bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Context of Epitope Presentation Can Influence Functional Quality of Recalled Influenza A Virus-Specific Memory CD8+ T Cells
Authors: Day E. Bridie , Zeng Weiguang , Doherty Peter C. , Jackson David C. , Kedzierska Katherine , Turner Stephen J. 
Published: April 2014

AbstractLipopeptide constructs offer a novel strategy for eliciting effective cellular and humoral immunity by directly targeting the vaccine Ag to dendritic cells. Importantly, it is not known how closely immunity generated after lipopeptide vaccination mimics that generated after natural infection. We have used a novel lipopeptide vaccine strategy to analyze both the quantity and quality of CD8+ T cell immunity to an influenza A virus epitope derived from the acidic polymerase protein (PA224) in B6 mice. Vaccination with the PA224 lipopeptide resulted in accelerated viral clearance after subsequent influenza virus infection. The lipopeptide was also effective at recalling secondary DbPA224 responses in the lung. Lipopeptide recalled DbPA224-specific CTL produced lower levels of IFN-γ and TNF-α, but produced similar levels of IL-2 when compared with DbPA224-specific CTL recalled after virus infection. Furthermore, lipopeptide- and virus-recalled CTL demonstrated similar TCR avidity. Interestingly, lipopeptide administration resulted in expansion of DbPA224-specific CTL using a normally subdominant TCRBV gene segment. Overall, these results demonstrate that protective CTL responses elicited by lipopeptide vaccines can be correlated with TCR avidity, IL-2 production, and broad TCR repertoire diversity. Furthermore, factors that impact the quality of immunity are discussed. These factors are important considerations when evaluating the efficacy of novel vaccine strategies that target dendritic cells for eliciting cellular immunity.
CD134 Costimulation Couples the CD137 Pathway to Induce Production of Supereffector CD8 T Cells That Become IL-7 Dependent
Authors: Lee Seung-Joo , Rossi Robert J. , Lee Sun-Kyeong , Croft Michael , Kwon Byoung S. , Mittler Robert S. , Vella Anthony T. 
Published: April 2014

AbstractThe TNFR superfamily members 4-1BB (CD137) and OX40 (CD134) are costimulatory molecules that potently boost CD8 and CD4 T cell responses. Concomitant therapeutic administration of agonist anti-CD137 and -CD134 mAbs mediates rejection of established tumors and fosters powerful CD8 T cell responses. To reveal the mechanism, the role of CD137 expression by specific CD8 T cells was determined to be essential for optimal clonal expansion and accumulation of effector cells. Nonetheless, dual costimulation induced production of supereffector CD8 T cells when either the specific T cells or the host alone bore CD137. Perhaps surprisingly, the total absence of CD137 prevented anti-CD134 augmentation of supereffector differentiation demonstrating an unappreciated link between these related pathways. Ultimately, it was reasoned that these powerful dual costimulatory responses involved common γ family members, and we show substantial increases of CD25 and IL-7Rα-chain expression by the specific CD8 T cells. To investigate this further, it was shown that IL-7 mediated T cell accumulation, but importantly, a gradual and preferential effect of survival was directed toward supereffector CD8 T cells. In fact, a clear enhancement of effector differentiation was demonstrated to be proportional to the increasing amount of IL-7Rα expression by the specific CD8 T cells. Therefore, dual costimulation through CD137 and CD134 drives production and survival of supereffector CD8 T cells through a distinct IL-7-dependent pathway.
MHC Class II+ Exosomes in Plasma Suppress Inflammation in an Antigen-Specific and Fas Ligand/Fas-Dependent Manner
Authors: Kim Seon Hee , Bianco Nicole R. , Shufesky William J. , Morelli Adrian E. , Robbins Paul D. 
Published: April 2014

