yw.jimmunol.org
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`Volume 174 / No. 8 / April 15, 2005
`
`UNOLOGY
`
` Miltenyi Ex. 1032 Page 1
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`Miltenyi Ex. 1032 Page 1
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`UNOLOGY
`
`Cys of the mosthighly cited journals in biomedicine, THE
`JOURNAL OF IMMUNOLOGYserves immunologists and
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`Each issue contains hundreds of pages of up-to-date research. In
`addition, the “Cutting Edge” section of the journal features the
`highest impact articles in the field. “In This Issue” provides
`summaries of the mostinteresting articles in an issue with a focus
`on eacharticle's importance to immunology.
`
`THE JOURNAL OF IMMUNOLOGYisthe trusted source for
`reports on immunology research for scientists from many disciplines.
`Every scientist working in immunology will want a subscription!
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`Judy M. Teale, Ph.D. Miltenyi Ex. 1032 Page 2
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`Miltenyi Ex. 1032 Page 2
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`| VOL. 174 1 NO. 8 | April 15, 2005 | Pages 4449-5156
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`4449INTHISISSUF
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`2JOURNALS
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`4451
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`
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`4453
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`TLRSignaling in the Gutin Health and Disease
`Maria T. Abreu, Masayuki Fukata, and Moshe Arditi
`
`
`
`4461
`
`Cutting Edge: Death of a Dogmaor Enforcingthe Artificial: Monomeric IgE Binding May Initiate Mast
`Cell Response by Inducing Its Receptor Aggregation
`Reinhard Schweitzer-Stenner and Israel Pecht
`
`4465 Cutting Edge: Type I IFNs Provide a Third Signal to CD8 T Cells to Stimulate Clonal Expansion and
`Differentiation
`Julie M. Curtsinger, Javier O. Valenzuela, Pujya Agarwal, Debra Lins, andMatthew F. Mescher
`
`4470 Cutting Edge: Fas Ligand (CD178) Cytoplasmic Tail Is a Positive Regulator of Fas Ligand-Mediated
`Cytotoxicity
`SatoshiJodo, VyankateshJ. Pidiyar, ShengXiao, Akira Furusaki, Rahul Sharma, Takao Koike, and Shyr-TeJu
`
`4475 Cutting Edge:Itk Is Not Essential for CD28 Signaling in Naive T Cells
`Cheng-Rui Li andLeslieJ. Berg
`
`4480 Cutting Edge: NKG2D Is a Costimulatory Receptor for Human Naive CD8" T Cells
`Kerima Maasho, Jessica Opoku-Anane, Alina I. Marusina, John E. Coligan, and Francisco Borrego
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`CELLULARIMMUNOLOGYIMMUNEREGULATIONAND
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`F
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`4485 Generation of High-Affinity Antibodyagainst T Cell-Dependent Antigen in the Ganp Gene-Transgenic
`Mouse
`Nobuo Sakaguchi, Tetsuya Kimura, Shuzo Matsushita, Satoru Fujimura, Junji Shibata, MasatakeAraki,
`Tamami Sakamoto, Chiemi Minoda, and Kazuhiko Kuwahara
`
`t
`'
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`bee
`ang
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`i |
`
`Huangetal. Intraepithelial cell neutralization of HIV-1 replication of IgA. J. Immunol. 174:4828.
`
`Onthecover: Confocal immunofluorescencecolocalization (yellow) of IgA Ab (green) and HIVenvelopeprotein (red) in
`polarized, polymeric IgR-expressing epithelial cells transfected with HIV proviral DNA and then exposed to Ab ar the
`basolateral surface. The imageillustrates the initial step in intraepithelial cell neutralization ofviral replication of IgA.
`
`TheJournal ofImmunology (ISSN 0022-1767) is published twice each month by The American Association of Immunologists,
`Inc., 9650 Rockville Pike, Bethesda, MD 20814-3998. Subscription rates: U.S.A. AND POSSESSIONS: personal, $370;
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`ae .
