bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Important Role of CD80/CD86-CTLA-4 Signaling during Photocarcinogenesis in Mice
Authors: Loser Karin , Scherer Andrea , Krummen Mathias B. W. , Varga Georg , Higuchi Tetsuya , Schwarz Thomas , Sharpe Arlene H. , Grabbe Stephan , Bluestone Jeffrey A. , Beissert Stefan 
Published: April 2014

Abstract
Although previous studies have shown that altered B7 costimulation plays a critical role in UV irradiation-induced regulation of immunity, the individual roles of the B7 receptors (CD28 and CTLA-4) or the B7 family members (CD80 and CD86) have not been explored. Thus, we investigated CTLA-4 signaling during photocarcinogenesis of chronically UV-B-exposed mice using an antagonistic anti-CTLA-4 Ab. Anti-CTLA-4-treated mice developed significantly fewer UV-induced tumors. Moreover, anti-CTLA-4 treatment induced long-lasting protective immunity because progressively growing UV tumors inoculated into anti-CTLA-4- and UV-treated mice that had not developed tumors were rejected. Next, we used mice deficient for CD80, CD86, or both in photocarcinogenesis studies to assess the relative contributions of these CTLA-4 ligands. Double-deficient mice showed significantly reduced UV-induced skin tumor development, whereas CD86−/− mice produced skin cancer earlier compared with CD80−/− and control mice. The growth of UV-induced tumors appears to be controlled by UV-induced suppressor T cells, because CD80−/−/CD86−/− mice had strongly reduced numbers of UV-induced CD4+CD25+ suppressor T cells. In vitro, CTLA-4 blockade inhibited the suppressor activity of UV-induced CD4+CD25+ T cells, suggesting that reduced photocarcinogenesis might be due to decreased numbers or function of suppressor T cells. Together, these data indicate that blocking CD80/86-CTLA-4 signaling induced immune protection against the development of UV-induced skin tumors. Furthermore, CD86-mediated costimulation appears to play a more critical role in the protection against photocarcinogenesis than CD80.
Identification of CD4+ T Cell-Specific Epitopes of Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein: A Novel β Cell Autoantigen in Type 1 Diabetes
Authors: Mukherjee Rinee , Wagar Danielle , Stephens Tracey A. , Lee-Chan Edwin , Singh Bhagirath 
Published: April 2014

Abstract
Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) has been identified as a novel CD8+ T cell-specific autoantigen in NOD mice. This study was undertaken to identify MHC class II-specific CD4+ T cell epitopes of IGRP. Peptides named P1, P2, P3, P4, P5, P6, and P7 were synthesized by aligning the IGRP protein amino acid sequence with peptide-binding motifs of the NOD MHC class II (I-Ag7) molecule. Peptides P1, P2, P3, and P7 were immunogenic and induced both spontaneous and primed responses. IGRP peptides P1-, P2-, P3-, and P7-induced responses were inhibited by the addition of anti-MHC class II (I-Ag7) Ab, confirming that the response is indeed I-Ag7 restricted. Experiments using purified CD4+ and CD8+ T cells from IGRP peptide-primed mice also showed a predominant CD4+ T cell response with no significant activation of CD8+ T cells. T cells from P1-, P3-, and P7-primed mice secreted both IFN-γ and IL-10 cytokines, whereas P2-primed cells secreted only IFN-γ. Peptides P3 and P7 prevented the development of spontaneous diabetes and delayed adoptive transfer of diabetes. Peptides P1 and P2 delayed the onset of diabetes in both these models. In summary, we have identified two I-Ag7-restricted CD4+ T cell epitopes of IGRP that can modulate and prevent the development of diabetes in NOD mice. These results provide the first evidence on the role of IGRP-specific, MHC class II-restricted CD4+ T cells in disease protection and may help in the development of novel therapies for type 1 diabetes.
Frequency, Specificity, and Sites of Expansion of CD8+ T Cells during Primary Pulmonary Influenza Virus Infection
Authors: Lawrence Christopher W. , Ream Rebecca M. , Braciale Thomas J. 
Published: April 2014

