bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen Drives Very Low Affinity B Cells to Become Plasmacytes and Enter Germinal Centers
Authors: Dal Porto Joseph M. , Haberman Ann M. , Shlomchik Mark J. , Kelsoe Garnett 
Published: December 2022

AbstractIn the first week of the primary immune response to the (4-hydroxy-3-nitrophenyl)acetyl (NP) hapten, plasmacytic foci and germinal centers (GCs) in C57BL/6 mice are comprised of polyclonal populations of B lymphocytes bearing the λ1 L-chain (λ1+). The Ig H-chains of these early populations of B cells are encoded by a variety of VH and D exons undiversified by hypermutation while later, oligoclonal populations are dominated by mutated rearrangements of the VH186.2 and DFL16.1 gene segments. To assess directly Ab affinities within these defined splenic microenvironments, representative VDJ rearrangements were recovered from B cells participating in the early immune response to NP, inserted into Ig H-chain expression cassettes, and transfected into J558L (H−; λ1+) myeloma cells. These transfectoma Abs expressed a remarkably wide range of measured affinities (Ka = 5 × 104-1.3 × 106 M−1) for NP. VDJs recovered from both foci and early GCs generated comparable affinities, suggesting that initial differentiation into these compartments occurs stochastically. We conclude that Ag normally activates B cells bearing an unexpectedly wide spectrum of Ab affinities and that this initial, promiscuous clonal activation is followed by affinity-driven competition to determine survival and clonal expansion within GCs and entry into the memory and bone marrow plasmacyte compartments.
Generation of Melanoma-Specific Cytotoxic T Lymphocytes by Dendritic Cells Transduced with a MART-1 Adenovirus
Authors: Butterfield Lisa H. , Jilani Syed M. , Chakraborty Nitya G. , Bui Lynne A. , Ribas Antoni , Dissette Vivian Beck , Lau Roy , Gamradt Seth C. , Glaspy John A. , McBride William H. , Mukherji Bijay , Economou James S. 
Published: December 2022

AbstractDendritic cells (DC) are potent stimulators of primary T cell responses. In this study, we demonstrate that DC, genetically engineered to express the MART-1/Melan-A (MART-1) tumor-associated Ag, express MART-1 mRNA and protein, correctly process and present the HLA-A2.1-restricted immunodominant MART-1 peptide (MART-127–35), and serve as potent stimulators of MART-1-specific CTL in vitro. A replication-defective E1-deleted adenovirus (AdV) was constructed that expresses MART-1 (AdVMART1). Transduced DC produce full length MART-1 mRNA as well as MART-1 protein. AdVMART1 does not significantly down-regulate cell surface class I expression despite having an intact E3 region. Transduction of an HLA-A2-positive/MART-1-negative cell line with AdVMART1 renders these cells sensitive to lysis by CTL specific for the MART-127–35 immunodominant peptide. In addition, DC transduced with AdVMART1 stimulated MART-127–35-specific tumor-infiltrating lymphocytes to synthesize IFN-γ. Finally, AdVMART1-transduced DC were able to generate MART-127–35 peptide-specific, class I-restricted CTL in PBL cultures from normal donors. This study supports the use of tumor Ag-engineered DC in genetic immunotherapy.
Human Complement Component C1q Inhibits the Infectivity of Cell-Free HTLV-I
Authors: Ikeda Fumihiro , Haraguchi Yuji , Jinno Atsushi , Iino Yuichi , Morishita Yasuo , Shiraki Hiroshi , Hoshino Hiroo 
Published: December 2022

