bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Antibody Polyspecificity and Lipid Reactivity in Binding of Broadly Neutralizing Anti-HIV-1 Envelope Human Monoclonal Antibodies 2F5 and 4E10 to Glycoprotein 41 Membrane Proximal Envelope Epitopes
Authors: Alam S. Munir , McAdams Mildred , Boren David , Rak Michael , Scearce Richard M. , Gao Feng , Camacho Zenaido T. , Gewirth Daniel , Kelsoe Garnett , Chen Pojen , Haynes Barton F. 
Published: April 2014

Abstract
Two neutralizing human mAbs, 2F5 and 4E10, that react with the HIV-1 envelope gp41 membrane proximal region are also polyspecific autoantibodies that bind to anionic phospholipids. To determine the autoantibody nature of these Abs, we have compared their reactivities with human anti-cardiolipin mAbs derived from a primary antiphospholipid syndrome patient. To define the role of lipid polyreactivity in binding of 2F5 and 4E10 mAbs to HIV-1 envelope membrane proximal epitopes, we determined the kinetics of binding of mAbs 2F5 and 4E10 to their nominal gp41 epitopes vs liposome-gp41 peptide conjugates. Both anti-HIV-1 mAbs 2F5 and 4E10 bound to cardiolipin with Kd values similar to those of autoimmune anti-cardiolipin Abs, IS4 and IS6. Binding kinetics studies revealed that mAb 2F5 and 4E10 binding to their respective gp41 peptide-lipid conjugates could best be defined by a two-step (encounter-docking) conformational change model. In contrast, binding of 2F5 and 4E10 mAbs to linear peptide epitopes followed a simple Langmuir model. A mouse mAb, 13H11, that cross-blocks mAb 2F5 binding to the gp41 epitope did not cross-react with lipids nor did it neutralize HIV-1 viruses. Taken together, these data demonstrate the similarity of 2F5 and 4E10 mAbs to known anti-cardiolipin Abs and support the model that mAb 2F5 and 4E10 binding to HIV-1 involves both viral lipid membrane and gp41 membrane proximal epitopes.
T Cell Recognition Patterns of Immunodominant Cytomegalovirus Antigens in Primary and Persistent Infection
Authors: Khan Naeem , Best Donna , Bruton Rachel , Nayak Laxman , Rickinson Alan B. , Moss Paul A. H. 
Published: April 2014

Abstract
Replication of human cytomegalovirus is controlled by a vigorous CD8 T cell response. The persistent nature of infection is believed to periodically stimulate T cell responses resulting in considerable expansions of virus-specific CD8 T cells over time. In this study, we describe the magnitude and breadth of CD8 T cell responses against the immunodominant viral Ags, IE-1 and pp65, in acute and long-term infection using the IFN-γ ELISPOT assay. Simultaneously, we have identified several novel MHC class I restricted CD8 T cell epitopes. Acute phase responses in immunocompetent donors appear to be extremely focused as early as 1 week post diagnosis with dominant peptide-specific responses observed against both proteins. These dominant responses remain detectable at all later time points over a 4-year follow-up. Interestingly the IE-1 responses show an increase over time whereas the pp65 responses do not, which contrasts with data showing that responses against both Ags are elevated in elderly individuals. We also observe the rapid emergence of an effector memory phenotype for virus-specific CD8 T cells as observed in persistent infection. Over time the revertant CD45RApos effector cell population is also expanded, and this is more evident in the preferentially expanded IE-1 responses. We postulate that periodic low-level virus reactivation after the acute infection phase preferentially stimulates these responses whereas pp65-specific T cell expansions probably occur during the infrequent episodes of lytic viral replication or secondary infection.
Resident Vδ1+ γδ T Cells Control Early Infiltration of Neutrophils after Escherichia coli Infection via IL-17 Production
Authors: Shibata Kensuke , Yamada Hisakata , Hara Hiromitsu , Kishihara Kenji , Yoshikai Yasunobu 
Published: April 2014

