The Journal of Experimental Medicine This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Context-dependent EMT programs in cancer metastasis
Epithelial–mesenchymal transition (EMT) is a developmental process whereby stationary, adherent cells acquire the ability to migrate. EMT is critical for dramatic cellular movements during embryogenesis; however, tumor cells can reactivate EMT programs, which increases their aggressiveness. In addition to motility, EMT is associated with enhanced stem cell properties and drug resistance; thus it can drive metastasis, tumor recurrence, and therapy resistance in the context of cancer. However, the precise requirements for EMT in metastasis have not been fully delineated, with different tumor types relying on discrete E...
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Aiello, N. M., Kang, Y. Tags: Solid Tumors Review Source Type: research

Stephanie Eisenbarth: Discovering the bigger picture
Stephanie Eisenbarth is an Associate Professor in the Immunology Faculty at Yale University. Her work has shown that the guanine nucleotide exchange factor Dock8 plays a role in the migration of a specific dendritic cell subset, and that when Dock8 is missing, some dendritic cells can no longer prime CD4+ T cells. Stephanie’s laboratory now focuses on understanding how T cell–driven pathology is initiated. We chatted with Stephanie to find out about her journey in science. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Houston, S. Tags: People & amp; Ideas Source Type: research

Gender disparity in HCC: Is it the fat and not the sex?
Men are more likely to develop hepatocellular carcinoma (HCC) than women, but it is not clear why. In this issue of JEM, Manieri et al. (https://doi.org/10.1084/jem.20181288) identify reduced adiponectin levels as responsible for the increased incidence of HCC in males. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Greten, T. F. Tags: Insights Source Type: research

When pregnancy tames the wolf
A state of relative immunosuppression exists in normal pregnancy. In this issue of JEM, Hong et al. (https://doi.org/10.1084/jem.20190185) perform blood immunomonitoring in pregnancy, in both healthy women and women with lupus, and observe early and sustained transcriptional modulation of lupus-related pathways in both groups. When signatures of inflammation did not normalize in lupus, risk of pregnancy complications was increased. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Niewold, T. B., Mehta-Lee, S. Tags: Autoimmunity, Tolerance Insights Source Type: research

The Aire family expands
T cell tolerance depends upon Aire-expressing cells to purge the T cell repertoire of autoreactive clones. Once thought to be the exclusive domain of thymic epithelial cells, a new study by Yamano et al. (https://doi.org/10.1084/jem.20181430) in this issue of JEM identifies ILC3-like cells in the lymph nodes with similar properties. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - May 5, 2019 Category: Internal Medicine Authors: Liston, A., Dooley, J. Tags: Autoimmunity Insights Source Type: research

Correction: KAT8 selectively inhibits antiviral immunity by acetylating IRF3
Vol. 216, No. 4, April 1, 2019. 10.1084/jem.20181773. The authors regret that in the original version of this paper, the peptide sequence in Fig. 6 B appeared incorrectly as "LVMVKVVP." Panel B appears below with... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Huai, W., Liu, X., Wang, C., Zhang, Y., Chen, X., Chen, X., Xu, S., Thomas, T., Li, N., Cao, X. Tags: Corrections Source Type: research

Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer
Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand PD-L1 often induces durable tumor responses in various cancers, including non–small cell lung cancer (NSCLC). However, therapeutic resistance is increasingly observed, and the mechanisms underlying anti–PD-L1 (aPD-L1) antibody treatment have not been clarified yet. Here, we identified two unique secreted PD-L1 splicing variants, which lacked the transmembrane domain, from aPD-L1–resistant NSCLC patients. These secreted PD-L1 variants worked as "decoys" of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Gong, B., Kiyotani, K., Sakata, S., Nagano, S., Kumehara, S., Baba, S., Besse, B., Yanagitani, N., Friboulet, L., Nishio, M., Takeuchi, K., Kawamoto, H., Fujita, N., Katayama, R. Tags: Tumor Immunology Articles Source Type: research

Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML
Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function EZH2 mutations are common in myeloid malignancies. We have examined the importance of cellular context for Ezh2 loss during the evolution of acute myeloid leukemia (AML), where we observed stage-specific and diametrically opposite functions for Ezh2 at the early and late stages of disease. During disease maintenance, WT Ezh2 exerts an oncogenic function that may be therapeutically targeted. In contrast, Ezh2 acts as a tumor suppressor during AML induction. Transcriptional analysis explains this apparent paradox, demonstrating that l...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Basheer, F., Giotopoulos, G., Meduri, E., Yun, H., Mazan, M., Sasca, D., Gallipoli, P., Marando, L., Gozdecka, M., Asby, R., Sheppard, O., Dudek, M., Bullinger, L., Döhner, H., Dillon, R., Freeman, S., Ottmann, O., Burnett, A., Russell, N., Papaem Tags: Leukemia & Lymphoma, Hematopoiesis Articles Source Type: research