Abstract
Human T cell leukemia virus type I (HTLV-I) is a retrovirus that is not lysed by human serum or complement. It has not been determined, however, whether HTLV-I directly binds to complement components or whether it retains infectivity after incubation with human serum. We investigated the effects of human serum on the infectivity of cell-free HTLV-I produced by human and animal cells. Plating of vesicular stomatitis virus (HTLV-I) pseudotypes prepared in cat or human cells and formation of HTLV-I DNA after infection of cell-free HTLV-I produced by cat or human cells were markedly inhibited by treatment with fresh human serum, but not by heat-inactivated serum. HTLV-I infection was also inhibited by treatment with C2-, C3-, C6-, or C9-deficient serum, but not by C1q-deficient serum. Inhibitory activities of normal human serum against HTLV-I were neutralized by anti-C1q serum. Furthermore, purified C1q inhibited HTLV-I infection. The direct binding of C1q to HTLV-I was confirmed by comigration of C1q with HTLV-I virion upon sucrose density gradient ultracentrifugation of HTLV-I virion treated with C1q. Binding assay using synthetic envelope peptides indicated that C1q bound to an extramembrane region of the gp21 transmembrane protein. These findings indicate that the human complement component C1q inactivates HTLV-I infectivity.
ICAM-1 Signaling Pathways Associated with Rho Activation in Microvascular Brain Endothelial Cells
Authors: Etienne Sandrine , Adamson Peter , Greenwood John , Strosberg A. Donny , Cazaubon Sylvie , Couraud Pierre-Olivier 
Published: December 2022

AbstractEndothelium of the cerebral blood vessels, which constitutes the blood-brain barrier, controls leukocyte adhesion and trafficking to the brain. Investigating signaling pathways triggered by the engagement of adhesion molecules expressed on brain endothelial cells, we report here that ICAM-1 cross-linking induces tyrosine phosphorylation of three cytoskeleton-associated proteins: focal adhesion kinase, paxillin, and p130Cas (Cas), which are found to associate as complexes. Tyrosine-phosphorylated Cas associates with the adaptor protein Crk and the GTP exchange factor C3G. In the same conditions the small G protein Rho was activated, as shown by the increase in its GTP loading. In addition, tyrosine phosphorylation of focal adhesion kinase, paxillin, and Cas as well as triggering of the Crk signaling pathway are blocked by pretreatment of the cells with the exoenzyme C3, a specific Rho inhibitor. C3-sensitive activation of the c-Jun N-terminal kinase in response to ICAM-1 cross-linking is also observed, whereas no significant activation of Ras or of the extracellular signal-regulated kinase was detected. In conclusion, these results suggest that through coupling to Rho activation and phosphorylation of cytoskeletal proteins and transcription factors, ICAM-1 cross-linking participates in the cell shape changes and gene regulation that may accompany lymphocyte migration through the blood-brain barrier.
Monocytes from Wiskott-Aldrich Patients Display Reduced Chemotaxis and Lack of Cell Polarization in Response to Monocyte Chemoattractant Protein-1 and Formyl-Methionyl-Leucyl-Phenylalanine
Authors: Badolato Raffaele , Sozzani Silvano , Malacarne Fabio , Bresciani Susanna , Fiorini Maurilia , Borsatti Alessandro , Albertini Alberto , Mantovani Alberto , Ugazio Alberto G. , Notarangelo Luigi D. 
Published: December 2022

AbstractWiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by trombocytopenia, eczema, and progressive decline of the immune function. In addition, lymphocytes and platelets from WAS patients have morphologic abnormalities. Since chemokines may induce morphologic changes and migration of leukocytes, we investigated the monocyte response to chemoattractants in cells from WAS patients with an identified mutation in the WAS protein gene. Here, we report that monocytes derived from four patients with molecularly defined typical WAS have a severely impaired migration in response to FMLP and to the chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α compared with normal donors. Conversely, neither MCP-1 binding to monocytes nor induction of the respiratory burst by MCP-1 and FMLP is significantly different between WAS patients and normal donors. Within a few minutes of stimulation, monocytes respond to chemokines with increased expression of adhesion molecules and with morphologic changes such as cell polarization. Although up-regulation of CD11b/CD18 expression following stimulation with FMLP or MCP-1 is preserved in WAS patients, cell polarization is dramatically decreased. Staining of F-actin by FITC-phalloidin in monocytes stimulated with chemoattractants shows F-actin to have a rounded shape in WAS patients, as opposed to the polymorphic distribution of F-actin in the polarized monocytes from healthy donors. These results suggest that WAS protein is involved in the monocyte response to the chemokines MCP-1 and macrophage inflammatory protein-1α.
Immunity to T Cell Receptor Peptides in Multiple Sclerosis. III. Preferential Immunogenicity of Complementarity-Determining Region 2 Peptides from Disease-Associated T Cell Receptor BV Genes*
Authors: Bourdette Dennis N. , Chou Yuan K. , Whitham Ruth H. , Buckner Jane , Kwon Hi Jong , Nepom Gerald T. , Buenafe Abigail , Cooper Shelley A. , Allegretta Mark , Hashim George A. , Offner Halina , Vandenbark Arthur A. 
Published: December 2022

