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Dobenecker MW, Kim JK, Marcello J, Fang TC, Prinjha R, Bosselut R, Tarakhovsky A
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Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation
JOURNAL OF EXPERIMENTAL MEDICINE 2015 MAR; 212(3):297-306
The fidelity of T cell immunity depends greatly on coupling T cell receptor signaling with specific T cell effector functions. Here, we describe a chromatin-based mechanism that enables integration of TCR specificity into definite T cell lineage commitment. Using natural killer T cells (iNKT cell) as a model of a T cell subset that differentiates in response to specific TCR signaling, we identified a key role of histone H3 lysine 27 trimethylation (H3K27me3) in coupling iNKT cell TCR specificity with the generation of iNKT cells. We found that the Zbtb16/PLZF gene promoter that drives iNKT cell differentiation possesses a bivalent chromatin state characterized by the simultaneous presence of negative and positive H3K27me3 and H3K4me3 modifications. Depletion of H3K27me3 at the Zbtb16/PLZF promoter leads to uncoupling of iNKT cell development from TCR specificity and is associated with accumulation of iNKT-like CD4(+) cells that express a non-iNKT cell specific T cell repertoire. In turn, stabilization of H3K27me3 leads to a drastic reduction of the iNKT cell population. Our data suggest that H3K27me3 levels at the bivalent Zbtb16/PLZF gene define a threshold enabling precise coupling of TCR specificity to lineage commitment.
Scheel TKH, Simmonds P, Kapoor A
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Surveying the global virome: Identification and characterization of HCV-related animal hepaciviruses
ANTIVIRAL RESEARCH 2015 MAR; 115(?):83-93
Recent advances in sequencing technologies have greatly enhanced our abilities to identify novel microbial sequences. Thus, our understanding of the global virome and the virome of specific host species in particular is rapidly expanding. Identification of animal viruses is important for understanding animal disease, the origin and evolution of human viruses, as well as zoonotic reservoirs for emerging infections. Although the human hepacivirus, hepatitis C virus (HCV), was identified 25 years ago, its origin has remained elusive. In 2011, the first HCV homolog was reported in dogs but subsequent studies showed the virus to be widely distributed in horses. This indicated a wider hepacivirus host range and paved the way for identification of rodent, bat and non-human primate hepaciviruses. The equine non-primate hepacivirus (NPHV) remains the closest relative of HCV and is so far the best characterized. Identification and characterization of novel hepaciviruses may in addition lead to development of tractable animal models to study HCV persistence, immune responses and pathogenesis. This could be particular important, given the current shortage of immunocompetent models for robust HCV infection. Much remains to be learned on the novel hepaciviruses, including their association with disease, and thereby how relevant they will become as HCV model systems and for studies of animal disease. This review discusses how virome analysis led to identification of novel hepaci- and pegiviruses, their genetic relationship and characterization and the potential use of animal hepaciviruses as models to study hepaciviral infection, immunity and pathogenesis. This article forms part of a symposium in Antiviral Research on "Hepatitis C: Next steps toward global eradication." (C) 2015 Elsevier B.V. All rights reserved.