Abstract
Neutrophils infiltrate the site of infection and play critical roles in host defense, especially against extracellular bacteria. In the present study, we found a rapid and transient production of IL-17 after i.p. infection with Escherichia coli, preceding the influx of neutrophils. Neutralization of IL-17 resulted in a reduced infiltration of neutrophils and an impaired bacterial clearance. Ex vivo intracellular cytokine flow cytometric analysis revealed that γδ T cell population was the major source of IL-17. Mice depleted of γδ T cells by mAb treatment or mice genetically lacking Vδ1 showed diminished IL-17 production and reduced neutrophil infiltration after E. coli infection, indicating an importance of Vδ1+ γδ T cells as the source of IL-17. It was further revealed that γδ T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23, which was induced rapidly after E. coli infection in a TLR4 signaling-dependent manner. Thus, although γδ T cells are generally regarded as a part of early induced immune responses, which bridge innate and adaptive immune responses, our study demonstrated a novel role of γδ T cells as a first line of host defense controlling neutrophil-mediated innate immune responses.
Tyk2 Signaling in Host Environment Plays an Important Role in Contraction of Antigen-Specific CD8+ T Cells following a Microbial Infection
Authors: Li Wei , Yamada Hisakata , Yajima Toshiki , Nakagawa Ryusuke , Shimoda Kazuya , Nakayama Keiichi , Yoshikai Yasunobu 
Published: April 2014

Abstract
Tyrosine kinase 2 (Tyk2), a member of JAK signal transducer family contributes to the signals triggered by IL-12 for IFN-γ production. To elucidate potential roles of Tyk2 in generation and maintenance of Ag-specific CD8+ T cells, we followed the fate of OVA-specific CD8+ T cells in Tyk2-deficient (−/−) mice after infection with recombinant Listeria monocytogenes expressing OVA (rLM-OVA). Results showed that the numbers of OVA257–264/Kb tetramer-positive CD8+ T cells in Tyk2−/− mice were almost the same as those in Tyk2+/+ mice at the expansion phase on day 7 but were significantly larger in Tyk2−/− mice than those in Tyk2+/+ mice at the contraction phase on day 10 and at the memory phase on day 60 after infection. The intracellular expression level of active caspase-3 was significantly decreased in the OVA-specific CD8+ T cells of Tyk2−/− mice on day 7 compared with those of Tyk2+/+ mice. Adaptive transfer experiments revealed that Tyk2 signaling in other factors rather than CD8+ T cells played a regulatory role in CD8+ T cell contraction following infection. Administration of exogenous IFN-γ from day 6 to day 9 restored the CD8+ T cell contraction in Tyk2−/− mice after infection with rLM-OVA. These results suggest that Tyk2 signaling for IFN-γ production in host environment plays an important role in contraction of effector CD8+ T cells following a microbial infection.
Oncostatin M Secreted by Skin Infiltrating T Lymphocytes Is a Potent Keratinocyte Activator Involved in Skin Inflammation
Authors: Boniface Katia , Diveu Caroline , Morel Franck , Pedretti Nathalie , Froger Josy , Ravon Elisa , Garcia Martine , Venereau Emilie , Preisser Laurence , Guignouard Emmanuel , Guillet Gérard , Dagregorio Guy , Pène Jérôme , Moles Jean-Pierre , Yssel Hans , Chevalier Sylvie , Bernard François-Xavier , Gascan Hugues , Lecron Jean-Claude 
Published: April 2014

Abstract
Cutaneous inflammatory diseases such as psoriasis vulgaris and atopic dermatitis are associated with altered keratinocyte function, as well as with a particular cytokine production profile of skin-infiltrating T lymphocytes. In this study we show that normal human epidermal keratinocytes express a functional type II oncostatin-M (OSM) receptor (OSMR) consisting of the gp130 and OSMRβ components, but not the type I OSMR. The type II OSMR is expressed in skin lesions from both psoriatic patients and those with atopic dermatitis. Its ligand, OSM, induces via the recruitment of the STAT3 and MAP kinase pathways a gene expression profile in primary keratinocytes and in a reconstituted epidermis that is characteristic of proinflammatory and innate immune responses. Moreover, OSM is a potent stimulator of keratinocyte migration in vitro and increases the thickness of a reconstituted epidermis. OSM transcripts are enhanced in both psoriatic and atopic dermatitic skin as compared with healthy skin and mirror the enhanced production of OSM by T cells isolated from diseased lesions. Results from a microarray analysis comparing the gene-modulating effects of OSM with those of 33 different cytokines indicate that OSM is a potent keratinocyte activator similar to TNF-α, IL-1, IL-17, and IL-22 and that it acts in synergy with the latter cytokines in the induction of S100A7 and β-defensin 2 expression, characteristic of psoriatic skin. Taken together, these results demonstrate that OSM and its receptor play an important role in cutaneous inflammatory responses in general and that the specific effects of OSM are associated with distinct inflammatory diseases depending on the cytokine environment.
Cutting Edge: B Cell Receptor (BCR) Cross-Talk: The IL-4-Induced Alternate Pathway for BCR Signaling Operates in Parallel with the Classical Pathway, Is Sensitive to Rottlerin, and Depends on Lyn
Authors: Guo Benchang , Blair Derek , Chiles Thomas C. , Lowell Clifford A. , Rothstein Thomas L. 
Published: April 2014