AbstractVaccination with synthetic TCR peptides from the BV5S2 complementarity-determining region 2 (CDR2) can boost significantly the frequency of circulating CD4+ peptide-specific Th2 cells in multiple sclerosis (MS) patients, with an associated decrease in the frequency of myelin basic protein (MBP)-reactive Th1 cells and possible clinical benefit. To evaluate the immunogenicity of CDR2 vs other regions of the TCR, we vaccinated seven MS patients with overlapping BV5S2 peptides spanning amino acids 1–94. Six patients responded to at least one of three overlapping or substituted CDR2 peptides possessing a core epitope of residues 44–52, and one patient also responded to a CDR1 peptide. Of the CDR2 peptides, the substituted (Y49T)BV5S2-38–58 peptide was the most immunogenic but cross-reacted with the native sequence and had the strongest binding affinity for MS-associated HLA-DR2 alleles, suggesting that position 49 is an MHC rather than a TCR contact residue. Two MS patients who did not respond to BV5S2 peptides were immunized successfully with CDR2 peptides from different BV gene families overexpressed by their MBP-specific T cells. Taken together, these results suggest that a widely active vaccine for MS might well involve a limited set of slightly modified CDR2 peptides from BV genes involved in T cell recognition of MBP.
Cutting Edge: The Chemokine Receptor CCR8 Is Preferentially Expressed in Th2 But Not Th1 Cells
Authors: Zingoni Alessandra , Soto Hortensia , Hedrick Joseph A. , Stoppacciaro Antonella , Storlazzi Clelia T. , Sinigaglia Francesco , D’Ambrosio Daniele , O’Garra Anne , Robinson Douglas , Rocchi Mariano , Santoni Angela , Zlotnik Albert , Napolitano Monica 
Published: December 2022

AbstractIn this paper we report on the cloning and characterization of mouse CCR8. Like its human homologue, it is predominantly expressed in the thymus. In the periphery, murine CCR8 mRNA was found most abundantly expressed in activated Th2-polarized cells and in NK1.1+CD4+ T cells. Human CCR8 is also preferentially expressed in human Th2-polarized cells and clones. This pattern of expression suggests that CCR8 is part of a Th2-specific gene expression program. The CCR8 ligands I-309 and its mouse homologue T cell activation gene 3 (TCA-3) are potent chemoattractants for Th2-polarized cells. Taken together, these observations strongly suggest that CCR8 plays a role in the control of Th2 responses, and may represent a potential target for treatment of allergic diseases.
Loss of Endogenous Mouse Mammary Tumor Virus Superantigen Increases Tumor Resistance
Authors: Schirrmacher Volker , Beutner Ulrich , Bucur Marianna , Umansky Victor , Rocha Marian , von Hoegen Paul 
Published: December 2022

