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Journal of Experimental Medicine

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https://www.readbyqxmd.com/read/27923908/estrogen-activation-of-microglia-underlies-the-sexually-dimorphic-differences-in-nf1-optic-glioma-induced-retinal-pathology
#1
Joseph A Toonen, Anne C Solga, Yu Ma, David H Gutmann
Children with neurofibromatosis type 1 (NF1) develop low-grade brain tumors throughout the optic pathway. Nearly 50% of children with optic pathway gliomas (OPGs) experience visual impairment, and few regain their vision after chemotherapy. Recent studies have revealed that girls with optic nerve gliomas are five times more likely to lose vision and require treatment than boys. To determine the mechanism underlying this sexually dimorphic difference in clinical outcome, we leveraged Nf1 optic glioma (Nf1-OPG) mice...
December 6, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27923907/deubiquitinase-usp13-maintains-glioblastoma-stem-cells-by-antagonizing-fbxl14-mediated-myc-ubiquitination
#2
Xiaoguang Fang, Wenchao Zhou, Qiulian Wu, Zhi Huang, Yu Shi, Kailin Yang, Cong Chen, Qi Xie, Stephen C Mack, Xiuxing Wang, Angel M Carcaboso, Andrew E Sloan, Gaoliang Ouyang, Roger E McLendon, Xiu-Wu Bian, Jeremy N Rich, Shideng Bao
Glioblastoma is the most lethal brain tumor and harbors glioma stem cells (GSCs) with potent tumorigenic capacity. The function of GSCs in tumor propagation is maintained by several core transcriptional regulators including c-Myc. c-Myc protein is tightly regulated by posttranslational modification. However, the posttranslational regulatory mechanisms for c-Myc in GSCs have not been defined. In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential...
December 6, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27923906/cd4-t-cell-effector-commitment-coupled-to-self-renewal-by-asymmetric-cell-divisions
#3
Simone A Nish, Kyra D Zens, Radomir Kratchmarov, Wen-Hsuan W Lin, William C Adams, Yen-Hua Chen, Bonnie Yen, Nyanza J Rothman, Avinash Bhandoola, Hai-Hui Xue, Donna L Farber, Steven L Reiner
Upon infection, an activated CD4(+) T cell produces terminally differentiated effector cells and renews itself for continued defense. In this study, we show that differentiation and self-renewal arise as opposing outcomes of sibling CD4(+) T cells. After influenza challenge, antigen-specific cells underwent several divisions in draining lymph nodes (LN; DLNs) while maintaining expression of TCF1. After four or five divisions, some cells silenced, whereas some cells maintained TCF1 expression. TCF1-silenced cells were T helper 1-like effectors and concentrated in the lungs...
December 6, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27913566/th2-responses-are-primed-by-skin-dendritic-cells-with-distinct-transcriptional-profiles
#4
Lisa M Connor, Shiau-Choot Tang, Emmanuelle Cognard, Sotaro Ochiai, Kerry L Hilligan, Samuel I Old, Christophe Pellefigues, Ruby F White, Deepa Patel, Adam Alexander T Smith, David A Eccles, Olivier Lamiable, Melanie J McConnell, Franca Ronchese
The dendritic cell signals required for the in vivo priming of IL-4-producing T cells are unknown. We used RNA sequencing to characterize DCs from skin LN of mice exposed to two different Th2 stimuli: the helminth parasite Nippostrongylus brasiliensis (Nb) and the contact sensitizer dibutyl phthalate (DBP)-FITC. Both Nb and DBP-FITC induced extensive transcriptional changes that involved multiple DC subsets. Surprisingly, these transcriptional changes were highly distinct in the two models, with only a small number of genes being similarly regulated in both conditions...
December 2, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27903604/what-does-pd-l1-positive-or-negative-mean
#5
Antoni Ribas, Siwen Hu-Lieskovan
Expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) is used to select patients and analyze responses to anti-PD-1/L1 antibodies. The expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence or absence. PD-L1 positivity may be a result of genetic events leading to constitutive PD-L1 expression on cancer cells or inducible PD-L1 expression on cancer cells and noncancer cells in response to a T cell infiltrate. A tumor may be PD-L1 negative because it has no T cell infiltrate, which may be reversed with an immune response...