`Miltenyi Ex. 1032 Page 3
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`Miltenyi Ex. 1032 Page 3
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`4495
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`4505
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`4516
`
`4525
`
`4535
`
`4545
`
`4551
`
`4559
`
`4567
`
`4579
`
`4584
`
`4590
`
`4598
`
`4606
`
`4613
`
`Regulation of Highly Cytokinergic IgE-Induced Mast Cell Adhesion by Src, Syk, Tec, and Protein Kinase
`C Family Kinases
`Jiro Kitaura, Koji Eto, Tatsuya Kinoshita, Yuko Kawakami, Michael Leitges, CliffordA. Lowell, and Toshiaki Kawakami
`
`Antinuclear Antigen B Cells That Down-Regulate Surface B Cell Receptor.during: Developmentto
`Mature,Follicular Phenotype Do Not Display Features ofAnergy In Vitro
`Xiaohe Liu and Tim Manser
`
`Active Tolerance Induction and Prevention ofAutoimmune Diabetes by Immunogene Therapy Using
`Recombinant Adenoassociated Virus Expressing Glutamic Acid Decarboxylase 65 Peptide GADs99_s¢5
`Gencheng Han, Yan Li, Jianan Wang, Renxi Wang, Guojiang Chen, Lun Song, Ruonan Xu, Ming Yu, Xiaobing Wu,
`Jiahua Qian, and Beifen Shen
`
`Treatment with Nonmitogenic Anti-CD3 Monoclonal Antibody Induces CD4* T Cell Unresponsiveness
`and Functional Reversal of Established Experimental Autoimmune Encephalomyelitis
`Adam P. Kohm, Julie S. Williams, Allison L. Bickford, Jeffrey 8. McMahon, Lucienne Chatenoud, Jean-Frangois Bach,
`Jeffrey A. Bluestone, and Stephen D. Miller
`
`Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged
`Cardiac Allograft Survival
`Boris P.-L. Lee, Elaine Mansfield, Seu-Chuan Hsieh, Tina Hernandez-Boussard, Wenhao Chen, Christopher W. Thomson,
`Megan S. Ford, Steven E. Bosinger, Sandy Der, Zhu-xis Zhang, Meixia Zhang, DavidJ. Kelvin, Minnie M. Sarwal,
`and Li Zhang
`
`A Sexual Dimorphism in Intrathymic Sialylation Survey Is Revealed by the trans-Sialidase from
`Trypanosoma cruzi
`Juan Mucei, Esteban Mocetti, Maria Susana Leguizamén, and Oscar Campetella
`
`Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease
`Ala Aoukaty and Rusung Tan
`
`Rapid Functional Exhaustion and Deletion of CTL following Immunization with Recombinant
`Adenovirus
`Philippe Krebs, Elke Scandella, Bernhard Odermatt, and Burkhard Ludewig
`
`Altered Migration, Recruitment, and Somatic Hypermutation in the Early Response of Marginal Zone B
`Cells to T Cell-Dependent Antigen
`Tri Giang Phan, Sandra Gardam, Antony Basten, and Robert Brink
`Supptessive Oligodeoxynucleotides Protect Mice from Lethal Endotoxic Shock
`Hidekazu Shirota, Ihsan Gursel, Mayda Gursel, and Dennis M. Klinman
`
`Microtubule Disruption Suppresses Allergic Response through the Inhibition of Calcium Influx in the
`Mast Cell Degranulation Pathway
`Tatsuya Oka, Masatoshi Hori, and Hiroshi Ozaki
`
`NKCells Inhibit T Cell Proliferation via p21-Mediated Cell Cycle Arrest
`Prachi P. Trivedi, Paul C. Roberts, NorbertA. Wolf, and Robert H. Swanborg
`
`Does the Frequency and Avidity Spectrum of the Neuroantigen-Specific T Cells in the Blood Mirror the
`AutoimmuneProcess in the Central Nervous System of Mice Undergoing Experimental Allergic
`Encephalomyelitis?
`Harald H. Hofstetter, Oleg S. Targont, Alexey Y. Karulin, Thomas G. Forsthuber, Magdalena Tary-Lehmann,
`and Paul V. Lehmann
`
`5 T Cell Homeostasis Is Controlled by IL-7 and IL-15 Together with Subset-Specific Factors
`Roberto Baccala, Deborah Witherden, Rosana Gonzalez-Quintial, Wolfgang Dummer, Charles D. Surh,
`Wendy L. Havran, andArgyrios N. Theofilopoulos
`Rac2 Regulates Neutrophil Chemotaxis, Superoxide Production, and Myeloid Colony Formation through
`Multiple Distinct Effector Pathways
`Dirk Carstanjen, Akira Yamauchi, Annemart Koornneef, Heesuk Zang, Marie-Dominique Filippi, Chad Harris,
`Jason Towe, Simon Atkinson, Yi Zheng, Mary C. Dinauer, and DavidA. Williams
`
` b
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`Miltenyi Ex. 1032 Page 4
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`Miltenyi Ex. 1032 Page 4
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`

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`4621
`
`Inhibitory NK Receptor Ly49Q Is Expressed on Subsets of Dendritic Cells in a Cellular Maturation- and
`Cytokine Stimulation-Dependent Manner
`Noriko Toyama-Sorimachi, Yoshiki Omatsu, Atsuko Onoda, Yusuke Tsujimura, Tomonori Iyoda, Akiko Kikuchi-Maki,