Abstract
From a cross between a tumor-susceptible mouse strain (DBA/2; D) and a tumor-resistant MHC-identical strain (B10.D2; D2) new recombinant inbred mouse strains were established over many generations of inbreeding and tumor resistance selection. Since resistance to the highly metastatic DBA/2 lymphoma variant ESb had an immunologic basis, and the two parental strains differed in endogenous viral superantigens (vSAGs), DNA of three D2×D recombinant inbred mouse lines was typed for endogenous mouse mammary tumor viruses using mouse mammary tumor virus long terminal repeat- and env gene-specific probes. The resistant D2×D mice were very similar to the susceptible parental strain D in their Mtv Southern blots, except for the lack of a single band corresponding to Mtv-7, the provirus coding for the strong DBA/2 superantigen Mls-1a. A backcross analysis revealed that Mtv-7-negative F2 mice were significantly more resistant than Mtv-7-positive F2 mice. When Mtv-7 was reintroduced into the resistant lines by crossing them with either CBA/J or BALB/D2.Mls-1a, the mice became again more tumor susceptible. Finally, we demonstrate the ability to transfer immunoresistance and graft-vs-leukemia reactivity from tumor-resistant to tumor-susceptible mice.
Relationship Between Peptide Selectivities of Human Transporters Associated with Antigen Processing and HLA Class I Molecules
Authors: Daniel Soizic , Brusic Vladimir , Caillat-Zucman Sophie , Petrovsky Nicolai , Harrison Leonard , Riganelli Daniela , Sinigaglia Francesco , Gallazzi Fabio , Hammer Jürgen , van Endert Peter M. 
Published: December 2022

AbstractEfficiency of presentation of a peptide epitope by a MHC class I molecule depends on two parameters: its binding to the MHC molecule and its generation by intracellular Ag processing. In contrast to the former parameter, the mechanisms underlying peptide selection in Ag processing are poorly understood. Peptide translocation by the TAP transporter is required for presentation of most epitopes and may modulate peptide supply to MHC class I molecules. To study the role of human TAP for peptide presentation by individual HLA class I molecules, we generated artificial neural networks capable of predicting the affinity of TAP for random sequence 9-mer peptides. Using neural network-based predictions of TAP affinity, we found that peptides eluted from three different HLA class I molecules had higher TAP affinities than control peptides with equal binding affinities for the same HLA class I molecules, suggesting that human TAP may contribute to epitope selection. In simulated TAP binding experiments with 408 HLA class I binding peptides, HLA class I molecules differed significantly with respect to TAP affinities of their ligands. As a result, some class I molecules, especially HLA-B27, may be particularly efficient in presentation of cytosolic peptides with low concentrations, while most class I molecules may predominantly present abundant cytosolic peptides.
The Role of IL-7 in Thymic and Extrathymic Development of TCRγδ Cells
Authors: Laky K. , Lefrançois L. , von Freeden-Jeffry U. , Murray R. , Puddington L. 
Published: December 2022

AbstractIL-7-deficient (IL-7−/−) mice have reduced numbers of B and TCRαβ cells, but lack mature TCRγδ cells. Although most T cell development occurs in the thymus, some intestinal intraepithelial lymphocytes (IEL), including TCRγδ cells, can develop extrathymically. Epithelial cells in both thymus and intestine synthesize IL-7, suggesting that TCRγδ cell development could occur in either site. To evaluate the role of thymic IL-7 in development of TCRγδ cells, newborn TCRβ-deficient (TCRβ−/−) thymi were grafted to IL-7−/− mice. Donor- and host-derived TCRγδ cells were recovered from thymus grafts, spleen, and IEL. However, when IL-7−/− thymi were grafted to TCRβ−/− mice, no development of graft-derived TCRγδ cells occurred, indicating that extrathymic IL-7 did not support TCRγδ IEL generation from newborn thymic precursors. In contrast, TCRγδ IEL development occurred efficiently in adult, thymectomized, irradiated C57BL/6J mice reconstituted with IL-7−/− bone marrow. This demonstrated that extrathymic development of TCRγδ IEL required extrathymic IL-7 production. Thus, intrathymic IL-7 was required for development of thymic TCRγδ cells, while peripheral IL-7 was sufficient for development of extrathymic TCRγδ IEL.
Identification of CD68+lin− Peripheral Blood Cells with Dendritic Precursor Characteristics
Authors: Strobl Herbert , Scheinecker Clemens , Riedl Elisabeth , Csmarits Bettina , Bello-Fernandez Concha , Pickl Winfried F. , Majdic Otto , Knapp Walter 
Published: December 2022