AbstractWe have used intracellular cytokine staining and MHC class I tetramer binding in conjunction with granzyme B protease expression and in vivo BrdU uptake to characterize the primary murine CD8+ T cell response to pulmonary influenza virus infection. We have observed that the majority (&gt;90%) of the CD8+ T cell response to the A/Japan/305/57 virus in the lung at the peak of the response (days 9–11) is directed to four epitopes (three dominant and one subdominant). Using induction of granzyme B as a surrogate to identify specific activated CD8+ T cells, we found that an unexpectedly large fraction (∼70%) of lung-infiltrating CD8+ T cells expressed granzyme B on day 6 of infection when estimates by MHC tetramer/intracellular cytokine staining yielded substantially lower frequencies (∼30%). In addition, by using intranasal administration of BrdU during infection, we obtained evidence for proliferative expansion of activated CD8+ T cells in the infected lung early (days 5–7) in the primary response. These results suggest that the frequency and number of specific CTL present in the lung early in infection may be underestimated by standard detection methods, and primary CD8+ T cell expansion may occur in both secondary lymphoid organs and the infected lung.
Protective Immunity against Disparate Tumors Is Mediated by a Nonpolymorphic MHC Class I Molecule
Authors: Chiang Eugene Y. , Stroynowski Iwona 
Published: April 2014

Abstract
Current peptide-based immunotherapies for treatment of model cancers target tumor Ags bound by the classical MHC class I (class Ia) molecules. The extensive polymorphism of class Ia loci greatly limits the effectiveness of these approaches. We demonstrate in this study that the murine nonpolymorphic, nonclassical MHC class I (class Ib) molecule Q9 (Qa-2) promotes potent immune responses against multiple syngeneic tumors. We have previously shown that ectopic expression of Q9 on the surface of class Ia-negative B78H1 melanoma led to efficient CTL-mediated rejection of this tumor. In this study, we report that surface-expressed Q9 on 3LLA9F1 Lewis lung carcinoma and RMA T cell lymphoma also induces potent antitumor CTL responses. Importantly, CTL harvested from animals surviving the initial challenge with Q9-positive 3LLA9F1, RMA, or B78H1 tumors recognized and killed their cognate tumors as well as the other cancer lines. Furthermore, immunization with Q9-expressing 3LLA9F1 or RMA tumor cells established immunological memory that enhanced protection against subsequent challenge with a weakly immunogenic, Q9-bearing melanoma variant. Collectively, the generation of cross-reactive CTL capable of eliminating multiple disparate Q9-expressing tumors suggests that this nonpolymorphic MHC class I molecule serves as a restriction element for a shared tumor Ag(s) common to lung carcinoma, T cell lymphoma, and melanoma.
B Cell Receptor (BCR) Cross-Talk: IL-4 Creates an Alternate Pathway for BCR-Induced ERK Activation That Is Phosphatidylinositol 3-Kinase Independent
Authors: Guo Benchang , Rothstein Thomas L. 
Published: April 2014

Abstract
IL-4 has pleiotropic effects on B cells. These effects include alteration of subsequent BCR-triggered responses. To identify a molecular basis for this receptor cross-talk, we examined ERK activation and NF-κB induction. We found that treatment with IL-4, but not other cytokines, affected subsequent BCR signaling by creating a new pathway in which the need for PI3K in ERK activation was eliminated. In contrast, the need for PI3K in NF-κB induction was not altered. The new pathway for ERK required time to develop, depended on STAT6, and was blocked by inhibition of macromolecular synthesis. As in the classical pathway, BCR-induced ERK activation in the new, PI3K-independent pathway required MEK and was reflected in c-Raf. Thus, IL-4 promotes an alternate pathway through which BCR is coupled to Raf/MEK/ERK that may function to heighten the responsiveness of B cells during times of immunological stress.
Corticotropin-Releasing Hormone Contributes to the Peripheral Inflammatory Response in Experimental Autoimmune Encephalomyelitis
Authors: Benou Christina , Wang Yue , Imitola Jaime , VanVlerken Lilian , Chandras Christina , Karalis Katia P. , Khoury Samia J. 
Published: April 2014