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Cimmino A, Costantini S, Crucy S, Dildick S, Fagot A, Garcia G, Mccartin J, Rios AAO, Poyraz D, Ryckbosch D, Diblen SS, Sigamani M, Strobbe N, Thyssen F, Tytgat M, Yazgan E, Zaganidis N, Basegmez S, Beluffi C, Bruno G, Castello R, Caudron A, Ceard L, Da Silveira GG, Delaere C, Du Pree T, Favart D, Forthomme L, Giammanco A, Hollar J, Jafari A, Jez P, Komm M, Lemaitre V, Nuttens C, Perrini L, Pin A, Piotrzkowski K, Popov A, Quertenmont L, Selvaggi M, Marono MV, Garcia JMV, Beliy N, Caebergs T, Daubie E, Hammad GH, Alda WL, Alves GA, Brito L, Martins MC, Martins TD, Molina J, Herrera CM, Pol ME, Teles PR, Carvalho W, Chinellato J, Custodio A, Da Costa EM, Damiao DD, Martins CD, De Souza SF, Malbouisson H, Figueiredo DM, Mundim L, Nogima H, Da Silva WLP, Santaolalla J, Santoro A, Sznajder A, Manganote EJT, Pereira AV, Bernardes CA, Dogra S, Tomei TRFP, Gregores EM, Mercadante PG, Novaes SF, Padula SS, Aleksandrov A, Genchev V, Hadjiiska R, Iaydjiev P, Marinov A, Piperov S, Rodozov M, 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Muller T, Nurnberg A, Quast G, Rabbertz K, Rocker S, Simonis HJ, Stober FM, Ulrich R, Wagner-Kuhr J, Wayand S, Weiler T, Wolf R, Anagnostou G, Daskalakis G, Geralis T, Giakoumopoulou VA, Kyriakis A, Loukas D, Markou A, Markou C, Psallidas A, Topsis-Giotis I, Agapitos A, Kesisoglou S, Panagiotou A, Saoulidou N, Stiliaris E, Tziaferi E, Aslanoglou X, Evangelou I, Flouris G, Foudas C, Kokkas P, Manthos N, Papadopoulos I, Paradas E, Strologas J, Bencze G, Hajdu C, Hidas P, Horvath D, Sikler F, Veszpremi V, Vesztergombi G, Zsigmond AJ, Beni N, Czellar S, Karancsi J, Molnar J, Palinkas J, Szillasi Z, Makovec A, Raics P, Trocsanyi ZL, Ujvari B, Swain SK, Beri SB, Bhatnagar V, Gupta R, Bhawandeep U, Kalsi AK, Kaur M, Kumar R, Mittal M, Nishu N, Singh JB, Kumar A, Kumar A, Ahuja S, Bhardwaj A, Choudhary BC, Kumar A, Malhotra S, Naimuddin M, Ranjan K, Sharma V, Banerjee S, Bhattacharya S, Chatterjee K, Dutta S, Gomber B, Jain S, Jain S, Khurana R, Modak A, Mukherjee S, Roy D, Sarkar S, Sharan M, 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Tatarinov A, Ulmer KA, Akchurin N, Cowden C, Damgov J, Dragoiu C, Dudero PR, Faulkner J, Kovitanggoon K, Kunori S, Lee SW, Libeiro T, Volobouev I, Appelt E, Delannoy AG, Greene S, Gurrola A, Johns W, Maguire C, Mao Y, Melo A, Sharma M, Sheldon P, Snook B, Tuo S, Velkovska J, Arenton MW, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Li H, Lin C, Neu C, Wolfe E, Wood J, Clarke C, Harr R, Karchin PE, Don CKK, Lamichhane P, Sturdy J, Belknap DA, Carlsmith D, Cepeda M, Dasu S, Dodd L, Duric S, Friis E, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Lanaro A, Lazaridis C, Levine A, Loveless R, Mohapatra A, Ojalvo I, Perry T, Pierro GA, Polese G, Ross I, Sarangi T, Savin A, Smith WH, Taylor D, Vuosalo C, Woods N
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Search for resonances and quantum black holes using dijet mass spectra in proton-proton collisions at root s=8 TeV
PHYSICAL REVIEW D 2015 MAR 12; 91(5):? Article 052009
A search for resonances and quantum black holes is performed using the dijet mass spectra measured in proton-proton collisions at root s = 8 TeV with the CMS detector at the LHC. The data set corresponds to an integrated luminosity of 19.7 fb(-1). In a search for narrow resonances that couple to quark-quark, quark-gluon, or gluon-gluon pairs, model-independent upper limits, at 95% confidence level, are obtained on the production cross section of resonances, with masses above 1.2 TeV. When interpreted in the context of specific models the limits exclude string resonances with masses below 5.0 TeV; excited quarks below 3.5 TeV; scalar diquarks below 4.7 TeV; W' bosons below 1.9 TeV or between 2.0 and 2.2 TeV; Z' bosons below 1.7 TeV; and Randall-Sundrum gravitons below 1.6 TeV. A separate search is conducted for narrow resonances that decay to final states including b quarks. The first exclusion limit is set for excited b quarks, with a lower mass limit between 1.2 and 1.6 TeV depending on their decay properties. Searches are also carried out for wide resonances, assuming for the first time width-to-mass ratios up to 30%, and for quantum black holes with a range of model parameters. The wide resonance search excludes axigluons and colorons with mass below 3.6 TeV, and color-octet scalars with mass below 2.5 TeV. Lower bounds between 5.0 and 6.3 TeV are set on the masses of quantum black holes.
