bluuebunny/crossref_metadata_2025_split huggingface dataset:
A B7.1-Antibody Fusion Protein Retains Antibody Specificity and Ability to Activate Via the T Cell Costimulatory Pathway
Authors: Challita-Eid Pia M. , Penichet Manuel L. , Shin Seung-Uon , Poles Tina , Mosammaparast Nima , Mahmood Kutubuddin , Slamon Dennis J. , Morrison Sherie L. , Rosenblatt Joseph D. 
Published: December 2022

AbstractWe describe the construction and characterization of an Ab fusion protein specific for the tumor-associated Ag HER2/neu linked to sequences encoding the extracellular domain of the B7.1 T cell costimulatory ligand. The Ab domain of the fusion molecule will specifically target HER2/neu-expressing tumor cells, while the B7.1 domain is designed to activate a specific immune response. We show that the B7.1 fusion Ab retained ability to selectively bind to the HER2/neu Ag and to the CTLA4/CD28 counter-receptors for B7.1. Specific T cell activation was observed when the B7.1 Ab fusion protein was bound to HER2/neu-expressing cells. The use of the B7.1 Ab fusion protein may overcome limitations of gene transfer and/or standard Ab therapy and represents a novel approach to the eradication of minimal residual disease.
Dominant-Negative Effect of the Lymphocyte Function-Associated Antigen-1 β (CD18) Cytoplasmic Domain on Leukocyte Adhesion to ICAM-1 and Fibronectin
Authors: Rey-Ladino Jose A. , Pyszniak Andrew M. , Takei Fumio 
Published: December 2022

AbstractThe cytoplasmic domains of LFA-1 (CD11a/CD18) are thought to play an important role in the regulation of LFA-1 function. To further elucidate the role of the LFA-1 cytoplasmic domains, we transfected chimeric proteins consisting of the extracellular domain of CD4 fused with the transmembrane and cytoplasmic domains of LFA-1 into T and B cell lines, EL-4 and A20, respectively, and examined their effects on LFA-1-mediated cell adhesion. The CD4/18, but not CD4/11a, chimera profoundly inhibited LFA-1-mediated cell adhesion to ICAM-1, as well as cell spreading following cell adhesion. Unexpectedly, cell adhesion to fibronectin was also inhibited by the CD4/18 chimera. The CD4/18 chimera did not affect the expression of endogenous LFA-1 or the association of CD11a and CD18. Truncation of the carboxyl-terminal 13 amino acid residues of the CD18 cytoplasmic domain of the chimera completely abrogated the inhibitory effect on LFA-1. Among these amino acid residues, the carboxyl-terminal six residues were dispensable for the inhibitory effect in EL-4 cells, whereas it significantly reduced the inhibitory activity of CD4/18 in A20 cells. A larger truncation of the CD18 cytoplasmic domain was needed to fully abrogate the inhibitory effects of CD4/18 on the adhesion to fibronectin. These results show that 1) the CD4/18 chimera has dominant-negative effects on cell adhesion mediated by LFA-1 as well as fibronectin receptors, and 2) amino acid residues of the CD18 cytoplasmic domain involved in the inhibition of LFA-1 seem to be different from those for fibronectin receptors.
The Role of the CD40 Pathway in Alloantigen-Induced Hyporesponsiveness In Vivo
Authors: Niimi Masanori , Pearson Thomas C. , Larsen Christian P. , Alexander Diane Z. , Hollenbaugh Diane , Aruffo Alejandro , Linsley Peter S. , Thomas Elaine , Campbell Kim , Fanslow William C. , Geha Raif S. , Morris Peter J. , Wood Kathryn J. 
Published: December 2022

Abstract
Resting B (rB) cells are known to be incompetent APCs in vitro, which alone can induce specific unresponsiveness to single minor histocompatibility (miH) Ags and, when combined with CD40 pathway blockade, can induce hyporesponsiveness to MHC molecules in vivo. Here we show that anti-CD40 ligand (CD40L) mAb does not prevent the expression of B7-2 on allogeneic rB cells in vivo but did prolong donor-specific cardiac allograft survival. Moreover, pretreatment with professional APCs combined with anti-CD40L mAb induced hyporesponsiveness to alloantigens in vivo. rB cells from CD40 knockout mice were unable to induce unresponsiveness, while graft prolongation was achieved in CD40L knockout recipients pretreated with wild-type rB cells. These data suggest that CD40-CD40L interactions in the recipient play a critical role in the induction of hyporesponsiveness to alloantigens in vivo and that the effect of the CD40 pathway may be independent of its effect on the B7 costimulatory pathway.
Alterations in Cytokine Production Following Intraocular Injection of Soluble Protein Antigen: Impairment in IFN-γ and Induction of TGF-β and IL-4 Production
Authors: Kosiewicz Michele M. , Alard Pascale , Streilein J. Wayne 
Published: December 2022