AbstractExosomes are 50- to 100-nm vesicles that are formed within the late endocytic compartment and released from a variety of cell types. Previously, we demonstrated that exosomes derived from dendritic cells transduced with adenoviral vectors expressing IL-10, IL-4, or Fas ligand (FasL) produce anti-inflammatory exosomes able to reduce inflammation in a murine paw delayed-type hypersensitivity model, suppress the onset on murine collagen-induced arthritis, and reduce the severity of established collagen-induce arthritis. In this study, we examined the ability of endogenous, blood-borne exosomes to regulate the immune response. Exosomes isolated from plasma of mice immunized to keyhole limpet hemocyanin, but not from naive or OVA-immunized mice, were able to suppress the keyhole limpet hemocyanin-specific delayed-type hypersensitivity inflammatory response. The anti-inflammatory effect was mediated by MHC class II+ plasma exosomes that were also FasL+ and CD11b+, but CD11c−. Moreover, the anti-inflammatory effect of the MHC class II+ plasma-derived exosomes was, in part, dependent upon the presence of FasL in the exosomes and Fas in the recipient mouse. These results suggest that exosomes in the plasma, produced by MHC class II+ and CD11b+ cells, have the ability to suppress the immune response in an Ag-specific manner in part through a Fas/FasL-dependent manner.
TACI Is Required for Efficient Plasma Cell Differentiation in Response to T-Independent Type 2 Antigens
Authors: Mantchev George T. , Cortesão Catarina S. , Rebrovich Michelle , Cascalho Marilia , Bram Richard J. 
Published: April 2014

AbstractThe control of systemic infection by encapsulated microorganisms requires T-independent type II (TI-2) Ab responses to bacterial polysaccharides. To understand how such responses evolve, we explored the function of transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI), a member of the TNFR family, required for TI-2 Ab production. Quasimonoclonal (QM) mice produce robust TI-2 responses to 4-hydroxy-3-nitrophenylacetate (NP)-Ficoll, owing to the high precursor frequency of NP-specific B cells in the marginal zone of the spleen. QM mice that lack TACI produce decreased numbers of IgM (2-fold) and IgG (1.6-fold) NP-specific ASCs, compared with TACI-positive QM mice in response to immunization with NP-Ficoll. Our studies indicate that TACI acts at a remote time from activation because TACI is not necessary for activation and proliferation of B cells both in vitro and in vivo. Instead, TACI-deficient QM B cells remained in the cell cycle longer than TACI-proficient QM cells and had impaired plasma cell differentiation in response to NP-Ficoll. We conclude that TACI has dual B cell-autonomous functions, inhibiting prolonged B cell proliferation and stimulating plasma cell differentiation, thus resolving the longstanding paradox that TACI may have both B cell-inhibitory and -stimulatory functions. By promoting plasma cell differentiation earlier during clonal expansion, TACI may decrease the chances of autoantibody production by somatic hypermutation of Ig genes in response to T-independent Ags.
CCR5 Blockade Modulates Inflammation and Alloimmunity in Primates
Authors: Schröder Carsten , Pierson Richard N. , Nguyen Bao-Ngoc H. , Kawka Douglas W. , Peterson Laurence B. , Wu Guosheng , Zhang Tianshu , Springer Martin S. , Siciliano Sal J. , Iliff Susan , Ayala Julia M. , Lu Min , Mudgett John S. , Lyons Kathy , Mills Sander G. , Miller Geraldine G. , Singer Irwin I. , Azimzadeh Agnes M. , DeMartino Julie A. 
Published: April 2014