Abstract
Peripheral corticotropin-releasing hormone (CRH) is thought to have proinflammatory effects. We used the model of experimental autoimmune encephalomyelitis (EAE) to study the role of CRH in an immune-mediated disease. We showed that CRH-deficient mice are resistant to EAE, with a decrease in clinical score as well as decreased cellular infiltration in the CNS. Furthermore, Ag-specific responses of primed T cells as well as anti-CD3/anti-CD28 TCR costimulation were decreased in crh−/− mice with decreased production of Th1 cytokines and increased production of Th2 cytokines. Wild-type mice treated in vivo with a CRH antagonist showed a decrease in IFN-γ production by primed T cells in vitro. This effect of CRH is independent of its ability to increase corticosterone production, because adrenalectomized wild-type mice had similar disease course and severity as control mice. We found that IκBα phosphorylation induced by TCR cross-linking was decreased in crh−/− T cells. We conclude that peripheral CRH exerts a proinflammatory effect in EAE with a selective increase in Th1-type responses. These findings have implications for the treatment of Th1-mediated diseases such as multiple sclerosis.
Phenotypic Characterization of CD3−7+ Cells in Developing Human Intestine and an Analysis of Their Ability to Differentiate into T Cells
Authors: Gunther Ute , Holloway Judith A. , Gordon John G. , Knight Andrea , Chance Victoria , Hanley Neil A. , Wilson David I. , French Ruth , Spencer Jo , Steer Howard , Anderson Graham , MacDonald Thomas T. 
Published: April 2014

Abstract
We have identified a large population of CD3−7+ cells in human fetal gut. Three- and four-color flow cytometry revealed a distinct surface Ag profile on this population; the majority were negative for CD4 and CD8, whereas most of the remainder expressed the CD8αα homodimer. In contrast about half of CD3+ cells expressed CD4 and half expressed CD8α. A large proportion of CD3−7+ cells expressed CD56, CD94, and CD161, and whereas CD3+ T cells also expressed CD161, they only rarely expressed CD56 or CD94. Further studies were conducted to determine whether the CD3−7+ cells have the potential to differentiate into CD3+ cells. About half of CD3−7+ cells contain intracellular CD3ε. Rearranged TCR γ-chains were detected in highly purified CD3−7+ cells as an early molecular sign of T cell commitment, and the pattern of rearrangement with V regions spliced to the most 5′ Jγ segment is reminiscent of early thymocyte differentiation. In reaggregate thymic organ cultures, CD3−7+ cells also gave rise to CD3+ T cells. Thus, we demonstrate that the CD3−7+ cells present in the human fetal gut display a distinct phenotype and are able to develop into CD3+ T cells.
Modulation of Memory CD4 T Cell Function and Survival Potential by Altering the Strength of the Recall Stimulus
Authors: Patke Deepa S. , Farber Donna L. 
Published: April 2014

