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Journal of Experimental Medicine

Linjia Jiang, Xue Han, Jin Wang, Chen Wang, Xiaoqiang Sun, Jiayi Xie, Guojin Wu, Hiep Phan, Zhenguo Liu, Edward T H Yeh, ChengCheng Zhang, Meng Zhao, Xunlei Kang
No abstract text is available yet for this article.
July 13, 2018: Journal of Experimental Medicine
Amelie V Guitart, Andrew J Finch, Kamil R Kranc
In this issue of JEM , Umemoto et al. ( demonstrate that calcium influx stimulates mitochondrial metabolism and initiates proliferation in hematopoietic stem cells (HSCs). Extracellular adenosine, sourced from surrounding hematopoietic progenitors, inhibits this calcium influx, thereby suppressing mitochondrial metabolism and promoting HSC quiescence. This is the first demonstration that a calcium-mitochondria pathway regulates HSC division.
July 12, 2018: Journal of Experimental Medicine
Sara E Meyer, David E Muench, Andrew M Rogers, Tess J Newkold, Emily Orr, Eric O'Brien, John P Perentesis, John G Doench, Ashish Lal, Patrick J Morris, Craig J Thomas, Judy Lieberman, Edwina McGlinn, Bruce J Aronow, Nathan Salomonis, H Leighton Grimes
We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1 ) is a direct miR-196b target whose repression enhanced an embryonic stem cell-like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo...
July 11, 2018: Journal of Experimental Medicine
Krista Stockenhuber, Ahmed N Hegazy, Nathaniel R West, Nicholas E Ilott, Alexander Stockenhuber, Samuel J Bullers, Emily E Thornton, Isabelle C Arnold, Andrea Tucci, Herman Waldmann, Graham S Ogg, Fiona Powrie
Psoriasis is a complex inflammatory skin disease affecting ∼3% of the population worldwide. Although type I interferons (IFN-I) are thought to be involved in its pathogenesis, the details of this relationship remain elusive. Here we show that in a murine model of imiquimod-driven psoriatic skin inflammation, Foxp3+ regulatory T cells (T reg cells) control inflammation severity by restraining IFN-I. Depletion of T reg cells induces IFN-I and IFN-stimulated gene expression, and leads to accumulation of CD8+ T cells in lesional skin...
July 6, 2018: Journal of Experimental Medicine
Guilin Chen, Shengkai Zuo, Juan Tang, Caojian Zuo, Daile Jia, Qian Liu, Guizhu Liu, Qian Zhu, Yuanyang Wang, Jian Zhang, Yujun Shen, Dongrui Chen, Ping Yuan, Zhiqiang Qin, Chengchao Ruan, Jue Ye, Xiao-Jian Wang, Yuping Zhou, Pingjin Gao, Peng Zhang, Jinming Liu, Zhi-Cheng Jing, Ankang Lu, Ying Yu
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3+ CD4+ T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models...
July 3, 2018: Journal of Experimental Medicine
Isabelle C Arnold, Mariela Artola-Borán, Paulino Tallón de Lara, Andreas Kyburz, Christian Taube, Karen Ottemann, Maries van den Broek, Shida Yousefi, Hans-Uwe Simon, Anne Müller
Eosinophils are predominantly known for their contribution to allergy. Here, we have examined the function and regulation of gastrointestinal eosinophils in the steady-state and during infection with Helicobacter pylori or Citrobacter rodentium We find that eosinophils are recruited to sites of infection, directly encounter live bacteria, and activate a signature transcriptional program; this applies also to human gastrointestinal eosinophils in humanized mice. The genetic or anti-IL-5-mediated depletion of eosinophils results in improved control of the infection, increased inflammation, and more pronounced Th1 responses...
July 3, 2018: Journal of Experimental Medicine
Simon Le Gallou, Zhicheng Zhou, Lan-Huong Thai, Remi Fritzen, Alba Verge de Los Aires, Jérôme Mégret, Philipp Yu, Daisuke Kitamura, Emmanuelle Bille, Fabiola Tros, Xavier Nassif, Alain Charbit, Sandra Weller, Jean-Claude Weill, Claude-Agnès Reynaud
To what extent immune responses against the gut flora are compartmentalized within mucosal tissues in homeostatic conditions remains a much-debated issue. We describe here, based on an inducible AID fate-mapping mouse model, that systemic memory B cell subsets, including mainly IgM+ B cells in spleen, together with IgA+ plasma cells in spleen and bone marrow, are generated in mice in the absence of deliberate immunization. While the IgA component appears dependent on the gut flora, IgM memory B cells are still generated in germ-free mice, albeit to a reduced extent...
