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Nature Immunology

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https://www.readbyqxmd.com/read/28805812/t-bet-dependent-nkp46-innate-lymphoid-cells-regulate-the-onset-of-th17-induced-neuroinflammation
#1
Brandon Kwong, Rejane Rua, Yuanyuan Gao, John Flickinger, Yan Wang, Michael J Kruhlak, Jinfang Zhu, Eric Vivier, Dorian B McGavern, Vanja Lazarevic
The transcription factor T-bet has been associated with increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role of T-bet-dependent NKp46(+) innate lymphoid cells (ILCs) in the initiation of CD4(+) TH17-mediated neuroinflammation. Loss of T-bet specifically in NKp46(+) ILCs profoundly impaired the ability of myelin-reactive TH17 cells to invade central nervous system (CNS) tissue and protected the mice from autoimmunity...
August 14, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28805811/caveolin-1-dependent-nanoscale-organization-of-the-bcr-regulates-b-cell-tolerance
#2
Susana Minguet, Kathrin Kläsener, Anna-Maria Schaffer, Gina J Fiala, Teresa Osteso-Ibánez, Katrin Raute, Inmaculada Navarro-Lérida, Frederike A Hartl, Maximilian Seidl, Michael Reth, Miguel A Del Pozo
Caveolin-1 (Cav1) regulates the nanoscale organization and compartmentalization of the plasma membrane. Here we found that Cav1 controlled the distribution of nanoclusters of isotype-specific B cell antigen receptors (BCRs) on the surface of B cells. In mature B cells stimulated with antigen, the immunoglobulin M BCR (IgM-BCR) gained access to lipid domains enriched for GM1 glycolipids, by a process that was dependent on the phosphorylation of Cav1 by the Src family of kinases. Antigen-induced reorganization of nanoclusters of IgM-BCRs and IgD-BCRs regulated BCR signaling in vivo...
August 14, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28783152/genome-wide-dna-methylation-landscape-defines-specialization-of-regulatory-t-cells-in-tissues
#3
Michael Delacher, Charles D Imbusch, Dieter Weichenhan, Achim Breiling, Agnes Hotz-Wagenblatt, Ulrike Träger, Ann-Cathrin Hofer, Danny Kägebein, Qi Wang, Felix Frauhammer, Jan-Philipp Mallm, Katharina Bauer, Carl Herrmann, Philipp A Lang, Benedikt Brors, Christoph Plass, Markus Feuerer
Regulatory T cells (Treg cells) perform two distinct functions: they maintain self-tolerance, and they support organ homeostasis by differentiating into specialized tissue Treg cells. We found that epigenetic modifications defined the molecular characteristics of tissue Treg cells. Tagmentation-based whole-genome bisulfite sequencing revealed more than 11,000 regions that were methylated differentially in pairwise comparisons of tissue Treg cell populations and lymphoid T cells. Similarities in the epigenetic landscape led to the identification of a common tissue Treg cell population that was present in many organs and was characterized by gain and loss of DNA methylation that included many gene sites associated with the TH2 subset of helper T cells, such as the gene encoding cytokine IL-33 receptor ST2, as well as the production of tissue-regenerative factors...
August 7, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28759003/mll4-prepares-the-enhancer-landscape-for-foxp3-induction-via-chromatin-looping
#4
Katarzyna Placek, Gangqing Hu, Kairong Cui, Dunfang Zhang, Yi Ding, Ji-Eun Lee, Younghoon Jang, Chaochen Wang, Joanne Elizabeth Konkel, Jiuzhou Song, Chengyu Liu, Kai Ge, Wanjun Chen, Keji Zhao
MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation complexes. We found that MLL4 deficiency compromised the development of regulatory T cells (Treg cells) and resulted in a substantial decrease in monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene enhancers, a considerable portion of which were not direct targets of MLL4 but were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the enhancers not bound by MLL4 correlated with MLL4 binding at distant interacting regions...
July 31, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28759002/smad4-impedes-the-conversion-of-nk-cells-into-ilc1-like-cells-by-curtailing-non-canonical-tgf-%C3%AE-signaling
#5
Victor S Cortez, Tyler K Ulland, Luisa Cervantes-Barragan, Jennifer K Bando, Michelle L Robinette, Qianli Wang, Andrew J White, Susan Gilfillan, Marina Cella, Marco Colonna
Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-β family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection...
