bluuebunny/crossref_metadata_2025_split huggingface dataset:
Butyrophilin, a Milk Protein, Modulates the Encephalitogenic T Cell Response to Myelin Oligodendrocyte Glycoprotein in Experimental Autoimmune Encephalomyelitis
Authors: Stefferl Andreas , Schubart Anna , Storch Maria , Amini Aminullah , Mather Ian , Lassmann Hans , Linington Christopher 
Published: April 2014

AbstractExperimental autoimmune encephalomyelitis (EAE) induced by sensitization with myelin oligodendrocyte glycoprotein (MOG) is a T cell-dependent autoimmune disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis. We report that an encephalitogenic T cell response to MOG can be either induced or alternatively suppressed as a consequence of immunological cross-reactivity, or “molecular mimicry” with the extracellular IgV-like domain of the milk protein butyrophilin (BTN). In the Dark Agouti rat, active immunization with native BTN triggers an inflammatory response in the CNS characterized by the formation of scattered meningeal and perivascular infiltrates of T cells and macrophages. We demonstrate that this pathology is mediated by a MHC class II-restricted T cell response that cross-reacts with the MOG peptide sequence 76–87, IGEGKVALRIQN (identities underlined). Conversely, molecular mimicry with BTN can be exploited to suppress disease activity in MOG-induced EAE. We demonstrate that not only is EAE mediated by the adoptive transfer of MOG74–90 T cell lines markedly ameliorated by i.v. treatment with the homologous BTN peptide, BTN74–90, but that this protective effect is also seen in actively induced disease following transmucosal (intranasal) administration of the peptide. These results identify a mechanism by which the consumption of milk products may modulate the pathogenic autoimmune response to MOG.
A Genetic Model of Stress Displays Decreased Lymphocytes and Impaired Antibody Responses Without Altered Susceptibility toStreptococcus pneumoniae
Authors: Murray Susan E. , Lallman Holly R. , Heard Amanda D. , Rittenberg Marvin B. , Stenzel-Poore Mary P. 
Published: April 2014

AbstractStress pathways affect immune function, the most notable of these pathways being activation of the hypothalamic-pituitary-adrenal (HPA) axis. Although HPA activation has generally been relegated to an immunosuppressive role, recent evidence suggests that stress and HPA activation can be immunoenhancing in certain situations. To investigate specific effects of stress on immune function, we used a genetic model of chronic stress wherein transgenic mice overexpress corticotropin-releasing hormone (CRH), a primary mediator of the stress response. In these mice, CRH is overproduced in the brain, leading to chronic activation of the HPA axis. We found that CRH-transgenic mice have decreased leukocyte numbers in lymphoid compartments, with preferential loss of B lymphocytes. They also exhibit decreased Ab production and impaired isotype switching in response to immunization with a thymus-dependent Ag, phosphocholine-keyhole limpet hemocyanin. Despite these deficits, immunization protected CRH-transgenic and wild-type mice equally well against lethal challenge with Streptococcus pneumoniae, an encapsulated Gram-positive bacterium known to require Ab-mediated opsonization for clearance. While IgG responses are severely depressed in these mice, IgM titers are only modestly decreased. This fairly robust IgM response may be sufficient to protect against S. pneumoniae. Additionally, while total leukocyte numbers are decreased in these mice, neutrophil numbers are increased. This increase in number of neutrophils may compensate for the depressed IgG response, allowing adequate host defense during chronic stress.
Competitive Inhibition In Vivo and Skewing of the T Cell Repertoire of Antigen-Specific CTL Priming by an Anti-Peptide-MHC Monoclonal Antibody
Authors: Chung Doo Hyun , Belyakov Igor M. , Derby Michael A. , Wang Jian , Boyd Lisa F. , Berzofsky Jay A. , Margulies David H. 
Published: April 2014