`Hiroyuki Sorimachi, Taeko Dohi, Shinsuke Taki, Kayo Inaba, and Hajime Karasuyama
`
`4630
`
`4639
`
`4647
`
`4657
`
`4662
`
`Suppressive Effect of IL-4 on IL-13-Induced Genes in Mouse Lung
`Fred D, Finkelman, Mingyan Yang, Charles Perkins, Kathleen Schleifer, Alyssa Sproles, JoAnna Santeliz,
`Jonathan A, Bernstein, Mare E. Rothenberg, Suzanne C. Morris, and Marsha Wills-Karp
`
`Signals from CD28 Induce Stable Epigenetic Modification of the IL-2 Promoter
`Rajan M. Thomas, Ling Gao, andAndrew D. Wells
`
`Translation from Cryptic Reading Frames of DNA Vaccines Generates an Extended Repertoire of
`Immunogenic, MHCClass I-Restricted Epitopes
`Reinhold Schirmbeck, Petra Riedl, Nicolas Fissolo, Francois A. Lemonnier, Antonio Bertoletti, andJérg Reimann
`
`Fetal Expression of Fas Ligand Is Necessary and Sufficient for Induction of CD8 T Cell Tolerance to the
`Fetal Antigen H-Y during Pregnancy
`Melanie S. Vacchio and RichardJ. Hodes
`
` T Cell-Mediated Delay of Spontaneous Mammary Tumor Onset: Increased Efficacy with In Vivo versus
`In Vitro Activation
`Leigh A. O'Mara, Lyse A, Norian, Darren Kreamalmeyer, J. Michael White, and Paul M. Allen
`
`4670 Glucose Availability Regulates IFN-y Production and p70S6 Kinase Activation in CD8* Effector T Cells
`Candace M. Cham and Thomas F. Gajewski
`
`4678
`
`4688
`
`y6T Cells Regulate the Extent and Duration of Inflammation in the Central Nervous System by a Fas
`Ligand-Dependent Mechanism
`Eugene D. Ponomarev and Bonnie N. Dittel
`
`IL-12-Independent LIGHTSignaling Enhances MHC Class II Disparate CD4* T Cell Alloproliferation,
`IFN-+y Responses, and Intestinal Graft-versus-Host Disease
`Geri R. Brown, Edward L. Lee, Jihad El-Hayek, Katherine Kintner, and Cheryl Luck
`
`4696 Distinct Roles of Dendritic Cells and B Cells in Val14Jal8 Natural T Cell Activation In Vivo
`Jelena S. Bezbradica, Aleksandar K. Stanic, Naoto Matsuki, Helene Bour-Jordan, Jeffrey A. Bluestone, James W. Thomas,
`Derya Unutmaz, Lue Van Kaer, and Sebastian Joyce
`
`Holden T. Maecker, John R. Mascola, Dennis Panicali, GaryJ. Nabel, and Norman L. Letvin Miltenyi Ex.
`
`4753 Dysfunction of Simian Immunodeficiency Virus/Simian Human Immunodeficiency Virus-Induced IL-2
`Expression by Central Memory CD4* T Lymphocytes
`Yue Sun, Jorn E. Schmitz, Paula M. Acierno, Sampa Santra, Ramu A. Subbramanian, Dan H. Barouch,
`Darei A: Gorgone, Michelle A. Lifton, Kristin R. Beaudry, Kelledy Manson, Valerie Philippon, LingXu,
`
`4706 Macrophage Colony-Stimulating Factor Drives Cord Blood Monocyte Differentiation into
`IL-10™8"]L-12°°%"" Dendritic Cells with Tolerogenic Potential
`Geling Li, Young-June Kim, and Hal E. Broxmeyer
`
`4718 T Regulatory-1 Cells Induce IgG4 Production by B Cells: Role of IL-10
`Judith S. Satoguina, Esther Weyand, John Larbi, andAchim ‘Hoerauf
`
`4727
`
`4736
`
`TumorVaccine Based on Cell Surface Expression of DcR3/TR6
`Guixiu Shi, Jianning Mao, Guang Yu, Jun Zhang, andJiangping Wu
`
`Pattern of Kv Subunit Expression in Macrophages Depends upon Proliferation and the Mode of
`Activation
`Rubén Vicente, Artur Escalada, Concepcié Soler, Maribel Grande, Antonio Celada, MichaelM. Tamkun, Carles Solsona,
`andAntonio Felipe
`
`4745 A Role for SATB1, a Nuclear Matrix Association Region-Binding Protein, in the Development of CD8SP
`Thymocytes and Peripheral T Lymphocytes
`Hui Nie, Shanna D. Maika, Philip W. Tucker, and Paul D, Gottlieb
`
`Miltenyi Ex. 1032 Page 5
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`4761
`
`IL-6 Increases Primed Cell Expansion and Survival
`Trina Rochman, William £. Paul, and S. Z. Ben-Sasson
`
`
`
`MOLECULARANDSTRUCTURALIMMUNOLOGY
`
`Recognition of Human Cytomegalovirus by Human Primary Immunoglobulins Identifies an Innate
`Foundation to an Adaptive Immune Response
`Gary R. McLean, Ole A, Olsen, Ian N. Watt, P. Rathanaswami, Kevin B. Leslie, John S. Babcook, andJohn W. Schrader
`
`HIV Type 1 Can Act as an APC upon Acquisition from the Host Cell of Peptide-Loaded HLA-DR and
`CD86 Molecules
`Jocelyn Roy, Genevieve Martin, Jean-Francois Giguere, Dave Bélanger, Myriam Pétrin, andMichelJ. Tremblay
`
`Funcriona! Requirements for Signaling through the Stimulatory and Inhibitory Mouse NKR-P1 (CD161)
`NKCell Receptors
`Belma Ljutic, James R. Carlyle, Dominik Filipp, Rinako Nakagawa, MichaelJulius, andJuan Carlos Ziniga-Pfliicker
`
`B Cell Hyperresponsiveness and Expansion of MatureFollicular B Cells but Not of Marginal Zone B