AbstractPharmacologic antagonism of CCR5, a chemokine receptor expressed on macrophages and activated T cells, is an effective antiviral therapy in patients with macrophage-tropic HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this regard, the recruitment of CCR5-bearing cells into clinical allografts is a hallmark of acute rejection and may anticipate chronic rejection, whereas conventionally immunosuppressed renal transplant patients homozygous for a nonfunctional Δ32 CCR5 receptor rarely exhibit late graft loss. Therefore, we explored the effects of a potent, highly selective CCR5 antagonist, Merck’s compound 167 (CMPD 167), in an established cynomolgus monkey cardiac allograft model. Although perioperative stress responses (fever, diminished activity) and the recruitment of CCR5-bearing leukocytes into the graft were markedly attenuated, anti-CCR5 monotherapy only marginally prolonged allograft survival. In contrast, relative to cyclosporine A monotherapy, CMPD 167 with cyclosporine A delayed alloantibody production, suppressed cardiac allograft vasculopathy, and tended to further prolong graft survival. CCR5 therefore represents an attractive therapeutic target for attenuating postsurgical stress responses and favorably modulating pathogenic alloimmunity in primates, including man.
Molecular and Cellular Requirements for Enhanced Antigen Cross-Presentation to CD8 Cytotoxic T Lymphocytes
Authors: Oizumi Satoshi , Strbo Natasa , Pahwa Savita , Deyev Vadim , Podack Eckhard R. 
Published: April 2014

AbstractMHC class I-mediated cross-priming of CD8 T cells by APCs is critical for CTL-based immunity to viral infections and tumors. We have shown previously that tumor-secreted heat shock protein gp96-chaperoned peptides cross prime CD8 CTL that are specific for genuine tumor Ags and for the surrogate Ag OVA. We now show that tumor-secreted heat shock protein gp96-chaperoned peptides enhance the efficiency of Ag cross-priming of CD8 CTL by several million-fold over the cross-priming activity of unchaperoned protein alone. Gp96 also acts as adjuvant for cross-priming by unchaperoned proteins, but in this capacity gp96 is 1000-fold less active than as a peptide chaperone. Mechanistically, the in situ secretion of gp96-Ig by transfected tumor cells recruits and activates dendritic cells and NK cells to the site of gp96 release and promotes CD8 CTL expansion locally. Gp96-mediated cross-priming of CD8 T cells requires B7.1/2 costimulation but proceeds unimpeded in lymph node-deficient mice, in the absence of NKT and CD4 cells and without CD40L. Gp96-driven MHC I cross-priming of CD8 CTL in the absence of lymph nodes provides a novel mechanism for local, tissue-based CTL generation at the site of gp96 release. This pathway may constitute a critically important, early detection, and rapid response mechanism that is operative in parenchymal tissues for effective defense against tissue damaging antigenic agents.
O-Glycosylated Human MUC1 Repeats Are Processed In Vitro by Immunoproteasomes
Authors: Ninkovic Tanja , Hanisch Franz-Georg 
Published: April 2014

Abstract
The targeting of epitopes on tumor-associated glycoforms of human MUC1 represents a primary goal in immunotherapeutic anticancer strategies. Effective immune responses to cancer cells certainly require the activation of specific cytotoxic T cell repertoires by cross-priming of dendritic cells either via immunoproteasomal or by endosomal processing of ectodomain epitopes on MUC1-positive carcinomas. Because no evidence is currently available on the capacities of human immunoproteasomes to cleave mucin-type O-glycosylated peptides, we performed in vitro studies to address the questions of whether glycosylated MUC1 repeats are cleaved by immunoproteasomes and in which way O-linked glycans control the site specificity of peptide cleavage via their localization and structures. We show for the first time that mucin-type O-glycosylated peptides are effective substrates of immunoproteasomes, however, the patterns of cleavage are qualitatively and quantitatively influenced by O-glycosylation. The nonglycosylated MUC1 repeat peptide (clusters of oligorepeats AHGVTSAPDTRPAPGSTAPP or AHGVTSAPESRPAPGSTAPA) is cleaved preferentially within or adjacent to the SAP and GST motifs with formation of a complex fragment pattern that includes major nona- and decapeptides. O-GalNAc modified peptides are largely resistant to proteolysis if these preferred cleavage sites are located adjacent to O-glycosylation, whereas peptides even with elongated glycans at more distant sites can form effective substrates yielding major glycopeptide fragments in the class I size range.
IL-10 Is Excluded from the Functional Cytokine Memory of Human CD4+ Memory T Lymphocytes
Authors: Dong Jun , Ivascu Claudia , Chang Hyun-Dong , Wu Peihua , Angeli Roberta , Maggi Laura , Eckhardt Florian , Tykocinski Lars , Haefliger Carolina , Möwes Beate , Sieper Jochen , Radbruch Andreas , Annunziato Francesco , Thiel Andreas 
Published: April 2014