AbstractWe have recently described a mAb, KP15, directed against the MHC-I/peptide molecular complex consisting of H-2Dd and a decamer peptide corresponding to residues 311–320 of the HIV IIIB envelope glycoprotein gp160. When administered at the time of primary immunization with a vaccinia virus vector encoding gp160, the mAb blocks the subsequent appearance of CD8+ CTL with specificity for the immunodominant Ag, P18-I10, presented by H-2Dd. This inhibition is specific for this particular peptide Ag; another H-2Dd-restricted gp160 encoded epitope from a different HIV strain is not affected, and an H-2Ld-restricted epitope encoded by the viral vector is also not affected. Using functional assays and specific immunofluorescent staining with multivalent, labeled H-2Dd/P18-I10 complexes (tetramers), we have enumerated the effects of blocking of priming on the subsequent appearance, avidity, and TCR Vβ usage of Ag-specific CTL. Ab blocking skews the proportion of high avidity cells emerging from immunization. Surprisingly, Vβ7-bearing Ag-specific TCR are predominantly inhibited, while TCR of several other families studied are not affected. The ability of a specific MHC/peptide mAb to inhibit and divert the CD8+ T cell response holds implications for vaccine design and approaches to modulate the immune response in autoimmunity.
Identification of New Epitopes from Four Different Tumor-Associated Antigens: Recognition of Naturally Processed Epitopes Correlates with HLA-A∗0201-Binding Affinity
Authors: Keogh Elissa , Fikes John , Southwood Scott , Celis Esteban , Chesnut Robert , Sette Alessandro 
Published: April 2014

AbstractForty-two wild-type and analogue peptides derived from p53, carcinoembryonic Ag, Her2/neu, and MAGE2/3 were screened for their capacity to induce CTLs, in vitro, capable of recognizing tumor target lines. All the peptides bound HLA-A*0201 and two or more additional A2 supertype alleles with an IC50 of 500 nM or less. A total of 20 of 22 wild-type and 9 of 12 single amino acid substitution analogues were found to be immunogenic in primary in vitro CTL induction assays, using normal PBMCs and GM-CSF/IL-4-induced dendritic cells. These results suggest that peripheral T cell tolerance does not prevent, in this system, induction of CTL responses against tumor-associated Ag peptides, and confirm that an HLA class I affinity of 500 nM or less is associated with CTL epitope immunogenicity. CTLs generated by 13 of 20 of the wild-type epitopes, 6 of 9 of the single, and 2 of 5 of the double substitution analogues tested recognized epitopes generated by endogenous processing of tumor-associated Ags and expressed by HLA-matched cancer cell lines. Further analysis revealed that recognition of naturally processed Ag was correlated with high HLA-A2.1-binding affinity (IC50 = 200 nM or less; p = 0.008), suggesting that high binding affinity epitopes are frequently generated and can be recognized as a result of natural Ag processing. These results have implications for the development of cancer vaccines, in particular, and for the process of epitope selection in general.
CD28 Signaling Augments Elk-1-Dependent Transcription at the c-fosGene During Antigen Stimulation
Authors: Li Wei , Whaley Carmella D. , Bonnevier Jody L. , Mondino Anna , Martin Molly E. , Aagaard-Tillery Kjersti M. , Mueller Daniel L. 
Published: April 2014

AbstractUntransformed CD4+ Th1 cells stimulated with Ag and APC demonstrated a dependence on B7- and CD28-mediated costimulatory signals for the expression and function of AP-1 proteins. The induction of transactivation by the c-fos gene regulator Elk-1 mirrored this requirement for TCR and CD28 signal integration. c-Jun N-terminal kinase (JNK) (but not extracellular signal-regulated kinase or p38) protein kinase activity was similarly inhibited by neutralizing anti-B7 mAbs. Blockade of JNK protein kinase activity with SB 202190 prevented both Elk-1 transactivation and c-Fos induction. These results identify a unique role for B7 costimulatory molecules and CD28 in the activation of JNK during Ag stimulation in Th1 cells, and suggest that JNK regulates Elk-1 transactivation at the c-fos gene to promote the formation of AP-1 complexes important to IL-2 gene expression.
Functional Evidence That Conserved TCR CDRα3 Loop Docking Governs the Cross-Recognition of Closely Related Peptide:Class I Complexes
Authors: Messaoudi Ilhem , LeMaoult Joel , Metzner Beatrix M. , Miley Michael J. , Fremont Daved H. , Nikolich-Žugich Janko 
Published: April 2014