`Cells in NFATc2/c3 Double-Deficient Mice
`Devapriya Nandini Samanta, Alois Palmetshofer, Dragan Marinkovic, Thomas Wirth, Edgar Serfling, and Lars Nitschke
`
`Exocytosis of CTLA-4 Is Dependent on Phospholipase D and ADP Ribosylation Factor-1 and Stimulated
`during Activation of Regulatory T Cells
`Karen I. Mead, Yong Zheng, Claire N. Manzotti, Laura C. A. Perry, Michael K. P. Liu, Fiona Burke, DaleJ. Powner,
`MichaelJ. O. Wakelam, and David M. Sansom
`
`Increased Immunogenicity of an Anchor-Modified Tumor-Associated Antigen Is Due to the Enhanced
`Stability of the Peptide/MHC Complex: Implications for Vaccine Design
`Oleg Y. Borbulevych, Tiffany K. Baxter, Zhiya Yu, Nicholas P. Restifo, and Brian M. Baker
`
`
`
`4768
`
`4779
`
`4789
`
`4797
`
`4803
`
`4812
`
`4821
`
`IMMUNOGENETICS00
`The Enlarged Population of Marginal Zone/CD 1d" B Lymphocytes in Nonobese Diabetic Mice Maps
`to Diabetes Susceptibility Region fddJ 1
`Julia Rolf, Vinicius Motta, Nadia Duarte, Marie Lundholm, Emma Berntman, Marie-Louise Bergman, Lydia Sorokin,
`Susanna L. Cardell, and Dan Holmberg
`
`Miltenyi Ex. 1032 Page 6
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`
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`Hh
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`4828
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`4836
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`4845
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`4852
`
`4860
`
`
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`caersass
`
`HOSTDEFENSE
`
`Intraepithelial CellNeutralization of HIV-1 Replication by IgA
`Yung T. Huang, Alison Wright, Xing Gao, Lesya Kulick, Huimin Yan, andMichael E. Lamm
`
`Polymorphonuclear Neutrophils Improve Replication of Chlamydia pneumoniae In Vivo upon
`MyD88-DependentAttraction
`Nuria Rodriguez, Falko Fend, LuiseJennen, Matthias Schiemann, Nina Wantia, Clarissa U. Prazeres da Costa,
`Susanne Diirr, Ulrich Heinzmann, Hermann Wagner, and Thomas Miethke
`
`Microbial Antigen Triggers Rapid Mobilization of TNF-a to the Surface of Mouse Neutrophils
`Transforming Them into Inducers of High-Level Dendritic Cell TNF-a Production
`Saumaya Bennouna and Eric Y. Denkers
`
`Transmembrane TNFIs Sufficient to Initiate Cell Migration and Granuloma Formation and Provide
`Acute, but Not Long-Term, Control of Mycobacterium tuberculosis Infection
`Bernadette M. Saunders, Stephen Tran, Sigrid Ruuls, Jonathon D, Sedgwick, Helen Briscoe, and WarwickJ. Britton
`
`Molecular Basis for the Potency of IL-10-Deficient Dendritic Cells as a Highly Efficient APC System for
`Activating Th1 Response
`QingHe, Terri T. Moore, Francis O. Eko, Deborah Lyn, Godlwin A. Ananaba, Amy Martin, Shailesh Singh,
`LillardJames, Jonathan Stiles, Carolyn M. Black, andJoseph U. Igietseme
`
`4870
`
`Differential Regulation of B-Defensin Expression in Human Skin by Microbial Stimuli
`Ole E. Sorensen, Dharma R. Thapa, Adam Rosenthal, Lide Liu, AliceA. Roberts, and Tomas Ganz
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`Miltenyi Ex. 1032 Page 6
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`
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`
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`4880
`
`4892
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`4901
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`4908
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`4916
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`4924
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`4934
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`4942
`
`4953
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`4960
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`4966
`
`4972
`
`4979
`
`4985
`
`4991
`
`STATI Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion
`Sergei Kusmartsev and Dmitry I. Gabritlovich
`
`Roles for CXC Chemokine Ligands 10 and 11 in Recruiting CD4* T Cells to HIV-1-Infected
`Monocyte-Derived Macrophages, Dendritic Cells, and Lymph Nodes
`John F. Foley, Cheng-Rong Yu, Rikki Solow, Maureen Yacobucct, Keith W. C. Peden, andJoshua M. Farber
`
`Cathelicidin Mediates Innate Intestinal Defense against Colonization with Epithelial Adherent Bacterial
`Pathogens
`Mitsutoshi limura, Richard L. Gallo, Koji Hase, Yukiko Miyamoto, Lars Eckmann, and Martin F. Kagnoff
`
`Receptor-Binding Domain of Severe Acute Respiratory Syndrome Coronavirus Spike Protein Contains