July 31, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28759001/tumor-immunoevasion-by-the-conversion-of-effector-nk-cells-into-type-1-innate-lymphoid-cells
#6
Yulong Gao, Fernando Souza-Fonseca-Guimaraes, Tobias Bald, Susanna S Ng, Arabella Young, Shin Foong Ngiow, Jai Rautela, Jasmin Straube, Nic Waddell, Stephen J Blake, Juming Yan, Laurent Bartholin, Jason S Lee, Eric Vivier, Kazuyoshi Takeda, Meriem Messaoudene, Laurence Zitvogel, Michele W L Teng, Gabrielle T Belz, Christian R Engwerda, Nicholas D Huntington, Kyohei Nakamura, Michael Hölzel, Mark J Smyth
Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-β-signaling-dependent conversion of NK cells (CD49a(-)CD49b(+)Eomes(+)) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a(+)CD49b(+)Eomes(+)) populations and ILC1 (CD49a(+)CD49b(-)Eomes(int)) populations in the tumor microenvironment...
July 31, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28737753/metabolic-control-of-the-scaffold-protein-tks5-in-tissue-invasive-proinflammatory-t-cells
#7
Yi Shen, Zhenke Wen, Yinyin Li, Eric L Matteson, Jison Hong, Jörg J Goronzy, Cornelia M Weyand
Pathogenic T cells in individuals with rheumatoid arthritis (RA) infiltrate non-lymphoid tissue sites, maneuver through extracellular matrix and form lasting inflammatory microstructures. Here we found that RA T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells-specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate...
July 24, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28714979/translation-is-actively-regulated-during-the-differentiation-of-cd8-effector-t-cells
#8
Koichi Araki, Masahiro Morita, Annelise G Bederman, Bogumila T Konieczny, Haydn T Kissick, Nahum Sonenberg, Rafi Ahmed
Translation is a critical process in protein synthesis, but translational regulation in antigen-specific T cells in vivo has not been well defined. Here we have characterized the translatome of virus-specific CD8(+) effector T cells (Teff cells) during acute infection of mice with lymphocytic choriomeningitis virus (LCMV). Antigen-specific T cells exerted dynamic translational control of gene expression that correlated with cell proliferation and stimulation via the T cell antigen receptor (TCR). The translation of mRNAs that encode translation machinery, including ribosomal proteins, was upregulated during the T cell clonal-expansion phase, followed by inhibition of the translation of those transcripts when the CD8(+) Teff cells stopped dividing just before the contraction phase...
July 17, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28714978/%C3%AE-ketoglutarate-orchestrates-macrophage-activation-through-metabolic-and-epigenetic-reprogramming
#9
Pu-Ste Liu, Haiping Wang, Xiaoyun Li, Tung Chao, Tony Teav, Stefan Christen, Giusy Di Conza, Wan-Chen Cheng, Chih-Hung Chou, Magdalena Vavakova, Charlotte Muret, Koen Debackere, Massimiliano Mazzone, Hsien-Da Huang, Sarah-Maria Fendt, Julijana Ivanisevic, Ping-Chih Ho
Glutamine metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the underlying mechanisms regulated by glutamine metabolism to orchestrate macrophage activation remain unclear. Here we show that the production of α-ketoglutarate (αKG) via glutaminolysis is important for alternative (M2) activation of macrophages, including engagement of fatty acid oxidation (FAO) and Jmjd3-dependent epigenetic reprogramming of M2 genes. This M2-promoting mechanism is further modulated by a high αKG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages...
July 17, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28692065/increased-cathepsin-s-in-prdm1-dendritic-cells-alters-the-tfh-cell-repertoire-and-contributes-to-lupus
#10
Sun Jung Kim, Sebastian Schätzle, S Sohail Ahmed, Wolfgang Haap, Su Hwa Jang, Peter K Gregersen, George Georgiou, Betty Diamond
Aberrant population expansion of follicular helper T cells (TFH cells) occurs in patients with lupus. An unanswered question is whether an altered repertoire of T cell antigen receptors (TCRs) is associated with such expansion. Here we found that the transcription factor Blimp-1 (encoded by Prdm1) repressed expression of the gene encoding cathepsin S (Ctss), a cysteine protease that cleaves invariant chains and produces antigenic peptides for loading onto major histocompatibility complex (MHC) class II molecules...
July 10, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28671690/skewing-of-the-population-balance-of-lymphoid-and-myeloid-cells-by-secreted-and-intracellular-osteopontin
#11
Masashi Kanayama, Shengjie Xu, Keiko Danzaki, Jason R Gibson, Makoto Inoue, Simon G Gregory, Mari L Shinohara
The balance of myeloid populations and lymphoid populations must be well controlled. Here we found that osteopontin (OPN) skewed this balance during pathogenic conditions such as infection and autoimmunity. Notably, two isoforms of OPN exerted distinct effects in shifting this balance through cell-type-specific regulation of apoptosis. Intracellular OPN (iOPN) diminished the population size of myeloid progenitor cells and myeloid cells, and secreted OPN (sOPN) increase the population size of lymphoid cells...