AbstractThe TCR recognizes its peptide:MHC (pMHC) ligand by assuming a diagonal orientation relative to the MHC helices, but it is unclear whether and to what degree individual TCRs exhibit docking variations when contacting similar pMHC complexes. We analyzed monospecific and cross-reactive recognition by diverse TCRs of an immunodominant HVH-1 glycoprotein B epitope (HSV-8p) bound to two closely related MHC class I molecules, H-2Kb and H-2Kbm8. Previous studies indicated that the pMHC portion likely to vary in conformation between the two complexes resided at the N-terminal part of the complex, adjacent to peptide residues 2–4 and the neighboring MHC side chains. We found that CTL clones sharing TCR β-chains exhibited disparate recognition patterns, whereas those with drastically different TCRβ-chains but sharing identical TCRα CDR3 loops displayed identical functional specificity. This suggested that the CDRα3 loop determines the TCR specificity in our model, the conclusion supported by modeling of the TCR over the actual HSV-8:Kb crystal structure. Importantly, these results indicate a remarkable conservation in CDRα3 positioning, and, therefore, in docking of diverse TCRαβ heterodimers onto variant peptide:class I complexes, implying a high degree of determinism in thymic selection and T cell activation.
Glucocorticoid Augmentation of Macrophage Capacity for Phagocytosis of Apoptotic Cells Is Associated with Reduced p130Cas Expression, Loss of Paxillin/pyk2 Phosphorylation, and High Levels of Active Rac
Authors: Giles Katherine M. , Ross Katherine , Rossi Adriano G. , Hotchin Neil A. , Haslett Christopher , Dransfield Ian 
Published: April 2014

AbstractPhagocytic clearance of apoptotic granulocytes has a pivotal role in determining an inflammatory outcome, resolution or progression to a chronic state associated with development of fibrotic repair mechanisms, and/or autoimmune responses. In this study, we describe reprogramming of monocyte to macrophage differentiation by glucocorticoids, resulting in a marked augmentation of their capacity for phagocytosis of apoptotic neutrophils. This monocyte/macrophage phenotype was characterized by decreased phosphorylation, and therefore recruitment of paxillin and pyk2 to focal contacts and a down-regulation of p130Cas, a key adaptor molecule in integrin adhesion signaling. Glucocorticoid-treated cells also displayed higher levels of active Rac and cytoskeletal activity, which were mirrored by increases in phagocytic capability for apoptotic neutrophils. We propose that changes in the capacity for reorganization of cytoskeletal elements induced by glucocorticoids are essential for efficient phagocytic uptake of apoptotic cells.
Recombinant Adenovirus Coexpressing Covalent Peptide/MHC Class II Complex and B7-1: In Vitro and In Vivo Activation of Myelin Basic Protein-Specific T Cells
Authors: Chen Jiang , Huber Brigitte T. , Grand Richard J. , Li Wei 
Published: April 2014