`Multiple Conformation-Dependent Epitopes that Induce Highly Potent Neutralizing Antibodies
`Yuxian He, Hong Lu, Pamela Siddiqui, Yusen Zhou, and Shibo Jiang
`
`Prevention of Relapse after Chemotherapy in a Chronic Intracellular Infection:
`Mechanisms in Experimental Visceral Leishmaniasis
`Henry W. Murray
`
`Removal of Regulatory T Cell Activity Reverses Hyporesponsiveness and Leadsto Filarial Parasite
`Clearance In Vivo
`Matthew D. Taylor, Laetitia LeGoff, Anjanette Harris, Eva Malone, Judith E. Allen, and Rick M. Maizels
`
`Anthrax Edema Toxin Cooperates with Lethal Toxin to Impair Cytokine Secretion during Infection of
`Dendritic Cells
`Jean-Nicolas Tournier, Anne Quesnel-Hellmann, Jacques Mathieu, Cesare Montecucco, Wei-Jen Tang, Michéle Mock,
`Dominique R. Vidal, and Pierre L. Goossens
`Apoptosis Induced by the Toll-Like Receptor Adaptor TRIF Is Dependent on Its ReceptorInteracting
`Protein Homotypic Interaction Motif
`Wilkam J. Kaiser and Margaret K. Offermann
`
`Surfactant Protein-D Regulates Soluble CD14 through Matrix Metalloproteinase-12
`Albert P. Senft, Thomas R. Korfhagen, Jeffrey A. Whitsett, Steven D. Shapiro, andAnn Marie LeVine
`
`Activation-Induced Depletion of Protein Kinase Ca Provokes Desensitization of Monocytes/Macrophages
`in Sepsis
`Andreas von Knethen, Anja Tautenhahn, Hartmut Link, Dirk Lindemann, and Bernhard Briine
`
`Anthrax Lethal Toxin Blocks MAPK Kinase-Dependent IL-2 Production in CD4* T Cells
`Hui Fang, Ruth Cordoba-Rodriguez, Carla S. R. Lankford, and David M. Frucht
`
`Early Establishmentof y-Herpesvirus Latency: Implications for Immune Control
`Emilio Flafio, QingmeiJia, John Moore, David L. Woodland, Ren Sun, and Marcia A. Blackman
`
`INFLAMMATION
`Leukotriene B4 Receptor-1 Is Essential for Allergen-Mediated Recruitment of CD8* T Cells and Airway
`Hyperresponsiveness
`Nobuaki Miyahara, Katsuyuki Takeda, Satoko Miyahara, Christian Taube, AnthonyJoetham, Toshiyuki Keya,
`Shigeki Matsubara, Azzeddine Dakbama, Andrew M. Tager, Andrew D, Luster, and Erwin W. Gelfand
`
`DominantRole for TL1A/DR3 Pathway in IL-12 plus IL-18-Induced IFN-y Production by Peripheral
`Blood and Mucosal CCR9* T Lymphocytes
`Konstantinos A. Papadakis, Daocheng Zhu, John L. Prehn, Carol Landers, Armine Avanesyan, Gina Lafkas,
`ana Stephan R. Targan
`IL-18-Mediated Innate Immunity Is Amplified in the dbldb Mouse ModelofType 2 Diabetes
`Jason C. O’Connor, Ansuman Satpathy, Maithew E. Hartman, Emily M. Horvath, Keith W. Kelley, Robert Dantzer,
`Rodney W. Johnson, and Gregory G. Freund
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`Miltenyi Ex. 1032 Page 7
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`Miltenyi Ex. 1032 Page 7
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`4998
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`5007
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`5016
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`5024
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`5033
`
`5040
`
`5047
`
`Composition of the Lectin Pathway of Complementin Gallus gallus: Absence of Mannan-Binding
`Lectin-Associated Serine Protease-1 in Birds
`NicholasJ. Lynch, Saeed-ul-Hassan Khan, Cordula M. Stover, Sara M. Sandrini, Denise Marston, Julia S. Presanis,
`and Wilhelm J. Schwaeble
`
`In Vivo Activity of Released Cell Wall Lipids of Mycobacterium bovis Bacillus Calmette-Guérin Is Due
`Principally to Trehalose Mycolates
`Rachel E. Geisel, Kaori Sakamoto, David G. Russell, and Elizabeth R. Rhoades
`
`TLR2 Signaling in Chondrocytes Drives Calcium Pyrophosphate Dihydrate and Monosodium Urate
`Crystal-Induced Nitric Oxide Generation
`Ru Liu-Bryan, Kenneth Pritzker, Gary S. Firestein, and Robert Terkeltaub
`
`Allergen Drives Class Switching to IgE in the Nasal Mucosa in Allergic Rhinitis
`Pooja Takhar, Lyn Smurthwaite, HeatherA. Coker, DavidJ. Fear, Graham K. Banfield, Victoria A. Carr,
`Stephen R. Durham, and Hannah J. Gould
`
`Cyclooxygenase 2 Plays a Pivotal Role in the Resolution ofAcute Lung Injury
`Koichi Fukunaga, Payal Kohli, Caroline Bonnans, Laura E. Fredenburgh, and Bruce D. Levy
`
`Ava Adenosine Receptors on Bone Marrow-Derived Cells Protect Liver from Ischemia-Reperfusion Injury
`Yuan-Ji Day, Yuesheng Li, Jayson M. Rieger, Susan I. Ramos, Mark D. Okusa, andJoel Linden
`
`ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation
`Saveria Pastore, Francesca Mascia, Feliciana Mariotti, Cristina Dattilo, Valentina Mariani; and Giampiero Girolomoni
`
`eeotee
`
`9057
`
`CLINICALIMMUNOLOGY
`
`Fibrin Deimination in Synovial Tissue Is Not Specific for Rheumatoid Arthritis but Commonly Occurs
`during Synovitides
`Sabine Chapuy-Regaud, Mireille Sebbag, Dominique Baeten, Cyril Clavel, Céline Foulquier, Filip De Keyser,
`and Guy Serre
`
` i
`
`5065
`
`5074
`
`5082
`
`5092
`
`5100
`
`5110
`
`AutoimmuneAlterations Induced by the New Zealand Black Low2 Locus in BWF1 Mice
`Maria K. Haraldsson, Nathanial G. dela Paz, Jason G. Kuan, Gary S. Gilkeson, Argyrios N. Theofilopoulos,
`and Dwight H. Kono
`
`Bone Marrow Clonogenic Capability, Cytokine Production, and Thymic Output in Patients with
`CommonVariable Immunodeficiency
`Antonella Isgré, Marco Marziali, Ivano Mezzaroma, Giuseppe Luzi, Anna Maria Mazzone, Vanessa Guazzi,
`Grazia Andolfi, Barbara Cassani, Alessandro Aiuti, and Fernando Aiuti
`
`CCL1-CCR8Interactions: An Axis Mediating the Recruitment of T Cells and Langerhans-Type
`Dendritic Cells to Sites ofAtopic Skin Inflammation
`Michael Gombert, Marie-Caroline Dieu-Nosjean, Franziska Winterberg, Erich Biinemann, Robert C. Kubitza,
`Ludivine Da Cunha, Anna Haahtela, Sari Lehtimidki, Anja Miiller, Juliane Rieker, Stephan Meller, Andor Pivarcsi,
`Andrea Koreck, Wolf-Herman Fridman, Hans-Waker Zentgraf, Hermann Pavenstédt, Ali Amara, Christophe Caux,
`Lajos Kemeny, Harri Alenius, Antti Lauerma, Thomas Ruzicka, Albert Zlotnik, and Bernhard Homey
`
`CD4? T Cell Responses to SSX-4 in MelanomaPatients
`Maha Ayyoub, Andrea Merlo, Charles S. Hesdorffer, Donata Rimoldi, Daniel Speiser, Jean-Charles Cerottini,
`Yao-Tseng Chen, LloydJ. Old, Stefan Stevanovic, and Danila Valmori
`
`Naive CD4* T Cells from Lupus-ProneFas-Intact MRL Mice Display TCR-Mediated
`Hyperproliferation Due to Intrinsic Threshold Defects in Activation
`Christing E. Zielinski, Simon N. Jacob, Farida Bouzahzah, Barbara E. Ehrlich, andJoe Craft
`Accelerated Lymphocyte Death in Sepsis Occurs by béth the Death Receptor and Mitochondrial
`Pathways
`Richard S. Hotchkiss, Stephen B. Osmon, Katherine C. Chang, Tracey H. Wagner, Craig M. Coopersmith,
`and Irene E. Karl
`
`Miltenyi Ex.
`
`1032 Page 8
`
`Miltenyi Ex. 1032 Page 8
`
`

`

`i
`
`5119
`
`Coinfection with Schistosoma mansoni 1s Associated with Decreased HIV-Specific Cytolysis and Increased
`IL-10 Production
`Michael D. McElroy, Mohamed Elrefaei, Norman Jones, Francis Ssali, Peter Mugyenyi, Banson Barugabare,
`and Huyen Cao
`
`|
`
`y
`
`i?
`
`y
`i.
`
`5124
`
`Neutrophils That Infiltrate the Central Nervous System Regulate T Cell Responses
`Simone P, Zehntner, Cristina Brickman, Lyne Bourbonniére, Leah Remington, Maria Caruso, and Trevor Owens
`
`5132
`
`Corrections
`
`5136
`
`5139
`5140
`
`Author Index
`
`AAI Membership Application
`
`AAI Trainee Membership Application
`
` |
`
`ii
`
`, |\
`
`zi
`1]
`Miltenyi Ex. 1032 Page 9
`
`Miltenyi Ex. 1032 Page 9
`
`

`

`
`Rod
`;
`The Journal of Immunology
`
`Dysfunction of Simian Immunodeficiency Virus/Simian Human
`Immunodeficiency Virus-Induced IL-2 Expression by Central
`Memory CD4* T Lymphocytes’
`
`FeRee
`
`YueSun,* Jérn E. Schmitz,* Paula M. Acierno,* Sampa Santra,* Ramu A. Subbramanian,*
`Dan H. Barouch,* Darci A. Gorgone,* Michelle A. Lifton,* Kristin R. Beaudry,*
`Kelledy Manson,‘ Valerie Philippon,’ Ling Xu,* Holden T. Maecker,® John R. Mascola,*
`Dennis Panicali,' Gary J. Nabel,* and Norman L, Letvin”*+
`Production of IL-2 and IFN-y by CD4* T lymphocytes is important for the maintenance of a functional immunesystem in infected
`individuals. In the present study, we assessed the cytokine production profiles of functionally distinct subsets of CD4* T lym-
`phocytes in rhesus monkeysinfected with pathogenic or attenuated SIV/simian human immunodeficiency virus (SHIV) isolates,
`and these responses were.compared with those in vaccinated monkeys that were protected from immunodeficiency following
`pathogenic SHIV challenge. We observed that preserved central memory CD4* T lymphocyte production of SIV/SHIV-induced
`IL-2 was associated with disease protection following primate lentivirus infection. Persisting clinical protection in vaccinated and
`challenged monkeysis thus correlated with a preserved capacity of the peripheral blood central memory CD4*Tcells to express
`this important immunomodulatory cytokine. The Journal of Immunology, 2005, 174: 4753-4760.