Kong R, Louder MK, Wagh K, Bailer RT, deCamp A, Greene K, Gao HM, Taft JD, Gazumyan A, Liu C, Nussenzweig MC, Korber B, Montefiori DC, Mascola JR
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Improving Neutralization Potency and Breadth by Combining Broadly Reactive HIV-1 Antibodies Targeting Major Neutralization Epitopes
JOURNAL OF VIROLOGY 2015 MAR; 89(5):2659-2671
The isolation of broadly neutralizing HIV-1 monoclonal antibodies (MAbs) to distinct epitopes on the viral envelope glycoprotein (Env) provides the potential to use combinations of MAbs for prevention and treatment of HIV-1 infection. Since many of these MAbs have been isolated in the last few years, the potency and breadth of MAb combinations have not been well characterized. In two parallel experiments, we examined the in vitro neutralizing activities of double-, triple-, and quadruple-MAb combinations targeting four distinct epitopes, including the CD4-binding site, the V1V2-glycan region, the V3-glycan supersite, and the gp41 membrane-proximal external region (MPER), using a panel of 125 Env-pseudotyped viruses. All MAb combinations showed substantially improved neutralization breadth compared to the corresponding single MAbs, while the neutralization potency of individual MAbs was maintained. At a 50% inhibitory concentration (IC50) cutoff of 1 mu g/ml per antibody, double-MAb combinations neutralized 89 to 98% of viruses, and triple combinations neutralized 98 to 100%. Overall, the improvement of neutralization breadth was closely predicted by an additive-effect model and explained by complementary neutralization profiles of antibodies recognizing distinct epitopes. Subtle but consistent favorable interactions were observed in some MAb combinations, whereas less favorable interactions were observed on a small subset of viruses that are highly sensitive to V3-glycan MAbs. These data demonstrate favorable in vitro combinations of broadly neutralizing HIV-1 MAbs and suggest that such combinations could have utility for HIV-1 prevention and treatment. IMPORTANCE Over the last 5 years, numerous broadly reactive HIV-1-neutralizing MAbs have been isolated from B cells of HIV-1-infected donors. Each of these MAbs binds to one of the major vulnerable sites (epitopes) on the surface of the viral envelope glycoprotein. Since antibodies to distinct viral epitopes could theoretically act together to provide greater potency and breadth of virus neutralization, we tested physical mixtures of double, triple, and quadruple combinations of neutralizing MAbs targeting four major epitopes on HIV-1 Env. When tested together, antibody combinations showed substantially improved neutralization breadth compared to single MAbs. This improvement could be explained by the complementary neutralization profiles of individual MAbs. We further demonstrated that each antibody maintained its full neutralization potency when used in combination with other MAbs. These data provide a rationale for clinical use of antibody-based combinations for HIV-1 prevention and therapy.
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Study of Vector Boson Scattering and Search for New Physics in Events with Two Same-Sign Leptons and Two Jets
PHYSICAL REVIEW LETTERS 2015 FEB 2; 114(5):?