AbstractPrevious studies have demonstrated that an MHC class II molecule with an antigenic peptide genetically fused to its β-chain is capable of presenting this peptide to CD4+ T cells. We hypothesized that covalent peptide/class II complex may direct the accessory molecules to exert their function specifically onto T cells in a TCR-guided fashion. To test this hypothesis, we generated several recombinant adenoviruses expressing covalent myelin basic protein peptide/I-Au complex (MBP1–11/I-Au) and the costimulatory molecule B7-1. Functional studies demonstrated that adenovirus-infected cells are capable of activating an MBP1–11-specific T cell hybridoma. Coexpression of the B7-1 molecule and MBP1–11/I-Au by the same adenovirus leads to synergy in T cell activation elicited by virus-infected cells. Furthermore, studies in syngeneic mice infected with the various adenoviruses revealed that MBP1–11-specific T cells are specifically activated by the coexpression of B7-1 and MBP1–11/I-Au in vivo. In conclusion, the coexpression of the covalent peptide/class II complex and accessory molecules by the same adenovirus provides a unique strategy to modulate the epitope-specific T cell response in a TCR-guided fashion. This approach may be applicable to investigate the roles of other accessory molecules in the engagement of the TCR class II molecule by substituting B7-1 with other accessory molecules in the recombinant adenovirus.
Enhanced Proliferation and Increased IFN-γ Production in T Cells by Signal Transduced Through TNF-Related Apoptosis-Inducing Ligand
Authors: Chou Ai-Hsiang , Tsai Hwei-Fang , Lin Ling-Li , Hsieh Shie-Liang , Hsu Ping-I , Hsu Ping-Ning 
Published: April 2014

AbstractTNF-related apoptosis-inducing ligand (TRAIL, also called Apo2L), a novel member of TNF superfamily, induces apoptosis in transformed cell lines of diverse origin. TRAIL is expressed in most of the cells, and the expression is up-regulated in activated T cells. Four receptors for TRAIL have been identified, and there is complex interplay between TRAIL and TRAIL receptors in vivo. The actual biological function of TRAIL/TRAIL receptor is still not clear. Growing evidence has demonstrated that members of TNF superfamily transduce signals after engagement with their receptors. Cross-linking of TRAIL by plate-bound rTRAIL receptor, death receptor 4-Fc fusion protein enhanced T cell proliferation and increased IFN-γ production in conjunction with immobilized suboptimal anti-CD3 stimulation in mouse splenocytes. The increase of T cell proliferation by death receptor 4-Fc was dose dependent, and this effect could be blocked by soluble rTRAIL proteins, indicating the occurrence of reverse signaling through TRAIL on T cell. The enhanced secretion of IFN-γ mediated via TRAIL could be blocked by SB203580, a p38 mitogen-activated protein kinase-specific inhibitor. Thus, in addition to its role in inducing apoptosis by binding to the death receptors, TRAIL itself can enhance T cell proliferation after TCR engagement and signal the augmentation of IFN-γ secretion via a p38-dependent pathway. This provides another example of reverse signaling by a member of TNF superfamily. In conclusion, our data suggest that TRAIL can itself transduce a reverse signal, and this may shed light on the biological function of TRAIL.
Antibody-Independent Antiviral Function of Memory CD4+ T Cells In Vivo Requires Regulatory Signals from CD8+ Effector T Cells
Authors: Zhong Weimin , Roberts Alan D. , Woodland David L. 
Published: April 2014

AbstractPrevious studies have shown that vaccine-primed CD4+ T cells can mediate accelerated clearance of respiratory virus infection. However, the relative contributions of Ab and CD8+ T cells, and the mechanism of viral clearance, are poorly understood. Here we show that control of a Sendai virus infection by primed CD4+ T cells is mediated through the production of IFN-γ and does not depend on Ab. This effect is critically dependent on CD8+ cells for the expansion of CD4+ T cells in the lymph nodes and the recruitment of memory CD4+ T cells to the lungs. Passive transfer of a CD8+ T cell supernatant into CD8+ T cell-depleted, hemagglutinin-neuraminidase (HN)421–436-immune μMT mice substantially restored the virus-specific memory CD4+ response and enhanced viral control in the lung. Together, the data demonstrate for the first time that in vivo primed CD4+ T cells have the capacity to control a respiratory virus infection in the lung by an Ab-independent mechanism, provided that CD8+ T cell “help” in the form of soluble factor(s) is available during the virus infection. These studies highlight the importance of synergistic interactions between CD4+ and CD8+ T cell subsets in the generation of optimal antiviral immunity.
Virally Infected Hepatocytes Are Resistant to Perforin-Dependent CTL Effector Mechanisms
Authors: Kafrouni Michel I. , Brown Geri R. , Thiele Dwain L. 
Published: April 2014