`
`—iss
`
`.thaa—uenebaieneitentiies
`
`Seeaeoeseeee>oe
`eeee
`—_—eoASThl
`ahLpatt,
`
`TEEayana.altaree
`
`V/
`
`irus-specifi¢ CD4* T lymphocytes play a central role in
`
`the immune containment of HIV. They contribute to
`
`HIV cleardnce both by providing help for B cell re-
`sponses and by maintaining effective CTL (1, 2). Recent studies
`suggest that functional CD4* T lymphocytes are also required at
`the time of immune priming for the development of memory
`CD8* T lymphocytes (3-5).
`CD4* T lymphocytes of HIV-infected individuals display func-
`tional defects, including reduced proliferative responses to both
`Ags and mitogens (6). These functional CD4* T lymphocyte de-
`fects are associated with reduced production of IL-2, which can be
`partially corrected invitro by the addition of exogenous IL-2 (7,
`8). The integrity of CD4* T lymphocytes that secrete IL-2, or a
`subset of CD4* T lymphocytesthat secrete both IFN-y and IL-2,
`is associated with good clinical outcome in HIV-infected individ-
`uals (9-11). Thus, production of IL-2 by CD4* T lymphocytesis
`important for the maintenance of a functional immune system in
`infected individuals.
`CD4* T lymphocytes have been divided into central memory
`and effector memory cell subsets based on their homing capacity
`and effector function (12, 13). Central memory T lymphocytes
`
`*Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess
`Medical Center, Harvard Medical School, Boston, MA 02115; *Therion Biologics,
`Cambridge, MA 02142; *Vaccine Research Center, National Institute of Allergy and
`Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and §BD
`Biosciences, San Jose, CA 95131
`°
`
`me
`
`Received for publication September 7, 2004. Accepted for publication February
`8, 2005.
`
`home to lymphoid organs, havelittle or no effector function, pro-
`duce predominantly IL-2, and have a high capacity to proliferate.
`In contrast, effector memory T lymphocytes migrate to peripheral
`tissues, display effector function, produce primarily IFN-y, and
`lack significant proliferative capacity. Precisely how the defective
`cellular production of cytokines is associated with the develop-
`ment of memory CD4* T lymphocytes in HIV-infected individu-
`als remains to be elucidated.
`In the present study, the cytokine production of CD4* T lym-
`phocyte subsets was analyzed in rhesus monkeys infected with
`pathogenicviruses andattenuated viruses, and in vaccinated mon-
`keys that were protected from developing disease following patho-
`genic simian human immunodeficiency virus (SHIV)* challenge.
`The results of this study suggest that the ability of SIV/SHIV-
`stimulated central memory CD4* T lymphocytes to synthesize
`IL-2 is an immunecorrelate of disease protection following pri-
`mate immunodeficiency virus infection.
`
`eee
`
`eed
`
`Materials and Methods
`Animals and viruses
`
`Heparinized blood samples were obtained from rhesus monkeys (Macaca
`mulatta). All animals were maintained in accordance with the guidelines of
`the Committee on Animals for the Harvard Medical School and the Guide
`for the Care and Use of Laboratory Animals (14). Viruses used in this study
`were the nonpathogenic SHIV-89.6,
`the pathogenic SHIV-89.6P,
`the
`pathogenic SIVmac251, the attenuated J5 strain of SIVmac251, and the
`pathogenic SIVsmE660.
`
`CD4* T lymphocyte counts and plasma viral RNA levels
`
`Thecosts of publication of this article were defrayed in part by the paymentof page
`Peripheral blood CD4* T lymphocyte counts were calculated by multiply-
`charges. This article must therefore be hereby marked advertisement in accordance
`jng the total lymphocyte count by the percentage of CD3*CD4*Tcells
`with 18 U.S.C. Section 1734 solely to indicate this fact.
`determined by mAbstaining and flow cytometric analysis. Plasma viral
`' This work was supported by National Institutes of Health Grants AI20729, AI30033,
`RNAlevels were measured byan ultrasensitive branched DNA amplifica-
`and A148394, and by Dana-Farber Cancer Institute/Beth Israel Deaconess Medical
`tion assay with a detection limit of 125 copies per ml (Bayer Diagnostics).
`Center/Children’s Hospital Center for AIDS Research Grant AI28691.
`
`2 Address correspondence and reprint requests to Dr. Norman L. Letvin, Division of
`Viral Pathogenesis, Department of Medicine, Beth Israel] Deaconess’Medical Center,
`Harvard Medical School, Research East Room 113, 330 Brookline Avenue, Boston,
`MA 02215. E-mail address; nletvin@bidme.harvard.edu
`
`wr
`
`Agee
`
`3 Abbreviations used in this paper: SHIV, simian human immunodeficiency virus;
`rAd5, recombinant adenovirus serotype 5; MVA, modified vaccinia virus Ankara,
`SEB, staphylococcal enterotoxin B.