AbstractExpression of CD68 (macrosialin) in the absence of surface and lysosomal lineage marker molecules is a characteristic feature of T zone-associated plasmacytoid monocytes, which were recently shown to represent precursors of dendritic cells (DC). We demonstrate here a minor population of strongly CD68-positive (CD68bright) blood cells that lack all analyzed myeloid surface (CD14−, CD33−, CD13−, CD11b−, CD11c−) and lysosomal (myeloperoxidase, MPO− and lysozyme, LZ−) marker molecules (0.4 ± 2% of the total mononuclear cells). These CD68bright, lineage marker-negative (lin−) cells can be induced to proliferate in the presence of IL-3. They do not acquire myeloid features even upon stimulation with granulocyte-macrophage CSF plus IL-1, IL-3, and IL-6. Instead, these cells develop typical DC characteristics upon culture. Furthermore, these CD68brightlin− DC precursors acquire mature DC characteristics (CD86+, CD83+, CD54bright) upon stimulation with CD40 ligand plus IL-3. A second subset of DC precursor-like blood cells was found to weakly express CD68 (0.3 ± 0.2% of the total mononuclear cells) and to coexpress several myeloid lineage associated molecules (LZ+, CD11c+, CD33+, CD13+). Cells of this second subset resemble both previously described myeloid-related peripheral blood DC and germinal center DC. Analysis of peripheral blood leukocytes for CD68 thus revealed the existence of two cell subsets that phenotypically resemble lymphoid tissue-associated DC. The unique phenotype CD68brightlin− is highly reminiscent of T zone-associated plasmacytoid monocytes. CD68brightlin− blood leukocytes also functionally resemble plasmacytoid monocytes. The lack of all analyzed myeloid features by CD68brightlin− blood leukocytes suggests that these cells arise from a novel nonmyeloid human DC differentiation pathway.
Anti-MUC1 Antibodies React Directly with MUC1 Peptides Presented by Class I H2 and HLA Molecules
Authors: Apostolopoulos Vasso , Chelvanayagam Gareth , Xing Pei-Xiang , McKenzie Ian F. C. 
Published: December 2022

AbstractPeptides bound in the groove of MHC class I molecules and detected by CTLs are not normally accessible to Ab. We now report that MUC1 peptides that are bound within the groove of MHC class I molecules (H2 and HLA) and that can be detected by CTLs can also be detected by anti-MUC1 Abs. mAbs to the middle and C-terminal regions of the class I-associated peptides but not to the N terminus were able to react with MUC1 peptides bound to H2Kb and HLA-A*0201, and only to the mid-region for H2Db, by flow cytometry and also to block CTL activity. Molecular modeling showed that the N terminus is buried (and not accessible), whereas the midpeptide residues form a loop and the C terminus is free, making these two regions accessible to Ab. The findings demonstrate for the first time that peptides associated with class I molecules can be detected by anti-peptide Abs.
HLA Class II Expression in Uninducible Hepatocarcinoma Cells After Transfection ofAIR-1Gene Product CIITA: Acquisition of Antigen Processing and Presentation Capacity
Authors: Sartoris Silvia , Valle Maria Teresa , Barbaro Andrea De Lerma , Tosi Giovanna , Cestari Tiziana , D’Agostino Antonella , Megiovanni Anna Maria , Manca Fabrizio , Accolla2 Roberto S. 
Published: December 2022