AbstractImmune deviation induced by intraocular injection of soluble protein Ag, referred to as anterior chamber-associated immune deviation (ACAID), is characterized by impairment of delayed hypersensitivity (DH). Two populations of splenic regulatory cells that impair the induction and expression phases of DH are involved in the ACAID response and may mediate their effects through cytokines. The purpose of the present study was to evaluate the role that cytokines play in ACAID. IFN-γ production in draining lymph nodes induced by conventional immunization with protein Ag and adjuvant was suppressed after intraocular injection of protein Ag administered either before or after sensitization; IL-12 production in these mice was not decreased, suggesting that suppression of IL-12 may not be the mechanism involved in the impairment in IFN-γ production. Surprisingly, although significant amounts of IL-4 (but not IL-10) were produced by spleen and lymph node cells from several different strains of mice, experiments in IL-4 knockout mice showed that impairment of neither DH nor IFN-γ production required IL-4. Interestingly, significant levels of TGF-β were detected in cultures of spleen cells from mice with ACAID. As determined by quantitative RT-PCR, TGF-β was produced primarily by the splenic CD4 and non-T cells and was of the TGF-β1 type. These results suggest that the Th1 response is impaired in ACAID by a mechanism(s) that does not require Th2-type cytokines, but may involve TGF-β at several different (including the effector) phases during the response.
IL-2Rα on One Cell Can Present IL-2 to IL-2Rβ/γc on Another Cell to Augment IL-2 Signaling
Authors: Eicher Donald M. , Waldmann Thomas A. 
Published: December 2022

AbstractIL-2Rα augments IL-2 signaling. Although this is generally believed to occur only when the three known components of IL-2R are associated within a single cell membrane, we demonstrate here an intercellular interaction. Cocultivation of cells individually expressing chimerae incorporating the extracellular domain of IL-2Rα alone with cells expressing chimerae of IL-2Rβ alone permitted IL-2 dose-dependent oligomerization of the chimerae. Likewise, native IL-2Rα-bearing cells augmented the IL-2 proliferative response of ex vivo large granular lymphocytic leukemia cells expressing IL-2Rβ/γc but lacking IL-2Rα. In both cases, the response was inhibitable by an Ab to IL-2Rα. Intercellular augmentation of cytokine effects, acting in trans, has important implications for biology and medicine.
Early IL-4 Induction in Bone Marrow Lymphoid Precursor Cells by Mycobacterial Lipoarabinomannan
Authors: Collins Helen L. , Schaible Ulrich E. , Kaufmann Stefan H. E. 
Published: December 2022

AbstractIL-4 is produced promptly in response to certain infections and plays a key role in the Th1/Th2 T cell dichotomy; however, the cellular source remains a matter of debate. Here we describe the induction of IL-4 in bone marrow cells of normal and RAG−/− mice by both Mycobacterium tuberculosis and its major cell wall glycolipid, lipoarabinomannan. Characterization of the cell type responsible indicated that it was distinct from the NK1+ or CD4+ T cell previously ascribed the function of rapid IL-4 secretion. Cell-sorting experiments identified CD19+/B220+ precursor cells, presumably pre-B cells that produced IL-4 constitutively and whose frequency was rapidly and markedly up-regulated by lipoarabinomannan. Thus, pathogenic mycobacteria and their glycolipids may influence hemopoiesis by rapidly inducing IL-4 secretion in the bone marrow.
Optimization of Codon Usage of Plasmid DNA Vaccine Is Required for the Effective MHC Class I-Restricted T Cell Responses Against an Intracellular Bacterium
Authors: Uchijima Masato , Yoshida Atsushi , Nagata Toshi , Koide Yukio 
Published: December 2022