Abstract
B cell exposure to IL-4 alters subsequent BCR signaling such that ERK phosphorylation becomes signalosome-independent; however, the nature of this new, alternate signaling pathway and its relationship to the classical, signalosome-dependent signaling pathway are not known. In this study, we report that the alternate and classical pathways for BCR signaling are differentially affected by rottlerin, and by Go6976 or LY294002, respectively. Furthermore, in B cells lacking protein kinase C (PKC)β, the classical pathway for BCR signaling is blocked, whereas the alternate pathway is little affected. Conversely, in B cells lacking Lyn, the alternate pathway for BCR signaling is blocked, whereas the classical pathway is little affected. The rottlerin-sensitive element is not PKCδ, inasmuch as the alternate pathway is not blocked in PKCδ-deficient B cells. These results indicate that the rottlerin-sensitive, Lyn-dependent alternate pathway, and the classical pathway, for BCR signaling operate in parallel when BCR engagement follows IL-4 exposure.
IL-7 Is Essential for the Development and the Persistence of Chronic Colitis
Authors: Totsuka Teruji , Kanai Takanori , Nemoto Yasuhiro , Makita Shin , Okamoto Ryuichi , Tsuchiya Kiichiro , Watanabe Mamoru 
Published: April 2014

Abstract
Although IL-7 has recently emerged as a key cytokine involved in controlling the homeostatic turnover and the survival of peripheral resting memory CD4+ T cells, its potential to be sustained pathogenic CD4+ T cells in chronic immune diseases, such as inflammatory bowel diseases, still remains unclear. In this study, we demonstrate that IL-7 is essential for the development and the persistence of chronic colitis induced by adoptive transfer of normal CD4+CD45RBhigh T cells or colitogenic lamina propria (LP) CD4+ memory T cells into immunodeficient IL-7+/+ × RAG-1−/− and IL-7−/− × RAG-1−/− mice. Although IL-7+/+ × RAG-1−/− recipients transferred with CD4+CD45RBhigh splenocytes developed massive inflammation of the large intestinal mucosa concurrent with massive expansion of Th1 cells, IL-7−/− × RAG-1−/− recipients did not. Furthermore, IL-7−/− × RAG-1−/−, but not IL-7+/+ × RAG-1−/−, mice transferred with LP CD4+CD44highCD62L−IL-7Rαhigh effector-memory T cells (TEM) isolated from colitic CD4+CD45RBhigh-transferred mice did not develop colitis. Although rapid proliferation of transferred colitogenic LP CD4+ TEM cells was observed in the in IL-7−/− × RAG-1−/− mice to a similar extent of those in IL-7+/+ × RAG-1−/− mice, Bcl-2 expression was significantly down-modulated in the transferred CD4+ T cells in IL-7−/− × RAG-1−/− mice compared with those in IL-7+/+ × RAG-1−/− mice. Taken together, IL-7 is essential for the development and the persistence of chronic colitis as a critical survival factor for colitogenic CD4+ TEM cells, suggesting that therapeutic approaches targeting IL-7/IL-7R signaling pathway may be feasible in the treatment of inflammatory bowel diseases.
Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation
Authors: Bagley Jessamyn , Singh Gyanesh , Iacomini John 
Published: April 2014

Abstract
Mutations in the gene encoding ataxia-telangiectasia (A-T) mutated (Atm) cause the disease A-T, characterized by immunodeficiency, the molecular basis of which is not known. Following stimulation through the TCR, Atm-deficient T cells and normal T cells in which Atm is inhibited undergo apoptosis rather than proliferation. Apoptosis is prevented by scavenging reactive oxygen species (ROS) during activation. Atm therefore plays a critical role in T cell proliferation by regulating responses to ROS generated following T cell activation. The inability of Atm-deficient T cells to control responses to ROS is therefore the molecular basis of immunodeficiency associated with A-T.
Spontaneous Autoreactive Memory B Cell Formation Driven by a High Frequency of Autoreactive CD4+ T Cells
Authors: Guay Heath M. , Larkin Joseph , Picca Cristina Cozzo , Panarey Laura , Caton Andrew J. 
Published: April 2014