AbstractEpigenetic modifications, including DNA methylation, profoundly influence gene expression of CD4+ Th-specific cells thereby shaping memory Th cell function. We demonstrate here a correlation between a lacking fixed potential of human memory Th cells to re-express the immunoregulatory cytokine gene IL10 and its DNA methylation status. Memory Th cells secreting IL-10 or IFN-γ were directly isolated ex vivo from peripheral blood of healthy volunteers, and the DNA methylation status of IL10 and IFNG was assessed. Limited difference in methylation was found for the IL10 gene locus in IL-10-secreting Th cells, as compared with Th cells not secreting IL-10 isolated directly ex vivo or from in vitro-established human Th1 and Th2 clones. In contrast, in IFN-γ+ memory Th cells the promoter of the IFNG gene was hypomethylated, as compared with IFN-γ-nonsecreting memory Th cells. In accordance with the lack of epigenetic memory, almost 90% of ex vivo-isolated IL-10-secreting Th cells lacked a functional memory for IL-10 re-expression after restimulation. Our data indicate that IL10 does not become epigenetically marked in human memory Th cells unlike effector cytokine genes such as IFNG. The exclusion of IL-10, but not effector cytokines, from the functional memory of human CD4+ T lymphocytes ex vivo may reflect the need for appropriate regulation of IL-10 secretion, due to its potent immunoregulatory potential.
Human Anti-CXCR4 Antibodies Undergo VH Replacement, Exhibit Functional V-Region Sulfation, and Define CXCR4 Antigenic Heterogeneity
Authors: Xu Chen , Sui Jianhua , Tao Hong , Zhu Quan , Marasco Wayne A. 
Published: April 2014

Abstract
The chemokine receptor CXCR4 and its ligand stromal-derived factor-1 (SDF-1/CXCL12) are essential for many biological processes and various pathological conditions. However, the relationship between CXCR4 antigenic structure and SDF-1-mediated biological responses is poorly understood. In this report, a panel of human anti-CXCR4 Abs were isolated and used to explore CXCR4 antigenic heterogeneity and function. Multiple fixed CXCR4 antigenic isoforms were detected on the surface of hemopoietic cells. Epitope mapping studies demonstrated the complex nature of the surface-exposed CXCR4 epitopes. Ab-mediated inhibition of chemotaxis correlated strongly with binding affinity, epitope recognition, as well as the level of CXCR4 isoform expression. In addition, detailed genetic analyses of these Abs showed evidence of VH replacement. Importantly, structural and biochemical studies demonstrated tyrosine sulfation in novel regions of the V genes that contributed bidirectionally to the binding activity of the Abs. These data provide the first evidence that functional tyrosine sulfation occurs in self-reactive Abs and suggest a potential new mechanism that may contribute to the pathogenesis of Ab-mediated autoimmune disease. These Abs also provide valuable tools to explore the selective in vivo targeting of CXCR4 isoforms that may be preferentially expressed in certain disease states and involved in steady-state CXCR4-SDF-1 homeostasis.
Sequence and Characterization of the Ig Heavy Chain Constant and Partial Variable Region of the Mouse Strain 129S1
Authors: Retter Ida , Chevillard Christophe , Scharfe Maren , Conrad Ansgar , Hafner Martin , Im Tschong-Hun , Ludewig Monika , Nordsiek Gabriele , Severitt Simone , Thies Stephanie , Mauhar America , Blöcker Helmut , Müller Werner , Riblet Roy 
Published: April 2014