Abstract
Optimization of long term immunity depends on the functional persistence of memory T cells; however, there are no defined strategies for promoting memory T cell function and survival. In this study, we hypothesized that varying the strength of the recall stimulus could modulate the function and survival potential of memory CD4 T cells. We tested the ability of peptide variants of influenza hemagglutinin (HA) exhibiting strong and weak avidity for an HA-specific TCR, to modulate HA-specific memory CD4 T cells in vitro and in vivo. In vitro stimulation with a weak avidity peptide (L115) uncoupled memory CD4 T proliferation from effector cytokine production with low apoptosis, whereas stimulation with a strong avidity peptide (Y117) fully recalled memory T cell functions but triggered increased apoptosis. To determine how differential recall would affect memory T cells in vivo, we boosted BALB/c hosts of transferred, CFSE-labeled HA-specific memory CD4 T cells with native HA, Y117, and L115 variant peptides and found differences in early Ag-driven memory T cell proliferation and IL-7R expression, with subsequent changes in memory T cell yield. High avidity boosting resulted in rapid proliferation, extensive IL-7R down-regulation, and the lowest yield of HA-specific memory cells, whereas low avidity boosting triggered low in vivo proliferation, maintenance of IL-7R expression, and the highest memory T cell yield. Our results indicate that memory CD4 T cell function and survival can be modulated at the recall level, and can be optimized by low level stimulation that minimizes apoptosis and enhances responses to survival factors.
Immature Neutrophils Mediate Tumor Cell Killing via IgA but Not IgG Fc Receptors
Authors: Otten Marielle A. , Rudolph Esther , Dechant Michael , Tuk Cornelis W. , Reijmers Rogier M. , Beelen Robert H. J. , van de Winkel Jan G. J. , van Egmond Marjolein 
Published: April 2014

Abstract
Antitumor Abs are promising therapeutics for cancer. Currently, most Ab-based therapies focus on IgG Ab, which interact with IgG FcR (FcγR) on effector cells. In this study, we examined human and mouse neutrophil-mediated tumor cell lysis via targeting the IgA FcR, FcαRI (CD89), in more detail. FcαRI was the most effective FcR in triggering tumor cell killing, and initiated enhanced migration of neutrophils into tumor colonies. Importantly, immature neutrophils that are mobilized from the bone marrow upon G-CSF treatment efficiently triggered tumor cell lysis via FcαRI, but proved incapable of initiating tumor cell killing via FcγR. This may provide a rationale for the disappointing results observed in some earlier clinical trials in which patients were treated with G-CSF and antitumor Ab-targeting FcγR.
Targeted Delivery of the ErbB2/HER2 Tumor Antigen to Professional APCs Results in Effective Antitumor Immunity
Authors: Rohrbach Florian , Weth Robert , Kursar Mischo , Sloots Arjen , Mittrücker Hans-Willi , Wels Winfried S. 
Published: April 2014

Abstract
Activation of T cells by professional APCs that present peptide epitopes of tumor-associated Ags is critical for the induction of cell-mediated immunity against tumors. To facilitate targeted delivery of the ErbB2 (HER2, neu) tumor Ag to APCs in vivo, we have generated chimeric proteins that contain the extracellular domain of CTLA-4 for binding to B7 molecules on the APC surface, which is genetically fused to a human ErbB2 fragment as an antigenic determinant. Bacterially expressed CTLA-4-ErbB2 fusion protein and a similar molecule harboring in addition the translocation domain of Pseudomonas exotoxin A as an endosome escape function displayed specific binding to B7-expressing cells, followed by protein internalization and intracellular degradation. Vaccination of BALB/c mice with the fusion proteins resulted in the induction of ErbB2-specific CD8+ T cells and CTL-dependent protection from subsequent challenge with ErbB2-expressing but not ErbB2-negative murine renal carcinoma cells. In a therapeutic setting, injection of CTLA-4-ErbB2 protein vaccines caused rejection of established ErbB2-expressing tumors. Thereby, immunological memory was induced, leading to long-term systemic immunity and protection against rechallenge several months later. Our results demonstrate that these chimeric protein vaccines are effective tools for the induction of ErbB2-specific, T cell-mediated immunity.
Blocking IL-15 Prevents the Induction of Allergen-Specific T Cells and Allergic Inflammation In Vivo
Authors: Rückert René , Brandt Katja , Braun Armin , Hoymann Heinz-Gerd , Herz Udo , Budagian Vadim , Dürkop Horst , Renz Harald , Bulfone-Paus Silvia 
Published: April 2014