`
`Copyright © 2005 by The American Association of Immunologists, Inc,
`
`0022-1767/05/$02.00
`
`Miltenyi Ex. 1032 Page 10
`
`Miltenyi Ex. 1032 Page 10
`
`

`

`Table I. Vaccination/challenge history of study animals
`
`DETERMINANTS OF DISEASE PROGRESSIONIN SIV/SHIV INFECTION
`
`Immunogens
`
`Immunizations
`
`Challenge
`
`‘\
`Plasmid DNAsexpressing
`genes encoding gag, pol, nef, and
`env CTL epitopes
`Pox virus or rAd5 expressing
`STVmac239 Gag/Pol, HIV-1 89.6P
`Env
`
`Plasmid DNAsand/or rAd5
`expressing
`SIVmac239 Gag/Pol/Nef, HIV-1
`89.6P Envy
`
`Plasmid DNA i.m.
`MVA,vaccinia, or rAd5 im.
`
`Plasmid DNA i.m.—wk 0, 4, 8
`rAd5 i.m.—wk 26, 159
`
`No
`
`No
`
`Hee
`
`:
`
`Plasmid DNAsand rAd5 expressing
`SIVmac239 Gag/Pol/Nef, HIV-1
`89.6P Env
`
`Plasmid DNA i.m.—wk 0, 4, 8
`rAd5 i.m.—wk 26
`
`SHIV-89.6P i.v.wk38
`
`Vaccinated only
`(Vaccinated)
`90-98, 95-98, 135-97, 128-97,
`132-97, 196-97
`
`(Vaccinated)
`AW2P, AW13, AW28, AV83
`
`Vaccinated/SHIV-89.6P challenged
`(Gag-Pol-Nef/Env)
`PKB, AV8T, AK67, AK85,
`AW2V, PWE, AV2E, AV67,
`AX7H, AE6B
`
` 4754
`
`(Gag-Pol-Nef/Mock Env)
`JBA, TKF, AV65, TC], AK6X,
`AV5K
`
`Plasmid DNAsand rAd5 expressing
`SIVmac239 Gag/Pol/Nef
`
`Plasmid DNA i.m.—wk 0, 4, 8
`rAd5 i.m—wk 26
`
`SHIV-89.6P i.v.—wk 38
`
`Vaccination protocol
`
`Three groups of vaccinated monkeys were included in this study (Table I). The
`first group of monkeys (vaccinated/SHIV-89.6P challenged) was immunized
`three times by the im.
`route with 10 mg of plasmid DNA containing
`STVmac239 Gag/Pol/Nef, with or without HIV-1 89.6P Env. Following an
`18-wkrest, each of the DNA-primed monkeys was boosted with 2 x 10’? PFU
`of recombinant adenovirus serotype 5 (rAd5) expressing the same STV/HIV-1
`genes by the im. route. Animals were challenged at wk 38 with 100 50%
`monkey infectious doses (MID.9) of SHIV-89.6P by the i.v. route. The
`second group of monkeys (vaccinated only) was immunized twoto four
`times by the i.m. route with plasmid DNAcontaining gag,pol, nef, and
`env genes encoding for CTL epitopes (15), and boosted by i.m. injection
`
`with recombinant modified vaccinia virus Ankara (MVA), vaccinia
`virus, or rAd5 constructs. The third group of monkeys (vaccinated only)
`either was immunized three times by i.m. route with 10 mg of plasmid
`DNAcontaining SIVmac239 Gag/Pol/Nef and HIV-1 89.6P Env, or
`received no plasmid DNA immunization. Following an 18-wk rest, all
`DNA-primed monkeys, as well as a group of naive monkeys, received
`2 X 10!? PFU of rAd5 expressing the same SIV/HIV-1 genes. Monkeys
`received a second inoculation of rAd5 constructs 133 wklater.
`
`Antibodies
`
`The Abs used in this study were directly coupled to FITC, PE, PE-Texas
`Red (ECD), allophycocyanin, PerCP-Cy5.5, Alexa Fluor 700, or PE-~Cy7.
`
`Table If.
`
`Clinical data on rhesus monkeys infected with pathogenic or attenuated viruses
`
`Group
`
`Infecting Virus
`
`Years of
`Infection
`
`Plasma Viral RNA
`(copies/ml)
`
`CD4* T Cells
`(count/j2})
`
`Monkeys with no detected
`plasma viral RNA?
`403-91
`191-96
`556-92
`287-94
`206-93
`267-95
`196-88
`
`Median
`
`Monkeys with detected
`plasma viral RNA?
`AV52
`PH0465
`JHB
`PH0685
`PHO0305
`AV8P
`136-99
`238-95
`223-95
`261-95
`BE86
`BR32
`BH25
`
`Median
`
`SIVmac251 (35)
`SIVmac251
`SHIV-89.6
`SHIV-89.6
`SHIV-89.6
`SHIV-89.6
`SHIV-89.6P
`
`STVmac251
`STVmac251
`STVmac251
`STVmac251
`SIVmac251
`SIVmac251
`STVsmE660
`SIVsmE660
`STVsmE660
`STVsmE660
`SIVmac251
`STVmac251
`SIVmac251
`
`“ Referred to in the figures as nonpathogenic virus.
`» Referred to in the figures a