Abstract
Cell-mediated cytotoxicity plays an important role in the clearance of noncytopathic viruses from infected tissues. Perforin-dependent cytotoxic mechanisms have been noted to play an important role in the clearance of infections from multiple extrahepatic organs. In contrast, mice with defects in the Fas/Fas ligand (FasL)-mediated cytotoxicity pathway exhibit delayed clearance of adenovirus from the liver without apparent delay in the clearance of viral infections from extrahepatic organs. The present studies examined the role of cytotoxic effector mechanisms in intrahepatic immune responses to a replication-defective, recombinant β-galactosidase-encoding adenovirus (AdCMV-lacZ). Delayed clearance of AdCMV-lacZ from the livers of FasL-defective B6.gld mice, but not perforin-deficient B6.pfp−/− mice, was noted despite no significant differences in initial hepatic CD8+ T cell IFN-γ or TNF responses or in activation of intrahepatic cytotoxic lymphocytes cells capable of killing AdCMV-lacZ-infected fibroblast targets. In contrast, AdCMV-lacZ-infected hepatocyte targets were far more sensitive to killing by intrahepatic cytotoxic lymphocytes from B6.pfp−/− than from B6.gld mice, and residual levels of virus-specific killing of hepatocyte targets by FasL-defective B6.gld CTL were blocked by TNF inhibition. These results suggest that inherent resistance of hepatocytes to cytotoxicity mediated by perforin-dependent mechanisms leaves Fas/FasL-dependent, cell-mediated cytotoxicity as the major pathway for CTL-mediated killing of virally infected hepatocytes and accounts for the more prominent role of perforin-independent anti-viral mechanisms in immune responses in the liver.
Autoantigen Glycoprotein 70 Expression Is Regulated by a Single Locus, Which Acts as a Checkpoint for Pathogenic Anti-Glycoprotein 70 Autoantibody Production and Hence for the Corresponding Development of Severe Nephritis, in Lupus-Prone BXSB Mice1
Authors: Haywood Michelle E. K. , Vyse Timothy J. , McDermott Aileen , Thompson E. Mary , Ida Akinori , Walport Mark J. , Izui Shozo , Morley Bernard J. 
Published: April 2014

AbstractRetroviral envelope glycoprotein gp70 is present in the sera of immunologically normal and autoimmune-prone strains of mice. However, only lupus-prone mice spontaneously develop gp70-anti-gp70 immune complexes (gp70IC), and these have been implicated in the development of nephritis. We investigated the genetic factors that affect the production of both free serum gp70 and gp70IC in the lupus-prone BXSB mouse strain by analyzing (BXSB × (C57BL/10 × BXSB)F1)- and (C57BL/10 × (C57BL/10 × BXSB)F1)-backcrossed male mice. Production of gp70 mapped to a single major locus located on chromosome 13 (Bxs6) with a maximum log likelihood of the odds of 36.7 (p = 1.6 × 10−38). The level of gp70IC was highly dependent on Bxs6-related gp70 production, and high titer autoantibody production only occurred when serum gp70 levels were greater than a threshold value of ∼4.0 μg/ml. The subdivision of the (BXSB × (C57BL/10 × BXSB)F1)-backcrossed mice into those homozygous or heterozygous for Bxs6 enabled a remarkable association to be observed between high levels of gp70IC and severe nephritis in the Bxs6 homozygote population. A further mapping study in these two subgroups identified a previously unrecognized interval associated with the production of autoantibodies.
MHC Class I-Restricted Determinants on the Glutamic Acid Decarboxylase 65 Molecule Induce Spontaneous CTL Activity
Authors: Quinn Anthony , McInerney Marcia F. , Sercarz Eli E. 
Published: April 2014