Abstract
Although the entire mouse genome has been sequenced, there remain challenges concerning the elucidation of particular complex and polymorphic genomic loci. In the murine Igh locus, different haplotypes exist in different inbred mouse strains. For example, the Ighb haplotype sequence of the Mouse Genome Project strain C57BL/6 differs considerably from the Igha haplotype of BALB/c, which has been widely used in the analyses of Ab responses. We have sequenced and annotated the 3′ half of the Igha locus of 129S1/SvImJ, covering the CH region and approximately half of the VH region. This sequence comprises 128 VH genes, of which 49 are judged to be functional. The comparison of the Igha sequence with the homologous Ighb region from C57BL/6 revealed two major expansions in the germline repertoire of Igha. In addition, we found smaller haplotype-specific differences like the duplication of five VH genes in the Igha locus. We generated a VH allele table by comparing the individual VH genes of both haplotypes. Surprisingly, the number and position of DH genes in the 129S1 strain differs not only from the sequence of C57BL/6 but also from the map published for BALB/c. Taken together, the contiguous genomic sequence of the 3′ part of the Igha locus allows a detailed view of the recent evolution of this highly dynamic locus in the mouse.
BXSB/long-livedIs a Recombinant Inbred Strain Containing Powerful Disease Suppressor Loci
Authors: Haywood Michelle E. K. , Gabriel Luisa , Rose S. Jane , Rogers Nicola J. , Izui Shozo , Morley Bernard J. 
Published: April 2014

AbstractThe BXSB strain of recombinant inbred mice develops a spontaneous pathology that closely resembles the human disease systemic lupus erythematosus. Six non-MHC loci, Yaa, Bxs1–4, and Bxs6, have been linked to the development of aspects of the disease while a further locus, Bxs5, may be a BXSB-derived disease suppressor. Disease development is delayed in a substrain of BXSB, BXSB/MpJScr-long-lived (BXSB/ll). We compared the genetic derivation of BXSB/ll mice to the original strain, BXSB/MpJ, using microsatellite markers and single nucleotide polymorphisms across the genome. These differences were clustered and included two regions known to be important in the disease-susceptibility of these mice, Bxs5 and 6, as well as regions on chromosomes 5, 6, 9, 11, 12, and 13. We compared BXSB/ll to &gt;20 strains including the BXSB parental SB/Le and C57BL/6 strains. This revealed that BXSB/ll is a separate recombinant inbred line derived from SB/Le and C57BL/6, but distinctly different from BXSB, that most likely arose due to residual heterozygosity in the BXSB stock. Despite the continued presence of the powerful disease-susceptibility locus Bxs3, BXSB/ll mice do not develop disease. We propose that the disappearance of the disease phenotype in the BXSB/ll mice is due to the inheritance of one or more suppressor loci in the differentially inherited intervals between the BXSB/ll and BXSB strains.
Filarial Parasites Induce NK Cell Activation, Type 1 and Type 2 Cytokine Secretion, and Subsequent Apoptotic Cell Death
Authors: Babu Subash , Blauvelt Carla P. , Nutman Thomas B. 
Published: April 2014

Abstract
NK cells are an important source of early cytokine production in a variety of intracellular viral, bacterial, and protozoan infections; however, the role of NK cells in extracellular parasitic infections such as filarial infections is not well-defined. To investigate the role of NK cells in filarial infections, we have used an in vitro model system of culturing live infective-stage larvae (L3) or live microfilariae (Mf) of Brugia malayi, a causative agent of human lymphatic filariasis, with PBMC of normal individuals. We found that NK cells undergo early cell activation and produce IFN-γ and TNF-α within 24 h after stimulation with both live L3 and Mf. Interestingly, NK cells also express IL-4 and IL-5 at this time point in response to live Mf but not L3. This is accompanied by significant alterations in NK cell expression of costimulatory molecules and natural cytotoxicity receptors. This activation is dependent on the presence of monocytes in the culture, IL-12, and direct contact with live parasites. The early activation event is subsequently followed by apoptosis of NK cells involving a caspase-dependent mechanism in response to live L3 but not live Mf. Thus, the NK cell-parasite interaction is complex, with filarial parasites inducing NK cell activation and cytokine secretion and finally NK cell apoptosis, which may provide an additional mechanism of down-regulating the host immune response.
A Role for IFN-γ from Antigen-Specific CD8+ T Cells in Protective Immunity toListeria monocytogenes
Authors: Messingham Kelly A. N. , Badovinac Vladimir P. , Jabbari Ali , Harty John T. 
Published: April 2014