July 3, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28650481/germinal-center-development-of-memory-b-cells-driven-by-il-9-from-follicular-helper-t-cells
#12
Yifeng Wang, Jingwen Shi, Jiacong Yan, Zhengtao Xiao, Xiaoxiao Hou, Peiwen Lu, Shiyue Hou, Tianyang Mao, Wanli Liu, Yuanwu Ma, Lianfeng Zhang, Xuerui Yang, Hai Qi
Germinal centers (GCs) support high-affinity, long-lived humoral immunity. How memory B cells develop in GCs is not clear. Through the use of a cell-cycle-reporting system, we identified GC-derived memory precursor cells (GC-MP cells) that had quit cycling and reached G0 phase while in the GC, exhibited memory-associated phenotypes with signs of affinity maturation and localized toward the GC border. After being transferred into adoptive hosts, GC-MP cells reconstituted a secondary response like genuine memory B cells...
August 2017: Nature Immunology
https://www.readbyqxmd.com/read/28650480/lineage-specification-of-human-dendritic-cells-is-marked-by-irf8-expression-in-hematopoietic-stem-cells-and-multipotent-progenitors
#13
Jaeyop Lee, Yu Jerry Zhou, Wenji Ma, Wanwei Zhang, Arafat Aljoufi, Thomas Luh, Kimberly Lucero, Deguang Liang, Matthew Thomsen, Govind Bhagat, Yufeng Shen, Kang Liu
The origin and specification of human dendritic cells (DCs) have not been investigated at the clonal level. Through the use of clonal assays, combined with statistical computation, to quantify the yield of granulocytes, monocytes, lymphocytes and three subsets of DCs from single human CD34(+) progenitor cells, we found that specification to the DC lineage occurred in parallel with specification of hematopoietic stem cells (HSCs) to the myeloid and lymphoid lineages. This started as a lineage bias defined by specific transcriptional programs that correlated with the combinatorial 'dose' of the transcription factors IRF8 and PU...
August 2017: Nature Immunology
https://www.readbyqxmd.com/read/28628092/tissue-resident-memory-features-are-linked-to-the-magnitude-of-cytotoxic-t-cell-responses-in-human-lung-cancer
#14
Anusha-Preethi Ganesan, James Clarke, Oliver Wood, Eva M Garrido-Martin, Serena J Chee, Toby Mellows, Daniela Samaniego-Castruita, Divya Singh, Grégory Seumois, Aiman Alzetani, Edwin Woo, Peter S Friedmann, Emma V King, Gareth J Thomas, Tilman Sanchez-Elsner, Pandurangan Vijayanand, Christian H Ottensmeier
Therapies that boost the anti-tumor responses of cytotoxic T lymphocytes (CTLs) have shown promise; however, clinical responses to the immunotherapeutic agents currently available vary considerably, and the molecular basis of this is unclear. We performed transcriptomic profiling of tumor-infiltrating CTLs from treatment-naive patients with lung cancer to define the molecular features associated with the robustness of anti-tumor immune responses. We observed considerable heterogeneity in the expression of molecules associated with activation of the T cell antigen receptor (TCR) and of immunological-checkpoint molecules such as 4-1BB, PD-1 and TIM-3...
August 2017: Nature Immunology
https://www.readbyqxmd.com/read/28628091/the-btg2-prmt1-module-limits-pre-b-cell-expansion-by-regulating-the-cdk4-cyclin-d3-complex
#15
Elmar Dolezal, Simona Infantino, Friedel Drepper, Theresa Börsig, Aparajita Singh, Thomas Wossning, Gina J Fiala, Susana Minguet, Bettina Warscheid, David M Tarlinton, Hassan Jumaa, David Medgyesi, Michael Reth
Developing pre-B cells in the bone marrow alternate between proliferation and differentiation phases. We found that protein arginine methyl transferase 1 (PRMT1) and B cell translocation gene 2 (BTG2) are critical components of the pre-B cell differentiation program. The BTG2-PRMT1 module induced a cell-cycle arrest of pre-B cells that was accompanied by re-expression of Rag1 and Rag2 and the onset of immunoglobulin light chain gene rearrangements. We found that PRMT1 methylated cyclin-dependent kinase 4 (CDK4), thereby preventing the formation of a CDK4-Cyclin-D3 complex and cell cycle progression...