Abstract
Although somatically mutated autoantibodies are characteristic of many autoimmune diseases, the processes that can lead to their development remain poorly understood. We have examined the formation of autoreactive memory B cells in PevHA mice, which express the influenza virus PR8 hemagglutinin (HA) as a transgenic membrane bound neo-self-Ag. Using a virus immunization strategy, we show that PR8 HA-specific memory B cell formation can occur in PevHA mice, even though a major subset of PR8 HA-specific B cells is negatively selected from the primary repertoire. Moreover, PR8 HA-specific memory B cells develop spontaneously in TS1 × PevHA mice, which coexpress a transgenic PR8 HA-specific TCR and contain a high frequency of HA-specific CD4+ T cells. Notably, autoreactive memory B cell formation occurred in TS1 × PevHA mice even though approximately half of the HA-specific CD4+ T cells were CD25+Foxp3+ cells that could significantly attenuate, but did not completely abolish HA-specific autoantibody production in an adoptive transfer setting. The findings provide evidence that a high frequency of autoreactive CD4+ T cells can be sufficient to promote autoreactive memory B cell formation in the absence of signals provided by overt immunization or infection and despite the presence of abundant autoantigen-specific CD4+CD25+Foxp3+ regulatory T cells.
Aggregated Ursolic Acid, a Natural Triterpenoid, Induces IL-1β Release from Murine Peritoneal Macrophages: Role of CD36
Authors: Ikeda Yasutaka , Murakami Akira , Fujimura Yoshinori , Tachibana Hirofumi , Yamada Koji , Masuda Daisaku , Hirano Ken-ichi , Yamashita Shizuya , Ohigashi Hajime 
Published: April 2014

Abstract
IL-1β has been shown to play a pivotal role in the development of inflammatory disorders. We recently found that a natural triterpene, ursolic acid (UA), enhanced MIF release from nonstimulated macrophages. In this study, we examined the effects of UA on the production of several cytokines in resident murine peritoneal macrophages (pMφ). UA increased the protein release of IL-1β, IL-6, and MIF, but not of TNF-α, in dose- and time-dependent manners. This triterpene also strikingly induced the activation of p38 MAPK and ERK1/2 together with that of upstream kinases. The release of UA-induced IL-1β was significantly inhibited by the inhibitors of p38 MAPK, MEK1/2, ATP-binding cassette transporter, and caspase-1. Furthermore, UA induced intracellular ROS generation for IL-1β production, which was suppressed by an antioxidant. Pretreatment with an anti-CD36 Ab significantly suppressed IL-1β release, and surface plasmon resonance assay results showed that UA bound to CD36 on macrophages. In addition, the amount of IL-1β released from UA-treated pMφ of CD36-deficient mice was markedly lower than that from those of wild-type mice. Interestingly, UA was found to aggregate in culture medium, and the aggregates were suggested to be responsible for IL-1β production. In addition, i.p. administration of UA increased the levels of IL-1β secretion and MPO activity in colonic mucosa of ICR mice. Taken together, our results indicate that aggregated UA is recognized, in part, by CD36 on macrophages for generating ROS, thereby activating p38 MAPK, ERK1/2, and caspase-1, as well as releasing IL-1β protein via the ATP-binding cassette transporter.
β1-Adrenergic Receptors on Immune Cells Impair Innate Defenses against Listeria
Authors: Emeny Rebecca T. , Gao Donghong , Lawrence David A. 
Published: April 2014