November 30, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27899444/antigen-dependent-competition-shapes-the-local-repertoire-of-tissue-resident-memory-cd8-t-cells
#6
Andreas Muschaweckh, Veit R Buchholz, Anne Fellenzer, Christian Hessel, Paul-Albert König, Sha Tao, Ronny Tao, Mathias Heikenwälder, Dirk H Busch, Thomas Korn, Wolfgang Kastenmüller, Ingo Drexler, Georg Gasteiger
Tissue-resident memory CD8(+) T cells (TRM) constitute a major component of the immune-surveillance system in nonlymphoid organs. Local, noncognate factors are both necessary and sufficient to support the programming of TRM cell fate in tissue-infiltrating T cells. Recent evidence suggests that TCR signals received in infected nonlymphoid tissues additionally contribute to TRM cell formation. Here, we asked how antigen-dependent pathways influence the generation of skin-resident memory T cells that arise from a polyclonal repertoire of cells induced by infection with an antigenically complex virus and recombinant vaccine vector...
November 29, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27899443/rab43-facilitates-cross-presentation-of-cell-associated-antigens-by-cd8%C3%AE-dendritic-cells
#7
Nicole M Kretzer, Derek J Theisen, Roxane Tussiwand, Carlos G Briseño, Gary E Grajales-Reyes, Xiaodi Wu, Vivek Durai, Jörn Albring, Prachi Bagadia, Theresa L Murphy, Kenneth M Murphy
In this study, to examine cross-presentation by classical dendritic cells (DCs; cDCs), we evaluated the role of RAB43, a protein found to be selectively expressed by Batf3-dependent CD8α(+) and CD103(+) compared with other DC subsets and immune lineages. Using a specific monoclonal antibody, we localized RAB43 expression to the Golgi apparatus and LAMP1(-) cytoplasmic vesicles. Mice with germline or conditional deletion of Rab43 are viable and fertile and have normal development of cDCs but show a defect for in vivo and in vitro cross-presentation of cell-associated antigen...
November 29, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27899442/early-generated-b1-b-cells-with-restricted-bcrs-become-chronic-lymphocytic-leukemia-with-continued-c-myc-and-low-bmf-expression
#8
Kyoko Hayakawa, Anthony M Formica, Joni Brill-Dashoff, Susan A Shinton, Daiju Ichikawa, Yan Zhou, Herbert C Morse, Richard R Hardy
In mice, generation of autoreactive CD5(+) B cells occurs as a consequence of BCR signaling induced by (self)-ligand exposure from fetal/neonatal B-1 B cell development. A fraction of these cells self-renew and persist as a minor B1 B cell subset throughout life. Here, we show that transfer of early generated B1 B cells from Eμ-TCL1 transgenic mice resulted in chronic lymphocytic leukemia (CLL) with a biased repertoire, including stereotyped BCRs. Thus, B1 B cells bearing restricted BCRs can become CLL during aging...
November 29, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27899441/interferon-regulatory-factor-2-protects-mice-from-lethal-viral-neuroinvasion
#9
Melody M H Li, Leonia Bozzacco, Hans-Heinrich Hoffmann, Gaëlle Breton, Jakob Loschko, Jing W Xiao, Sébastien Monette, Charles M Rice, Margaret R MacDonald
The host responds to virus infection by activating type I interferon (IFN) signaling leading to expression of IFN-stimulated genes (ISGs). Dysregulation of the IFN response results in inflammatory diseases and chronic infections. In this study, we demonstrate that IFN regulatory factor 2 (IRF2), an ISG and a negative regulator of IFN signaling, influences alphavirus neuroinvasion and pathogenesis. A Sindbis virus strain that in wild-type (WT) mice only causes disease when injected into the brain leads to lethal encephalitis in Irf2(-/-) mice after peripheral inoculation...
November 29, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27881735/therapy-activated-stromal-cells-can-dictate-tumor-fate
#10
Robert S Kerbel, Yuval Shaked
In this issue of JEM, Chan et al. describe a novel way by which an investigational form of chemotherapy known as low-dose metronomic chemotherapy can inhibit tumor growth, which also has therapeutic implications for targeting tumor-initiating cells (TICs), the tumor stroma, and chemokine receptors, as well as invasion and metastasis.