Disruption of FBXL5-mediated cellular iron homeostasis promotes liver carcinogenesis
Hepatic iron overload is a risk factor for progression of hepatocellular carcinoma (HCC), although the molecular mechanisms underlying this association have remained unclear. We now show that the iron-sensing ubiquitin ligase FBXL5 is a previously unrecognized oncosuppressor in liver carcinogenesis in mice. Hepatocellular iron overload elicited by FBXL5 ablation gave rise to oxidative stress, tissue damage, inflammation, and compensatory proliferation of hepatocytes and to consequent promotion of liver carcinogenesis induced by exposure to a chemical carcinogen. The tumor-promoting outcome of FBXL5 deficiency in the liver ...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Muto, Y., Moroishi, T., Ichihara, K., Nishiyama, M., Shimizu, H., Eguchi, H., Moriya, K., Koike, K., Mimori, K., Mori, M., Katayama, Y., Nakayama, K. I. Tags: Solid Tumors, Human Disease Genetics, Metabolism Articles Source Type: research

Targeting VE-PTP phosphatase protects the kidney from diabetic injury
Diabetic nephropathy is a leading cause of end-stage kidney failure. Reduced angiopoietin-TIE2 receptor tyrosine kinase signaling in the vasculature leads to increased vascular permeability, inflammation, and endothelial cell loss and is associated with the development of diabetic complications. Here, we identified a mechanism to explain how TIE2 signaling is attenuated in diabetic animals. Expression of vascular endothelial protein tyrosine phosphatase VE-PTP (also known as PTPRB), which dephosphorylates TIE2, is robustly up-regulated in the renal microvasculature of diabetic rodents, thereby reducing TIE2 activity. Incre...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Carota, I. A., Kenig-Kozlovsky, Y., Onay, T., Scott, R., Thomson, B. R., Souma, T., Bartlett, C. S., Li, Y., Procissi, D., Ramirez, V., Yamaguchi, S., Tarjus, A., Tanna, C. E., Li, C., Eremina, V., Vestweber, D., Oladipupo, S. S., Breyer, M. D., Quaggin, Tags: Cardiovascular Biology, Metabolism Articles Source Type: research

Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke
This study provides novel molecular insights and charts new avenues for therapeutic intervention associated with Cx43 function. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Freitas-Andrade, M., Wang, N., Bechberger, J. F., De Bock, M., Lampe, P. D., Leybaert, L., Naus, C. C. Tags: Neuroscience Articles Source Type: research

Impaired {alpha}V{beta}8 and TGF{beta} signaling lead to microglial dysmaturation and neuromotor dysfunction
Microglia play a pivotal role in the coordination of brain development and have emerged as a critical determinant in the progression of neurodegenerative diseases; however, the role of microglia in the onset and progression of neurodevelopmental disorders is less clear. Here we show that conditional deletion of αVβ8 from the central nervous system (Itgb8CNS mice) blocks microglia in their normal stepwise development from immature precursors to mature microglia. These "dysmature" microglia appear to result from reduced TGFβ signaling during a critical perinatal window, are distinct from microglia with induce...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Arnold, T. D., Lizama, C. O., Cautivo, K. M., Santander, N., Lin, L., Qiu, H., Huang, E. J., Liu, C., Mukouyama, Y.-s., Reichardt, L. F., Zovein, A. C., Sheppard, D. Tags: Neuroinflammation, Innate Immunity and Inflammation, Neuroscience Articles Source Type: research

Suppression of ILC2 differentiation from committed T cell precursors by E protein transcription factors
Current models propose that group 2 innate lymphoid cells (ILC2s) are generated in the bone marrow. Here, we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s exit the thymus, circulate in the blood, and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the ILC fate while impairing B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein d...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Qian, L., Bajana, S., Georgescu, C., Peng, V., Wang, H.-C., Adrianto, I., Colonna, M., Alberola-Ila, J., Wren, J. D., Sun, X.-H. Tags: Articles Source Type: research

STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death
STING gain-of-function mutations cause lung disease and T cell cytopenia through unknown mechanisms. Here, we found that these mutants induce chronic activation of ER stress and unfolded protein response (UPR), leading to T cell death by apoptosis in the StingN153S/+ mouse and in human T cells. Mechanistically, STING-N154S disrupts calcium homeostasis in T cells, thus intrinsically primes T cells to become hyperresponsive to T cell receptor signaling–induced ER stress and the UPR, leading to cell death. This intrinsic priming effect is mediated through a novel region of STING that we name "the UPR motif," which is di...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Wu, J., Chen, Y.-J., Dobbs, N., Sakai, T., Liou, J., Miner, J. J., Yan, N. Tags: Autoimmunity, Innate Immunity and Inflammation Articles Source Type: research

Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells
Tcf1 and Lef1 have versatile functions in regulating T cell development and differentiation, but intrinsic requirements for these factors in regulatory T (T reg) cells remain to be unequivocally defined. Specific ablation of Tcf1 and Lef1 in T reg cells resulted in spontaneous multi-organ autoimmunity that became more evident with age. Tcf1/Lef1-deficient T regs showed reduced protection against experimentally induced colitis, indicative of diminished immuno-suppressive capacity. Transcriptomic analysis revealed that Tcf1 and Lef1 were responsible for positive regulation of a subset of T reg–overrepresented signature...
Source: The Journal of Experimental Medicine - March 31, 2019 Category: Internal Medicine Authors: Xing, S., Gai, K., Li, X., Shao, P., Zeng, Z., Zhao, X., Zhao, X., Chen, X., Paradee, W. J., Meyerholz, D. K., Peng, W., Xue, H.-H. Tags: Articles Source Type: research