AbstractThe AIR-1-encoded CIITA transcriptional activator is crucial for both constitutive and IFN-γ-induced MHC class II gene transcription. We show here that the MHC class II negative phenotype of the human hepatocarcinoma cell lines Alexander and HepG2 remains unmodified after treatment with IFN-γ, although MHC class I expression is up-modulated. This correlates with absence of CIITA mature transcripts. Transfection of an expressible CIITA cDNA in Alexander cells resulted in a very high cell surface expression of all three human class II subsets, HLA-DR, -DP and -DQ, indicating that normally observed induction of CIITA expression by IFN-γ is probably blocked, in the hepatocarcinoma cell lines, at the level of CIITA transcription and not at the level of IFN-γ receptor binding and signal transduction mechanisms. To assess whether MHC class II expression on CIITA-transfected Alexander cells could have functional relevance, we tested their capacity to present antigenic peptides to an HLA-DR-restricted T cell line specific for a peptide of Mycobacterium tuberculosis Ag85 protein. It was found that the transfected cells could not only present the exogenously supplemented peptide but also process Ag85 protein to generate the specific epitope recognized by the HLA-DR-restricted T cell line. Similar results were obtained with CIITA-transfected CFPAC-1 pancreatic adenocarcinoma cells, which differed from Alexander cells in that they were inducible by IFN-γ. These results suggest new strategies to act on CIITA for increasing the potential of a tumor cell to present putative tumor Ags to the immune system.
Mapping Quantitative Trait Loci for Immune Capacity in the Pig
Authors: Edfors-Lilja Inger , Wattrang Eva , Marklund Lena , Moller Maria , Andersson-Eklund Lena , Andersson Leif , Fossum Caroline 
Published: December 2022

Abstract
Immune capacity traits show considerable genetic variation in outbred populations. To identify quantitative trait loci (QTLs) for immune capacity in the pig, various measures of immune function (total and differential leukocyte counts, neutrophil phagocytosis, mitogen-induced proliferation, IL-2 production, and virus induced IFN-α production in whole blood cultures, and Ab responses to two Escherichia coli antigens) were determined in 200 F2 animals from a wild pig–Swedish Yorkshire intercross. The pedigree has been typed for 236 genetic markers covering all autosomes, the X chromosome and the X/Y pseudoautosomal region. Through interval mapping using a least-squares method, four QTLs with significant effects were identified; one for total leukocyte counts, one for mitogen-induced proliferation, one for prevaccination levels of Abs to E. coli Ag K88, and one for Ab response to the O149 Ag. In addition, several putative QTLs were indicated. The results from the present study conclusively show that it is possible to identify QTLs for immune capacity traits in outbred pig populations by genome analysis.
Molecular Regulation of the Interaction Between Leukocyte Function-Associated Antigen-1 and Soluble ICAM-1 by Divalent Metal Cations
Authors: Labadia Mark E. , Jeanfavre Deborah Durham , Caviness Gary O. , Morelock Maurice M. 
Published: December 2022

AbstractSurface plasmon resonance (SPR) was used to investigate and characterize the interaction between LFA-1 and sICAM-1 (a soluble form of ICAM-1). Full-length LFA-1 was immobilized on a hydrophobic surface, and sICAM-1 binding was monitored in a flow cell format. The binding of sICAM-1 to LFA-1 was specific and dependent upon Mg2+; Abs to both sICAM-1 and LFA-1 blocked the interaction, and EDTA abolished all binding. Association and dissociation rate constants (ka and kd, respectively) for sICAM-1 were 2.24 × 105 M−1 s−1 and 2.98 × 10−2 s−1, respectively, giving a calculated KICAM of 133 nM. Since the LFA-1/ICAM-1 interaction is highly sensitive to the presence of metal cations, SPR was also used to probe the affinity of the metal binding sites. The KMg values were 160 and 12 μM in the absence (EGTA) and the presence of Ca2+ (100 μM), respectively; in addition, KMn was 2 μM in the presence of Ca2+ (100 μM). Increasing Ca2+ into the millimolar concentration range, however, resulted in a competitive displacement of Mg2+/Mn2+ and decreased sICAM-1 binding. Based on these data, a synergistic model for the molecular regulation of LFA-1 by divalent metal cations is proposed, and implications to cellular adhesion are discussed.