiang, Linjie Zhao, et al.
Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.20202669

Abstract:
Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors.
, , Kei Fujimura, Danny Li, Kathryn McCauley, , Shannon K.K. Best, Diana Zhu, Andrew J. Rasky, , et al.
Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.20210235

Abstract:
Development of the immune system can be influenced by diverse extrinsic and intrinsic factors that influence the risk of disease. Severe early life respiratory syncytial virus (RSV) infection is associated with persistent immune alterations. Previously, our group had shown that adult mice orally supplemented with Lactobacillus johnsonii exhibited decreased airway immunopathology following RSV infection. Here, we demonstrate that offspring of mice supplemented with L. johnsonii exhibit reduced airway mucus and Th2 cell–mediated response to RSV infection. Maternal supplementation resulted in a consistent gut microbiome in mothers and their offspring. Importantly, supplemented maternal plasma and breastmilk, and offspring plasma, exhibited decreased inflammatory metabolites. Cross-fostering studies showed that prenatal Lactobacillus exposure led to decreased Th2 cytokines and lung inflammation following RSV infection, while postnatal Lactobacillus exposure diminished goblet cell hypertrophy and mucus production in the lung in response to airway infection. These studies demonstrate that Lactobacillus modulation of the maternal microbiome and associated metabolic reprogramming enhance airway protection against RSV in neonates.
Correction
Vishwas Mishra, Avipsa Bose, Shashi Kiran, Sanghita Banerjee, Idrees A. Shah, Pooja Chaukimath, Mudasir M. Reshi, Swarna Srinivas, Anaxee Barman, Sandhya S. Visweswariah
Journal of Experimental Medicine, Volume 218; https://doi.org/10.1084/jem.2021047909292021c

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