AbstractIL-15 has been shown to accelerate and boost allergic sensitization in mice. Using a murine model of allergic sensitization to OVA, we present evidence that blocking endogenous IL-15 during the sensitization phase using a soluble IL-15Rα (sIL-15Rα) suppresses the induction of Ag-specific, Th2-differentiated T cells. This significantly reduces the production of OVA-specific IgE and IgG and prevents the induction of a pulmonary inflammation. Release of proinflammatory TNF-α, IL-1β, IL-6, and IL-12 as well as that of Th2 cytokines IL-4, IL-5, and IL-13 into the bronchi are significantly reduced, resulting in suppressed recruitment of eosinophils and lymphocytes after allergen challenge. It is of clinical relevance that the airway hyper-responsiveness, a major symptom of human asthma bronchiale, is significantly reduced by sIL-15Rα treatment. Ex vivo analysis of the draining lymph nodes revealed reduced numbers of CD8, but not CD4, memory cells and the inability of T cells of sIL-15Rα-treated mice to proliferate and to produce Th2 cytokines after in vitro OVA restimulation. This phenomenon is not mediated by enhanced numbers of CD4+/CD25+ T cells. These results show that IL-15 is important for the induction of allergen-specific, Th2-differentiated T cells and induction of allergic inflammation in vivo.
Lymphotoxin-β Receptor-Dependent Genes in Lymph Node and Follicular Dendritic Cell Transcriptomes
Authors: Huber Christoph , Thielen Caroline , Seeger Harald , Schwarz Petra , Montrasio Fabio , Wilson Mark R. , Heinen Ernst , Fu Yang-Xin , Miele Gino , Aguzzi Adriano 
Published: April 2014

AbstractAffinity maturation and Ab class switches occur in lymphoid germinal centers (GCs), in which differentiation and maintenance depend on lymphotoxin (LT) signaling and include differentiation of follicular dendritic cells (FDCs). The events leading to FDC and GC maturation are poorly defined. Using several approaches of functional genomics, we enumerated transcripts affected in mice by suppressing LT β receptor (LTβR) signaling and/or overrepresented in FDC-enriched GC isolates. Protein expression analysis of 3 of 12 genes both enriched in FDCs and down-regulated by LTβR signaling suppression validated them as FDC markers. Functional analysis of one of these three, clusterin, suggests a role as an FDC-derived trophic factor for GC B cells. Hence, the set of genes presented in this study includes markers emanating from LTβR signaling and transcripts relevant to GC and FDC function.
Antagonism of Antiviral and Allogeneic Activity of a Human Public CTL Clonotype by a Single Altered Peptide Ligand: Implications for Allograft Rejection
Authors: Ely Lauren K. , Green Katherine J. , Beddoe Travis , Clements Craig S. , Miles John J. , Bottomley Stephen P. , Zernich Danielle , Kjer-Nielsen Lars , Purcell Anthony W. , McCluskey James , Rossjohn Jamie , Burrows Scott R. 
Published: April 2014