A study of vector boson scattering in pp collisions at a center-of-mass energy of 8 TeV is presented. The data sample corresponds to an integrated luminosity of 19.4 fb(-1) collected with the CMS detector. Candidate events are selected with exactly two leptons of the same charge, two jets with large rapidity separation and high dijet mass, and moderate missing transverse energy. The signal region is expected to be dominated by electroweak same-sign W-boson pair production. The observation agrees with the standard model prediction. The observed significance is 2.0 standard deviations, where a significance of 3.1 standard deviations is expected based on the standard model. Cross section measurements for (WW +/-)-W-+/- and WZ processes in the fiducial region are reported. Bounds on the structure of quartic vector-boson interactions are given in the framework of dimension-eight effective field theory operators, as well as limits on the production of doubly charged Higgs bosons.
Huang J, Tsao T, Zhang M, Rai U, Tsuji M, Li XM
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A sufficient role of MHC class I molecules on hepatocytes in anti-plasmodial activity of CD8(+) T cells in vivo
FRONTIERS IN MICROBIOLOGY 2015 FEB 12; 6(?):? Article 09
Although CD8(+) T cells are shown to mediate the protective immunity against the liver stages of malaria parasites in mice, whether the direct presentation of malaria antigen by major histocompatibility complex (MHC) class I molecules expressed on the liver of infected host is required for anti-plasmodial activity of CD8(+) T cells is still unknown. Presently, there is only one CD8(+) epitope, SYVPSAEQI, derived from the circumsporozoite protein of Plasmodium yoelii (PyCS), that mediates anti-malarial protection and is presented in the context of a K-d molecule. Therefore, to investigate the mode of anti-plasmodial activity of CD8+ T cells, we have previously generated C57BL/6 transgenic (Tg) mice, in which a K-d molecule is expressed only on hepatocyte (Alb-K-d) or dendritic cell (DC; CD11c-K-d), by using albumin promoter or CD11c promoter, respectively. We have also generated MHC-I-K-d Tg mice, which express the K-d molecule under the MHC class I (MHC-I) promoter, as a positive control. From splenocytes collected from CD11c-K-d Tg mice immunized with a synthetic peptide, SYVPSAEQI, which corresponds to the CD8(+) T-cell epitope of PyCS, emulsified in incomplete Freund's adjuvant, a PyCS-specific CD8(+) T-cell line was generated. This PyCS-specific CD8(+) T-cell line was then adoptively transferred into a cohort of either MHC-K-d Tg or Alb-K-d Tg mice listed above, as well as wild-type C57BL/6 mice. Then both transferred and non-transferred mice were challenged with live malaria parasites. We found that the adoptive transfer of a PyCS-specific CD8(+) T-cell line resulted in a significant inhibition of the parasite burden in the liver of Alb-K-d Tg, as well as MHC-I-K-d Tg mice, but not of C57BL/6 mice. These results indicate that the K-d molecule expressed by hepatocytes is sufficient in mediating the anti-plasmodial activity of PyCS-specific CD8(+) T cells in vivo.
Wang TT, Ravetch JV
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Immune Complexes: Not Just an Innocent Bystander in Chronic Viral Infection
IMMUNITY 2015 FEB 17; 42(2):213-215
Understanding of how persistent viral infection impacts humoral immunity is incomplete. In this issue of Immunity, Wieland et al. (2015) and Yamada et al. (2015) find that high amounts of IgG-antigen complexes formed during chronic lymphocytic choriomeningitis infection can interfere with Fcg-receptor-mediated effector activities, potentially contributing to immune dysfunction.
Waters EM, Thompson LI, Patel P, Gonzales AD, Ye H, Filardo EJ, Clegg DJ, Gorecka J, Akama KT, McEwen BS, Milner TA
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G-Protein-Coupled Estrogen Receptor 1 Is Anatomically Positioned to Modulate Synaptic Plasticity in the Mouse Hippocampus
JOURNAL OF NEUROSCIENCE 2015 FEB 11; 35(6):2384-2397
Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors alpha and beta, and synaptic levels in the rodent dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3. Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles. Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen's actions via GPER1 may converge on the same synaptic elements, different pathways are used to achieve these actions.