August 2017: Nature Immunology
https://www.readbyqxmd.com/read/28604720/igg-fc-domains-that-bind-c1q-but-not-effector-fc%C3%AE-receptors-delineate-the-importance-of-complement-mediated-effector-functions
#16
Chang-Han Lee, Gabrielle Romain, Wupeng Yan, Makiko Watanabe, Wissam Charab, Biliana Todorova, Jiwon Lee, Kendra Triplett, Moses Donkor, Oana I Lungu, Anja Lux, Nicholas Marshall, Margaret A Lindorfer, Odile Richard-Le Goff, Bianca Balbino, Tae Hyun Kang, Hidetaka Tanno, George Delidakis, Corrine Alford, Ronald P Taylor, Falk Nimmerjahn, Navin Varadarajan, Pierre Bruhns, Yan Jessie Zhang, George Georgiou
Engineered crystallizable fragment (Fc) regions of antibody domains, which assume a unique and unprecedented asymmetric structure within the homodimeric Fc polypeptide, enable completely selective binding to the complement component C1q and activation of complement via the classical pathway without any concomitant engagement of the Fcγ receptor (FcγR). We used the engineered Fc domains to demonstrate in vitro and in mouse models that for therapeutic antibodies, complement-dependent cell-mediated cytotoxicity (CDCC) and complement-dependent cell-mediated phagocytosis (CDCP) by immunological effector molecules mediated the clearance of target cells with kinetics and efficacy comparable to those of the FcγR-dependent effector functions that are much better studied, while they circumvented certain adverse reactions associated with FcγR engagement...
August 2017: Nature Immunology
https://www.readbyqxmd.com/read/28604719/essential-role-for-gabarap-autophagy-proteins-in-interferon-inducible-gtpase-mediated-host-defense
#17
Miwa Sasai, Naoya Sakaguchi, Ji Su Ma, Shuhei Nakamura, Tsuyoshi Kawabata, Hironori Bando, Youngae Lee, Tatsuya Saitoh, Shizuo Akira, Akiko Iwasaki, Daron M Standley, Tamotsu Yoshimori, Masahiro Yamamoto
Mammalian autophagy-related 8 (Atg8) homologs consist of LC3 proteins and GABARAPs, all of which are known to be involved in canonical autophagy. In contrast, the roles of Atg8 homologs in noncanonical autophagic processes are not fully understood. Here we show a unique role of GABARAPs, in particular gamma-aminobutyric acid (GABA)-A-receptor-associated protein-like 2 (Gabarapl2; also known as Gate-16), in interferon-γ (IFN-γ)-mediated antimicrobial responses. Cells that lacked GABARAPs but not LC3 proteins and mice that lacked Gate-16 alone were defective in the IFN-γ-induced clearance of vacuolar pathogens such as Toxoplasma...
August 2017: Nature Immunology
https://www.readbyqxmd.com/read/28604718/the-transcription-factor-runx3-guards-cytotoxic-cd8-effector-t-cells-against-deviation-towards-follicular-helper-t-cell-lineage
#18
Qiang Shan, Zhouhao Zeng, Shaojun Xing, Fengyin Li, Stacey M Hartwig, Jodi A Gullicksrud, Samarchith P Kurup, Natalija Van Braeckel-Budimir, Yao Su, Matthew D Martin, Steven M Varga, Ichiro Taniuchi, John T Harty, Weiqun Peng, Vladimir P Badovinac, Hai-Hui Xue
Activated CD8(+) T cells differentiate into cytotoxic effector (TEFF) cells that eliminate target cells. How TEFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in TEFF cells. Runx3-deficient CD8(+) TEFF cells aberrantly upregulated genes characteristic of follicular helper T (TFH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFβ transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the TFH program...
August 2017: Nature Immunology
https://www.readbyqxmd.com/read/28722726/non-inflammatory-ifn
#19
Ioana Visan
No abstract text is available yet for this article.
July 19, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28722725/the-monogenic-autoinflammatory-diseases-define-new-pathways-in-human-innate-immunity-and-inflammation
#20
REVIEW
Kalpana Manthiram, Qing Zhou, Ivona Aksentijevich, Daniel L Kastner
Autoinflammatory diseases were first recognized nearly 20 years ago as distinct clinical and immunological entities caused by dysregulation in the innate immune system. Since then, advances in genomic techniques have led to the identification of new monogenic disorders and their corresponding signaling pathways. Here we review these monogenic autoinflammatory diseases, ranging from periodic fever syndromes caused by dysregulated inflammasome-mediated production of the cytokine IL-1β to disorders arising from perturbations in signaling by the transcription factor NF-κB, ubiquitination, cytokine signaling, protein folding, type I interferon production and complement activation, and we further examine their molecular mechanisms...
July 19, 2017: Nature Immunology
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