Abstract
Alloreactive T lymphocytes are central mediators of graft-versus-host disease and allograft rejection. A public CTL clonotype with specificity for the alloantigens HLA-B*4402 and B*4405 is often expanded to large numbers in healthy HLA-B*0801+ individuals, driven by cross-reactive stimulation with the common, persistent herpesvirus EBV. Since such alloreactive memory CTL expansions have the potential to influence transplantation outcome, altered peptide ligands (APLs) of the target HLA-B*0801-binding EBV peptide, FLRGRAYGL, were screened as specific antagonists for this immunodominant clonotype. One APL, FLRGRFYGL, exerted powerful antagonism of a prototypic T cell clone expressing this immunodominant TCR when costimulated with target cells presenting HLA-B*0801FLRGRAYGL. Significantly, this APL also reduced the lysis of allogeneic target cells expressing HLA-B*4402 by up to 99%. The affinities of the agonist and antagonist complexes for the public TCR, measured using solution and solid-phase assays, were 8 and 138 μM, respectively. Surprisingly, the half-life of the agonist and antagonist complexes was similar, yet the association rate for the antagonist complex was significantly slower. These observations were further supported by structural studies that suggested a large conformational hurdle was required to ligate the immunodominant TCR to the HLA-B*0801 antagonist complex. By defining an antagonist APL against an immunodominant alloreactive TCR, these findings raise the prospect of exploiting such peptides to inhibit clinical alloreactivity, particularly against clonal T cell expansions that react with alloantigens.
Mass Tag-Assisted Identification of Naturally Processed HLA Class II-Presented Meningococcal Peptides Recognized by CD4+ T Lymphocytes
Authors: Meiring Hugo D. , Kuipers Betsy , van Gaans-van den Brink Jacqueline A. M. , Poelen Martien C. M. , Timmermans Hans , Baart Gino , Brugghe Humphrey , van Schie Joost , Boog Claire J. P. , de Jong Ad P. J. M. , van Els Cécile A. C. M. 
Published: April 2014

Abstract
The meningococcal class I outer membrane protein porin A plays an important role in the development of T cell-dependent protective immunity against meningococcal serogroup B infection and is therefore a major component of candidate meningococcal vaccines. T cell epitopes from porin A are poorly characterized because of weak in vitro memory T cell responses against purified Ag and strain variation. We applied a novel strategy to identify relevant naturally processed and MHC class II-presented porin A epitopes, based on stable isotope labeling of Ag. Human immature HLA-DR1-positive dendritic cells were used for optimal uptake and MHC class II processing of 14N- and 15N-labeled isoforms of the neisserial porin A serosubtype P1.5–2,10 in bacterial outer membrane vesicles. HLA-DR1 bound peptides, obtained after 48 h of Ag processing, contained typical spectral doublets in mass spectrometry that could easily be assigned to four porin A regions, expressed at diverging densities (∼30–4000 copies/per cell). Epitopes from two of these regions are recognized by HLA-DR1-restricted CD4+ T cell lines and are conserved among different serosubtypes of meningococcal porin A. This mass tag-assisted approach provides a useful methodology for rapid identification of MHC class II presented bacterial CD4+ T cell epitopes relevant for vaccine development.
Unusually Similar Patterns of Antibody V Segment Diversity in Distantly Related Marsupials
Authors: Baker Michelle L. , Belov Katherine , Miller Robert D. 
Published: April 2014

AbstractA pattern of coevolution between the V gene segments of Ig H and L chains has been noted previously by several investigators. Species with restricted germline VH diversity tend to have limited germline VL diversity, whereas species with high levels of germline VH diversity have more diverse VL gene segments. Evidence for a limited pool of VH but diverse VL gene segments in a South American opossum, Monodelphis domestica, is consistent with this marsupial being an exception to the pattern. To determine whether M. domestica is unique or the norm for marsupials, the VH and VL of an Australian possum, Trichosurus vulpecula, were characterized. The Ig repertoire in T. vulpecula is also derived from a restricted VH pool but a diverse VL pool. The VL gene segments of T. vulpecula are highly complex and contain lineages that predate the separation of marsupials and placental mammals. Thus, neither marsupial follows a pattern of coevolution of VH and VL gene segments observed in other mammals. Rather, marsupial VH and VL complexity appears to be evolving divergently, retaining diversity in VL perhaps to compensate for limited VH diversity. There is a high degree of similarity between the VH and VL in M. domestica and T. vulpecula, with the majority of VL families being shared between both species. All marsupial VH sequences isolated so far form a common clade of closely related sequences, and in contrast to the VL genes, the VH likely underwent a major loss of diversity early in marsupial evolution.