November 23, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27881734/nlrp2-controls-age-associated-maternal-fertility
#11
Anna A Kuchmiy, Jinke D'Hont, Tino Hochepied, Mohamed Lamkanfi
Nucleotide-binding domain and leucine-rich repeat (NLR) proteins are well-known for their key roles in the immune system. Ectopically expressed NLRP2 in immortalized cell lines assembles an inflammasome and inhibits activation of the proinflammatory transcription factor NF-κB, but the physiological roles of NLRP2 are unknown. Here, we show that Nlrp2-deficient mice were born with expected Mendelian ratios and that Nlrp2 was dispensable for innate and adaptive immunity. The observation that Nlrp2 was exclusively expressed in oocytes led us to explore the role of Nlrp2 in parthenogenetic activation of oocytes...
November 23, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27881733/lysosomal-trafficking-regulator-lyst-links-membrane-trafficking-to-toll-like-receptor-mediated-inflammatory-responses
#12
Andreas Westphal, Weijia Cheng, Jinbo Yu, Guntram Grassl, Martina Krautkrämer, Otto Holst, Niko Föger, Kyeong-Hee Lee
Subcellular compartmentalization of receptor signaling is an emerging principle in innate immunity. However, the functional integration of receptor signaling pathways into membrane trafficking routes and its physiological relevance for immune responses is still largely unclear. In this study, using Lyst-mutant beige mice, we show that lysosomal trafficking regulator Lyst links endolysosomal organization to the selective control of toll-like receptor 3 (TLR3)- and TLR4-mediated proinflammatory responses. Consequently, Lyst-mutant mice showed increased susceptibility to bacterial infection and were largely resistant to endotoxin-induced septic shock...
November 23, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27881732/metronomic-chemotherapy-prevents-therapy-induced-stromal-activation-and-induction-of-tumor-initiating-cells
#13
Tze-Sian Chan, Chung-Chi Hsu, Vincent C Pai, Wen-Ying Liao, Shenq-Shyang Huang, Kok-Tong Tan, Chia-Jui Yen, Shu-Ching Hsu, Wei-Yu Chen, Yan-Shen Shan, Chi-Rong Li, Michael T Lee, Kuan-Ying Jiang, Jui-Mei Chu, Gi-Shih Lien, Valerie M Weaver, Kelvin K Tsai
Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts...
November 23, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27879287/tissue-specific-programming-of-memory-cd8-t-cell-subsets-impacts-protection-against-lethal-respiratory-virus-infection
#14
Georges Abboud, Pritesh Desai, Farhad Dastmalchi, Jessica Stanfield, Vikas Tahiliani, Tarun E Hutchinson, Shahram Salek-Ardakani
How tissue-specific anatomical distribution and phenotypic specialization are linked to protective efficacy of memory T cells against reinfection is unclear. Here, we show that lung environmental cues program recently recruited central-like memory cells with migratory potentials for their tissue-specific functions during lethal respiratory virus infection. After entering the lung, some central-like cells retain their original CD27(hi)CXCR3(hi) phenotype, enabling them to localize near the infected bronchiolar epithelium and airway lumen to function as the first line of defense against pathogen encounter...
November 22, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27864467/human-dendritic-cells-dcs-are-derived-from-distinct-circulating-precursors-that-are-precommitted-to-become-cd1c-or-cd141-dcs
#15
Gaëlle Breton, Shiwei Zheng, Renan Valieris, Israel Tojal da Silva, Rahul Satija, Michel C Nussenzweig
In humans, conventional dendritic cells (cDCs) exist as two unique populations characterized by expression of CD1c and CD141. cDCs arise from increasingly restricted but well-defined bone marrow progenitors that include the common DC progenitor that differentiates into the pre-cDC, which is the direct precursor of cDCs. In this study, we show that pre-cDCs in humans are heterogeneous, consisting of two distinct populations of precursors that are precommitted to become either CD1c(+) or CD141(+) cDCs. The two groups of lineage-primed precursors can be distinguished based on differential expression of CD172a...