Moberg CL
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Early antibiotic from a cranberry bog
NATURE 2015 FEB 19; 518(7539):303-303
Aaltonen T, Alon R, Amerio S, Amidei D, Anastassov A, Annovi A, Antos J, Apollinari G, Appel JA, Arisawa T, Artikov A, Asaadi J, Ashmanskas W, Auerbach B, Aurisano A, Azfar F, Badgett W, Bae T, Barbaro-Galtieri A, Barnes VE, Barnett BA, Barria P, Bartos P, Bauce M, Bedeschi F, Behari S, Bellettini G, Bellinger J, Benjamin D, Beretvas A, Bhatti A, Bland KR, Blumenfeld B, Bocci A, Bodek A, Bortoletto D, Boudreau J, Boveia A, Brigliadori L, Bromberg C, Brucken E, Budagov J, Budd HS, Burkett K, Busetto G, Bussey P, Butti P, Buzatu A, Calamba A, Camarda S, Campanelli M, Canelli F, Carls B, Carlsmith D, Carosi R, Carrillo S, Casal B, Casarsa M, Castro A, Catastini P, Cauz D, Cavaliere V, Cerri A, Cerrito L, Chen YC, Chertok M, Chiarelli G, Chlachidze G, Cho K, Chokheli D, Clark A, Clarke C, Convery ME, Conway J, Corbo M, Cordelli M, Cox CA, Cox DJ, Cremonesi M, Cruz D, Cuevas J, Culbertson R, d'Ascenzo N, Datta M, de Barbaro P, Demortier L, Deninno M, D'Errico M, Devoto F, Di Canto A, Di Ruzza B, Dittmann JR, Donati S, D'Onofrio M, Dorigo M, Driutti A, Duchovni E, Ebina K, Edgar R, Elagin A, Erbacher R, Errede S, Esham B, Farrington S, Ramos JPF, Field R, Flanagan G, Forrest R, Franklin M, Freeman JC, Frisch H, Funakoshi Y, Galloni C, Garfinkel AF, Garosi P, Gerberich H, Gerchtein E, Giagu S, Giakoumopoulou V, Gibson K, Ginsburg CM, Giokaris N, Giromini P, Glagolev V, Glenzinski D, Gold M, Goldin D, Golossanov A, Gomez G, Gomez-Ceballos G, Goncharov M, Lopez OG, Gorelov I, Goshaw AT, Goulianos K, Gramellini E, Grosso-Pilcher C, Group RC, da Costa JG, Hahn SR, Han JY, Happacher F, Hara K, Hare M, Harr RF, Harrington-Taber T, Hatakeyama K, Hays C, Heinrich J, Herndon M, Hocker A, Hong Z, Hopkins W, Hou S, Hughes RE, Husemann U, Hussein M, Huston J, Introzzi G, Iori M, Ivanov A, James E, Jang D, Jayatilaka B, Jeon EJ, Jindariani S, Jones M, Joo KK, Jun SY, Junk TR, Kambeitz M, Kamon T, Karchin PE, Kasmi A, Kato Y, Ketchum W, Keung J, Kilminster B, Kim DH, Kim HS, Kim JE, Kim MJ, Kim SH, Kim SB, Kim YJ, Kim YK, Kimura N, Kirby M, Knoepfel K, Kondo K, Kong DJ, Konigsberg J, Kotwal AV, Kreps M, Kroll J, Kruse M, Kuhr T, Kurata M, Laasanen AT, Lammel S, Lancaster M, Lannon K, Latino G, Lee HS, Lee JS, Leo S, Leone S, Lewis JD, Limosani A, Lipeles E, Lister A, Liu H, Liu Q, Liu T, Lockwitz S, Loginov A, Lucchesi D, Luca A, Lueck J, Lujan P, Lukens P, Lungu G, Lys J, Lysak R, Madrak R, Maestro P, Malik S, Manca G, Manousakis-Katsikakis A, Marchese L, Margaroli F, Marino P, Matera K, Mattson ME, Mazzacane A, Mazzanti P, McNulty R, Mehta