AbstractWhether IFN-γ contributes to the per-cell protective capacity of memory CD8+ T cells against Listeria monocytogenes (LM) has not been formally tested. In this study, we generated LM Ag-specific memory CD8+ T cells via immunization of wild-type (WT) and IFN-γ-deficient (gamma knockout (GKO)) mice with LM peptide-coated dendritic cells and compared them phenotypically and functionally. Immunization of WT and GKO mice resulted in memory CD8+ T cells that were similar in number, functional avidity, TCR repertoire use, and memory phenotype. The protective capacity of memory CD8+ T cells from immunized WT and GKO mice was evaluated after adoptive transfer of equal numbers of WT or GKO cells into naive BALB/c mice followed by LM challenge. The adoptively transferred CD8+ T cells from GKO donors exhibited a decreased ability to reduce bacterial numbers in the organs of recipient mice when compared with an equivalent number of Ag-matched WT CD8+ T cells. This deficiency was most evident early (day 3) after infection if a relatively low infectious dose was used; however, transferring fewer memory CD8+ T cells or increasing the LM challenge dose revealed a more pronounced defect in protective immunity mediated by the CD8+ T cells from GKO mice. Our studies identified a decrease in Ag-specific target cell lysis in vivo by CD8+ T cells from GKO mice as the mechanism for the decreased protective immunity after LM challenge. Further studies suggest that the lack of IFN-γ production by the Ag-specific CD8 T cells themselves diminishes target cell sensitivity to cytolysis, thereby reducing the lytic potency of IFN-γ-deficient LM-specific memory CD8+ T cells.
Icsbp1/IRF-8 Is Required for Innate and Adaptive Immune Responses against Intracellular Pathogens
Authors: Turcotte Karine , Gauthier Susan , Malo Danielle , Tam Mifong , Stevenson Mary M. , Gros Philippe 
Published: April 2014

AbstractThe chronic myeloid leukemia syndrome of the BXH-2 mouse strain (Mus musculus) is caused by a recessive mutation (R294C) in the transcriptional regulator Icsbp1/IRF-8. In trans activation assays using an IL-12p40 gene reporter construct introduced in RAW 264.7 mouse macrophages, we show that the Icsbp1C294 isoform behaves as a partial loss-of-function. The Icsbp1C294 hypomorph allele appears to have a threshold effect on IL-12 production, with pleiotropic consequences on resistance to different types of infections in vivo. Despite the presence of a resistance Nramp1G169 allele, BXH-2 mice (Icsbp1C294) show impaired control of Mycobacterium bovis (bacille Calmette-Guérin) multiplication both early and late during infection, with uncontrolled replication linked to inability to form granulomas in infected liver and spleen. Studies in informative (BXH-2 × BALB/cJ)F2 mice show that homozygosity for Icsbp1C294 causes susceptibility to Salmonella enterica serovar Typhimurium to a level comparable to that seen for mice lacking functional Nramp1 or TLR4. Finally, impaired Icsbp1C294 function is associated with the following: 1) increased replication of the Plasmodium chabaudi AS malarial parasite during the first burst of blood parasitemia, and 2) recurring waves of high blood parasitemia late during infection. These results show that Icsbp1 is required for orchestrating early innate responses and also long-term immune protection against unrelated intracellular pathogens.