Abstract
CD4+ T cell responses to glutamic acid decarboxylase (GAD65) spontaneously arise in nonobese diabetic (NOD) mice before the onset of insulin-dependent diabetes mellitus (IDDM) and may be critical to the pathogenic process. However, since both CD4+ and CD8+ T cells are involved in autoimmune diabetes, we sought to determine whether GAD65-specific CD8+ T cells were also present in prediabetic NOD mice and contribute to IDDM. To refine the analysis, putative Kd-binding determinants that were proximal to previously described dominant Th determinants (206–220 and 524–543) were examined for their ability to elicit cytolytic activity in young NOD mice. Naive NOD spleen cells stimulated with GAD65 peptides 206–214 (p206) and 546–554 (p546) produced IFN-γ and showed Ag-specific CTL responses against targets pulsed with homologous peptide. Conversely, several GAD peptides distal to the Th determinants, and control Kd-binding peptides did not induce similar responses. Spontaneous CTL responses to p206 and p546 were mediated by CD8+ T cells that are capable of lysing GAD65-expressing target cells, and p546-specific T cells transferred insulitis to NOD.scid mice. Young NOD mice pretreated with p206 and p546 showed reduced CTL responses to homologous peptides and a delay in the onset of IDDM. Thus, MHC class I-restricted responses to GAD65 may provide an inflammatory focus for the generation of islet-specific pathogenesis and β cell destruction. This report reveals a potential therapeutic role for MHC class I-restricted peptides in treating autoimmune disease and revisits the notion that the CD4- and CD8-inducing determinants on some molecules may benefit from a proximal relationship.
Dendritic Cells (DCs) in Rheumatoid Arthritis (RA): Progenitor Cells and Soluble Factors Contained in RA Synovial Fluid Yield a Subset of Myeloid DCs That Preferentially Activate Th1 Inflammatory-Type Responses
Authors: Santiago-Schwarz Frances , Anand Prachi , Liu Sean , Carsons Steven E. 
Published: April 2014

AbstractThere is evidence that mature dendritic cells (DCs) present in the rheumatoid arthritis (RA) joint mediate immunopathology in RA. In this study, we indicate that early myeloid progenitors for DCs and DC growth factors existing in RA synovial fluid (SF) are also likely participants in the RA disease process. A fraction of cells lacking markers associated with mature DCs or DC precursors and enriched in CD34negative myeloid progenitors was isolated from RA SF. These cells proliferated extensively when cultured in vitro with cytokines that promote the growth of myeloid DCs (GM-CSF/TNF/stem cell factor/IL-4) and, to a lesser degree, when cultured with monocyte/granulocyte-restricted growth factors (M-CSF/GM-CSF). Mature DCs derived from RA SF progenitors with CD14-DC cytokines known to be prevalent in the inflamed RA joint (GM-CSF/TNF/stem cell factor/IL-13) were potent stimulators of allogeneic T cells and inflammatory-type Th1 responses and included CD14-DC subtypes. Cell-free RA SF facilitated DC maturation from myeloid progenitors, providing direct evidence that the inflamed RA joint environment instructs DC growth. Enhanced development of CD14-derived DCs was correlated with the presence of soluble TNFR (p55), raising the possibility that soluble TNFR also regulate CD14-derived DC growth in vivo. SF from patients with osteoarthritis contained neither myeloid DC progenitors nor DC growth factors. The existence of DC progenitors and myeloid DC growth factors in RA SF supports the concept that RA SF may be a reservoir for joint-associated DCs and reveals a compelling mechanism for the amplification and perpetuation of DC-driven responses in the RA joint, including inflammatory-type Th1 responses.