June 29, 2018: Journal of Experimental Medicine
Terumasa Umemoto, Michihiro Hashimoto, Takayoshi Matsumura, Ayako Nakamura-Ishizu, Toshio Suda
Most of the hematopoietic stem cells (HSCs) within the bone marrow (BM) show quiescent state with a low mitochondrial membrane potential (ΔΨm ). In contrast, upon stress hematopoiesis, HSCs actively start to divide. However, the underlying mechanism for the initiation of HSC division still remains unclear. To elucidate the mechanism underlying the transition of cell cycle state in HSCs, we analyzed the change of mitochondria in HSCs after BM suppression induced by 5-fluoruracil (5-FU). We found that HSCs initiate cell division after exhibiting enhanced ΔΨm as a result of increased intracellular Ca2+ level...
June 26, 2018: Journal of Experimental Medicine
Aaron S Rapaport, Wenjun Ouyang
The precise downstream mediators of TGF-β signaling in Th17 and T reg cells remain unclear. In this issue of JE M, Tanaka et al. report that Trim33 transduces TGF-β signals in Th17 cells to generate an optimal proinflammatory cytokine profile.
June 26, 2018: Journal of Experimental Medicine
Marc R Mansour, Shuning He, Zhaodong Li, Riadh Lobbardi, Brian J Abraham, Clemens Hug, Sunniyat Rahman, Theresa E Leon, You-Yi Kuang, Mark W Zimmerman, Traci Blonquist, Evisa Gjini, Alejandro Gutierrez, Qin Tang, Laura Garcia-Perez, Karin Pike-Overzet, Lars Anders, Alla Berezovskaya, Yi Zhou, Leonard I Zon, Donna Neuberg, Adele K Fielding, Frank J T Staal, David M Langenau, Takaomi Sanda, Richard A Young, A Thomas Look
A substantial subset of patients with T cell acute lymphoblastic leukemia (T-ALL) develops resistance to steroids and succumbs to their disease. JDP2 encodes a bZIP protein that has been implicated as a T-ALL oncogene from insertional mutagenesis studies in mice, but its role in human T-ALL pathogenesis has remained obscure. Here we show that JDP2 is aberrantly expressed in a subset of T-ALL patients and is associated with poor survival. JDP2 is required for T-ALL cell survival, as its depletion by short hairpin RNA knockdown leads to apoptosis...
June 25, 2018: Journal of Experimental Medicine
Ken Cadwell
A20 and its binding partner ABIN-1 are genetically linked to inflammatory diseases. In this issue of JEM , Kattah et al. ( demonstrate that simultaneous deletion in a mouse model leads to instantaneous cell death in the intestinal epithelium and mortality.
June 22, 2018: Journal of Experimental Medicine
Akihiro Kimura, Masayuki Kitajima, Kyoko Nishida, Satoshi Serada, Minoru Fujimoto, Tetsuji Naka, Yoshiaki Fujii-Kuriyama, Satoshi Sakamato, Takumi Ito, Hiroshi Handa, Takashi Tanaka, Akihiko Yoshimura, Harumi Suzuki
NAD(P)H:quinone oxidoreductase 1 (NQO1) protects cells against oxidative stress and toxic quinones. In this study, we found a novel role of NQO1 in suppressing Toll-like receptor (TLR)-mediated innate immune responses. NQO1-deficient macrophages selectively produced excessive amounts of IL-6, IL-12, and GM-CSF on LPS stimulation, and the deletion of NQO1 in macrophages exacerbated LPS-induced septic shock. NQO1 interacted with the nuclear IκB protein IκB-ζ, which is essential for the TLR-mediated induction of a subset of secondary response genes, including IL-6, and promoted IκB-ζ degradation in a ubiquitin-dependent manner...
June 22, 2018: Journal of Experimental Medicine
Michael G Kattah, Ling Shao, Yenny Y Rosli, Hiromichi Shimizu, Michael I Whang, Rommel Advincula, Philip Achacoso, Sanjana Shah, Bao H Duong, Michio Onizawa, Priscilia Tanbun, Barbara A Malynn, Averil Ma
A20 ( TNFAIP3 ) and ABIN-1 ( TNIP1 ) are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells...
June 21, 2018: Journal of Experimental Medicine
Boyoung Shin, Robert L Kress, Philip A Kramer, Victor M Darley-Usmar, Susan L Bellis, Laurie E Harrington
Dysregulated CD4 T cell responses are causally linked to autoimmune and chronic inflammatory disorders, yet the cellular attributes responsible for maintaining the disease remain poorly understood. Herein, we identify a discrete population of effector CD4 T cells that is able to both sustain and confer intestinal inflammation. This subset of pathogenic CD4 T cells possesses a unique gene signature consistent with self-renewing T cells and hematopoietic progenitor cells, exhibits enhanced survival, and continually seeds the terminally differentiated IFNγ-producing cells in the inflamed intestine...