Abstract
Cold restraint (CR) for 1 h elicits a psychological and physiological stress that inhibits host defenses against Listeria monocytogenes (LM). Previous analyses indicated that this inhibition is not due to depletion of B or T cells but is instead dependent on signaling through β-adrenoceptors (βARs). We now show that impaired host resistance by CR cannot be accounted for by a decrease in LM-specific (listeriolysin O91–99 tetramer+) effector CD8+ T cells; this result is consistent with previous observations that CR-induced effects are mainly limited to early anti-LM responses. β2-Adrenoceptor (β2AR)−/− FVB/NJ and wild-type FVB/NJ mice had equivalent anti-LM defenses, whereas β1-adrenoceptor (β1AR)−/− FVB/NJ mice had lower levels of LM even when subjected to CR treatment. Additionally, host-resistance competency of β1AR−/− mice could be transferred to irradiated wild-type mice reconstituted with β1AR−/− bone marrow progenitors and spleen cells, indicating that β1AR signaling on immune cells reduces anti-LM responses. β1AR−/− mice had improved cellular (delayed-type hypersensitivity) responses while β2AR−/− mice had improved humoral responses (IgG1, IgG2, and IgM), a result that further explains the strain differences in LM defenses. CR-induced expression of β1AR and β2AR mRNA was assessed by real-time PCR. CR treatment significantly increased βAR mRNAs in Ficoll-purified and F4/80+-enhanced liver but not splenic homogenates, demonstrating an organ-specific effect of stress that alters host defenses. Finally, CR treatment induced early increases in perforin expression that may enhance immune cell apoptosis and interfere with LM clearance. In conclusion, β1AR signaling has immunomodulatory effects on early cell-mediated immune responses; a lack of β1AR signaling improves antilisterial defenses and cell-mediated immunity, in general.
TLR2-Mediated Survival of Staphylococcus aureus in Macrophages: A Novel Bacterial Strategy against Host Innate Immunity
Authors: Watanabe Ikuko , Ichiki Manami , Shiratsuchi Akiko , Nakanishi Yoshinobu 
Published: April 2014

Abstract
TLR2 plays a role as a pattern-recognition receptor in the innate immune response involving secreted proteins against microbial pathogens. To examine its possible involvement in the cellular response, we determined the levels of the engulfment and subsequent killing of bacteria by macrophages prepared from TLR2-deficient and wild-type mice. The level of the engulfment of Staphylococcus aureus or Escherichia coli was almost the same between TLR2-lacking and wild-type macrophages. However, the colony-forming ability of engulfed S. aureus, but not of E. coli, decreased to a greater extent in TLR2-lacking macrophages than in the wild-type control. The incubation with S. aureus caused activation of JNK in wild-type macrophages but not in TLR2-lacking macrophages, and the pretreatment of wild-type macrophages with a JNK inhibitor increased the rate of killing of engulfed S. aureus, but again not of E. coli. In addition, the number of colonies formed by engulfed S. aureus increased in the JNK-dependent manner when TLR2-lacking macrophages were pretreated with LPS. Furthermore, JNK seemed to inhibit the generation of superoxide, not of NO, in macrophages. These results collectively suggested that the level of superoxide is reduced in macrophages that have engulfed S. aureus through the actions of TLR2-activated JNK, resulting in the prolonged survival of the bacterium in phagosomes. The same regulation did not influence the survival of E. coli, because this bacterium was more resistant to superoxide than S. aureus. We propose a novel bacterial strategy for survival in macrophages involving the hijacking of an innate immune receptor.
Intestinal Lamina Propria Retaining CD4+CD25+ Regulatory T Cells Is A Suppressive Site of Intestinal Inflammation
Authors: Makita Shin , Kanai Takanori , Nemoto Yasuhiro , Totsuka Teruji , Okamoto Ryuichi , Tsuchiya Kiichiro , Yamamoto Masafumi , Kiyono Hiroshi , Watanabe Mamoru 
Published: April 2014

Abstract
It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only does active suppression by regulatory T (TREG) cells play an important role in the normal intestinal homeostasis, but also that its dysregulation of immune response leads to the development of inflammatory bowel disease. In this study, we demonstrate that murine CD4+CD25+ T cells residing in the intestinal lamina propria (LP) constitutively express CTLA-4, glucocorticoid-induced TNFR, and Foxp3 and suppress proliferation of responder CD4+ T cells in vitro. Furthermore, cotransfer of intestinal LP CD4+CD25+ T cells prevents the development of chronic colitis induced by adoptive transfer of CD4+CD45RBhigh T cells into SCID mice. When lymphotoxin (LT)α-deficient intercrossed Rag2 double knockout mice (LTα−/− × Rag2−/−), which lack mesenteric lymph nodes and Peyer’s patches, are transferred with CD4+CD45RBhigh T cells, they develop severe wasting disease and chronic colitis despite the delayed kinetics as compared with the control LTα+/+ × Rag2−/− mice transferred with CD4+CD45RBhigh T cells. Of note, when a mixture of splenic CD4+CD25+ TREG cells and CD4+CD45RBhigh T cells are transferred into LTα−/− × Rag2−/− recipients, CD4+CD25+ TREG cells migrate into the colon and prevent the development of colitis in LTα−/− × Rag2−/− recipients as well as in the control LTα+/+ × Rag2−/− recipients. These results suggest that the intestinal LP harboring CD4+CD25+ TREG cells contributes to the intestinal immune suppression.