November 18, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27856613/dorsal-horn-interneuron-derived-netrin-4-contributes-to-spinal-sensitization-in-chronic-pain-via-unc5b
#16
Yasufumi Hayano, Keiko Takasu, Yoshihisa Koyama, Moe Yamada, Koichi Ogawa, Kazuhisa Minami, Toshiyuki Asaki, Kazuhiro Kitada, Satoshi Kuwabara, Toshihide Yamashita
Because of the incomplete understanding of the molecular mechanisms that underlie chronic pain, the currently available treatments for this type of pain remain inefficient. In this study, we show that Netrin-4, a member of the axon guidance molecule family, was expressed in dorsal horn inner lamina II excitatory interneurons in the rat spinal cord. A similar expression pattern for Netrin-4 was also observed in human spinal cord. Behavioral analysis revealed that tactile and heat hyperalgesia after peripheral nerve injury or inflammation were abolished in Netrin-4-mutant rats...
November 17, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27852793/dampened-antiviral-immunity-to-intravaginal-exposure-to-rna-viral-pathogens-allows-enhanced-viral-replication
#17
Shahzada Khan, Erik M Woodruff, Martin Trapecar, Krystal A Fontaine, Ashley Ezaki, Timothy C Borbet, Melanie Ott, Shomyseh Sanjabi
Understanding the host immune response to vaginal exposure to RNA viruses is required to combat sexual transmission of this class of pathogens. In this study, using lymphocytic choriomeningitis virus (LCMV) and Zika virus (ZIKV) in wild-type mice, we show that these viruses replicate in the vaginal mucosa with minimal induction of antiviral interferon and inflammatory response, causing dampened innate-mediated control of viral replication and a failure to mature local antigen-presenting cells (APCs). Enhancement of innate-mediated inflammation in the vaginal mucosa rescues this phenotype and completely inhibits ZIKV replication...
November 16, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27849554/systemic-toxoplasma-infection-triggers-a-long-term-defect-in-the-generation-and-function-of-naive-t-lymphocytes
#18
David G Kugler, Francis A Flomerfelt, Diego L Costa, Karen Laky, Olena Kamenyeva, Paul R Mittelstadt, Ronald E Gress, Stephan P Rosshart, Barbara Rehermann, Jonathan D Ashwell, Alan Sher, Dragana Jankovic
Because antigen-stimulated naive T cells either die as effectors or enter the activated/memory pool, continuous egress of new T lymphocytes from thymus is essential for maintenance of peripheral immune homeostasis. Unexpectedly, we found that systemic infection with the protozoan Toxoplasma gondii triggers not only a transient increase in activated CD4(+) Th1 cells but also a persistent decrease in the size of the naive CD4(+) T lymphocyte pool. This immune defect is associated with decreased thymic output and parasite-induced destruction of the thymic epithelium, as well as disruption of the overall architecture of that primary lymphoid organ...
November 14, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27849553/stat1-regulates-marginal-zone-b-cell-differentiation-in-response-to-inflammation-and-infection-with-blood-borne-bacteria
#19
Ting-Ting Chen, Ming-Hsun Tsai, John T Kung, Kuo-I Lin, Thomas Decker, Chien-Kuo Lee
Marginal zone B (MZ B) cells can rapidly produce antibody in response to infection with blood-borne encapsulated pathogens. Although TLR-mediated activation of MZ B is known to trigger humoral immune response, the signal cascade directing this response remains undefined. Here, we demonstrate that STAT1 plays an essential role in TLR-mediated antibody response of MZ B cells. Further, the TLR-induced IgM response is impaired in a type I and type II IFN-independent manner. Although activation, proliferation, and apoptosis are not affected, both differentiation into plasma cells and IgM production are impaired in Stat1(-/-) MZ B cells...
November 14, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27836928/the-common-mouse-protozoa-tritrichomonas-muris-alters-mucosal-t-cell-homeostasis-and-colitis-susceptibility
#20
Nichole K Escalante, Paul Lemire, Mayra Cruz Tleugabulova, David Prescott, Arthur Mortha, Catherine J Streutker, Stephen E Girardin, Dana J Philpott, Thierry Mallevaey
The mammalian gastrointestinal tract hosts a diverse community of microbes including bacteria, fungi, protozoa, helminths, and viruses. Through coevolution, mammals and these microbes have developed a symbiosis that is sustained through the host's continuous sensing of microbial factors and the generation of a tolerant or pro-inflammatory response. While analyzing T cell-driven colitis in nonlittermate mouse strains, we serendipitously identified that a nongenetic transmissible factor dramatically increased disease susceptibility...
November 11, 2016: Journal of Experimental Medicine
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