A, Mehtala P, Mesropian C, Miao T, Mietlicki D, Mitra A, Miyake H, Moed S, Moggi N, Moon CS, Moore R, Morello MJ, Mukherjee A, Muller T, Murat P, Mussini M, Nachtman J, Nagai Y, Naganoma J, Nakano I, Napier A, Nett J, Neu C, Nigmanov T, Nodulman L, Noh SY, Norniella O, Oakes L, Oh SH, Oh YD, Oksuzian I, Okusawa T, Orava R, Ortolan L, Pagliarone C, Palencia E, Palni P, Papadimitriou V, Parker W, Pauletta G, Paulini M, Paus C, Perez G, Phillips TJ, Piacentino G, Pianori E, Pilot J, Pitts K, Plager C, Pondrom L, Poprocki S, Potamianos K, Pranko A, Prokoshin F, Ptohos F, Punzi G, Fernandez IR, Renton P, Rescigno M, Rimondi F, Ristori L, Robson A, Rodriguez T, Rolli S, Ronzani M, Roser R, Rosner JL, Ruffini F, Ruiz A, Russ J, Rusu V, Sakumoto WK, Sakurai Y, Santi L, Sato K, Saveliev V, Savoy-Navarro A, Schlabach P, Schmidt EE, Schwarz T, Scodellaro L, Scuri F, Seidel S, Seiya Y, Semenov A, Sforza F, Shalhout SZ, Shears T, Shepard PF, Shimojima M, Shochet M, Shreyber-Tecker I, Simonenko A, Sinervo P, Sliwa K, Smith JR, Snider FD, Song H, Sorin V, St Denis R, Stancari M, Stentz D, Strologas J, Sudo Y, Sukhanov A, Suslov I, Takemasa K, Takeuchi Y, Tang J, Tecchio M, Teng PK, Thom J, Thomson E, Thukral V, Toback D, Tokar S, Tollefson K, Tomura T, Tonelli D, Torre S, Torretta D, Totaro P, Trovato M, Ukegawa F, Uozumi S, Vazquez F, Velev G, Vellidis C, Vernieri C, Vidal M, Vilar R, Vizan J, Vogel M, Volpi G, Wagner P, Wallny R, Wang SM, Waters D, Wester WC, Whiteson D, Wicklund AB, Wilbur S, Williams HH, Wilson JS, Wilson P, Winer BL, Wittich P, Wolbers S, Wolfe H, Wright T, Wu X, Wu Z, Yamamoto K, Yamato D, Yang T, Yang UK, Yang YC, Yao WM, Yeh GP, Yi K, Yoh J, Yorita K, Yoshida T, Yu GB, Yu I, Zanetti AM, Zeng Y, Zhou C, Zucchellia S
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Studies of high-transverse momentum jet substructure and top quarks produced in 1.96 TeV proton-antiproton collisions
PHYSICAL REVIEW D 2015 FEB 19; 91(3):? Article 032006
Results of a study of the substructure of the highest transverse momentum (p(T)) jets observed by the CDF Collaboration are presented. Events containing at least one jet with p(T) > 400 GeV/c in a sample corresponding to an integrated luminosity of 5.95 fb(-1), collected in 1.96 TeV proton-antiproton collisions at the Fermilab Tevatron collider, are selected. A study of the jet mass, angularity, and planar-flow distributions is presented, and the measurements are compared with predictions of perturbative quantum chromodynamics. A search for boosted top-quark production is also described, leading to a 95% confidence level upper limit of 38 fb on the production cross section of top quarks with p(T) > 400 GeV/c.