June 18, 2018: Journal of Experimental Medicine
Christina T Jensen, Josefine Åhsberg, Mikael N E Sommarin, Tobias Strid, Rajesh Somasundaram, Kazuki Okuyama, Jonas Ungerbäck, Jussi Kupari, Matti S Airaksinen, Stefan Lang, David Bryder, Shamit Soneji, Göran Karlsson, Mikael Sigvardsson
To understand the developmental trajectories in early lymphocyte differentiation, we identified differentially expressed surface markers on lineage-negative lymphoid progenitors (LPs). Single-cell polymerase chain reaction experiments allowed us to link surface marker expression to that of lineage-associated transcription factors (TFs) and identify GFRA2 and BST1 as markers of early B cells. Functional analyses in vitro and in vivo as well as single-cell gene expression analyses supported that surface expression of these proteins defined distinct subpopulations that include cells from both the classical common LPs (CLPs) and Fraction A compartments...
June 13, 2018: Journal of Experimental Medicine
Jeremy P Huynh, Chih-Chung Lin, Jacqueline M Kimmey, Nicholas N Jarjour, Elizabeth A Schwarzkopf, Tara R Bradstreet, Irina Shchukina, Oleg Shpynov, Casey T Weaver, Reshma Taneja, Maxim N Artyomov, Brian T Edelson, Christina L Stallings
The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis ( Mtb ) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ...
May 17, 2018: Journal of Experimental Medicine
Fang Yu, Suveena Sharma, Dragana Jankovic, Rama Krishna Gurram, Pan Su, Gangqing Hu, Rao Li, Sadiye Rieder, Keji Zhao, Bing Sun, Jinfang Zhu
Type 1 T helper (Th1) cells play a critical role in host defense against intracellular pathogens and in autoimmune diseases by producing a key inflammatory cytokine interferon (IFN)-γ; some Th1 cells can also be antiinflammatory through producing IL-10. However, the molecular switch for regulating the differentiation of inflammatory and antiinflammatory Th1 cells is still elusive. Here, we show that Bhlhe40 -deficient CD4 Th1 cells produced less IFN-γ but substantially more IL-10 than wild-type Th1 cells both in vitro and in vivo...
May 17, 2018: Journal of Experimental Medicine
Geoffrey T Norris, Igor Smirnov, Anthony J Filiano, Hannah M Shadowen, Kris R Cody, Jeremy A Thompson, Tajie H Harris, Alban Gaultier, Christopher C Overall, Jonathan Kipnis
Phagocytosis of synaptic material by microglia is critical for central nervous system development. Less well understood is this microglial function in the injured adult brain. Assay of microglial phagocytosis is challenging, because peripheral myeloid cells engraft the site of injury, which could obscure interpretation of microglial roles. The model used here, optic nerve crush injury, results in degeneration of synapses in the dorsal lateral geniculate nucleus (dLGN), which stimulates rapid activation and engulfment of synaptic material by resident microglia without myeloid cell engraftment...
July 2, 2018: Journal of Experimental Medicine
Alexander Tarakhovsky, Rab K Prinjha
Humans carry trillions of viruses that thrive because of their ability to exploit the host. In this exploitation, viruses promote their own replication by suppressing the host antiviral response and by inducing changes in host biosynthetic processes, often with extremely small genomes of their own. In the review, we discuss the phenomenon of histone mimicry by viral proteins and how this mimicry allows the virus to dial in to the cell's transcriptional processes and establish a cell state that promotes infection...
July 2, 2018: Journal of Experimental Medicine
Shinya Tanaka, Yu Jiang, Gustavo J Martinez, Kentaro Tanaka, Xiaowei Yan, Tomohiro Kurosaki, Vesa Kaartinen, Xin-Hua Feng, Qiang Tian, Xiaohu Wang, Chen Dong
Transforming growth factor-β (TGF-β) regulates reciprocal regulatory T cell (T reg) and T helper 17 (Th17) differentiation, the underlying mechanism of which is still not understood. Here, we report that tripartite motif-containing 33 (Trim33), a modulator of TGF-β signaling that associates with Smad2, regulates the proinflammatory function of Th17 cells. Trim33 deficiency in T cells ameliorated an autoimmune disease in vivo . Trim33 was required for induction in vitro of Th17, but not T reg cells. Moreover, Smad4 and Trim33 play contrasting roles in the regulation of IL-10 expression; loss of Trim33 enhanced IL-10 production...
July 2, 2018: Journal of Experimental Medicine
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