AbstractIn an attempt to study codon usage effects of DNA vaccines on the induction of MHC class I-restricted T cell responses against an intracellular bacterium, Listeria monocytogenes, we designed two plasmid DNA vaccines encoding an H-2Kd-restricted epitope of listeriolysin O (LLO) of L. monocytogenes, LLO 91–99. One DNA vaccine, p91wt, carries the wild-type DNA sequence encoding LLO 91–99, and the other one, p91mam, possesses the altered DNA sequence in which the codon usage was optimized for murine system. Our read-through analyses with LLO 91–99/luciferase fusion genes confirmed that the optimized 91mam DNA sequence showed extremely higher translation efficiency than the wild-type sequence in murine cells. Consistent with this, i.m. injections of p91mam, but not of p91wt, into BALB/c mice were capable of inducing specific CTL- and IFN-γ-producing CD8+ T cells able to confer partial protection against listerial challenge. Taken together, these observations suggest that optimization of codon should be taken into consideration in the construction of DNA vaccines against nonviral pathogens.
The Efficiency of Antigen Recognition by CD8+ CTL Clones Is Determined by the Frequency of Serial TCR Engagement
Authors: Hudrisier Denis , Kessler Benedikt , Valitutti Salvatore , Horvath Clotilde , Cerottini Jean-Charles , Luescher Immanuel F. 
Published: December 2022

Abstract
Using H-2Kd-restricted CTL clones, which are specific for a photoreactive derivative of the Plasmodium berghei circumsporozoite peptide PbCS252–260 (SYIPSAEKI) and permit assessment of TCR-ligand interactions by TCR photoaffinity labeling, we have previously identified several peptide derivative variants for which TCR-ligand binding and the efficiency of Ag recognition deviated by fivefold or more. Here we report that the functional CTL response (cytotoxicity and IFN-γ production) correlated with the rate of TCR-ligand complex dissociation, but not the avidity of TCR-ligand binding. While peptide antagonists exhibited very rapid TCR-ligand complex dissociation, slightly slower dissociation was observed for strong agonists. Conversely and surprisingly, weak agonists typically displayed slower dissociation than the wild-type agonists. Acceleration of TCR-ligand complex dissociation by blocking CD8 participation in TCR-ligand binding increased the efficiency of Ag recognition in cases where dissociation was slow. In addition, permanent TCR engagement by TCR-ligand photocross-linking completely abolished sustained intracellular calcium mobilization, which is required for T cell activation. These results indicate that the functional CTL response depends on the frequency of serial TCR engagement, which, in turn, is determined by the rate of TCR-ligand complex dissociation.
A Novel Type II Complement C2 Deficiency Allele in an African-American Family
Authors: Zhu Zeng-Bian , Atkinson T. Prescott , Volanakis John E. 
Published: December 2022

Abstract
A 9-yr-old African-American male presenting with severe recurrent pyogenic infections was found to have C2 deficiency (C2D). Analysis of his genomic DNA demonstrated that he carried one type I C2D allele associated with the HLA-A25, B18, DR15 haplotype. Screening all 18 exons of the C2 gene by exon-specific PCR/single-strand conformation polymorphism indicated abnormal bands in exons 3, 7, and 6, the latter apparently caused by the 28-bp deletion of the typical type I C2D allele. Nucleotide (nt) sequencing of the PCR-amplified exons 3 and 7 revealed a heterozygous G to A transition at nt 392, causing a C111Y mutation, and a heterozygous G to C transversion at nt 954, causing a E298D mutation and a polymorphic MaeII site. Cys111 is the invariable third half-cystine of the second complement control protein module of C2. Pulse-chase biosynthetic labeling experiments indicated that the C111Y mutant C2 was retained by transfected COS cells and secreted only in minimal amounts. Therefore, this mutation causes a type II C2D. In contrast, the E298D mutation affected neither the secretion of C2 from transfected cells nor its specific hemolytic activity. Analysis of genomic DNA from members of the patient’s family indicated that 1) the proband as well as one of his sisters inherited the type I C2D allele from their father and the novel type II C2D allele from their mother; 2) the polymorphic MaeII site caused by the G954C transversion is associated with the type I C2D allele; and 3) the novel C111Y mutation is associated in this family with the haplotype HLA-A28, B58, DR12.
Alterations in Cell Surface Carbohydrates on T Cells from Virally Infected Mice Can Distinguish Effector/Memory CD8+ T Cells from Naive Cells
Authors: Galvan Marisa , Murali-Krishna Kaja , Ming Lisa Lau , Baum Linda , Ahmed Rafi 
Published: December 2022

Abstract
Glycosylation changes on surface molecules of T cells affect cell trafficking and function and may be useful in discriminating between naive, effector, and memory T cells. To analyze oligosaccharide structures on T cells activated in vivo, we examined alterations in sialic acid residues on T cells following infection of mice with lymphocytic choriomeningitis (LCMV), vaccinia virus, and vesicular stomatitis virus. We found that the majority of CD8 T cells from mice acutely infected with these viruses showed increased binding to peanut agglutinin (PNA). All of the PNAhighCD8 T cells from infected mice were CD44high, indicating that glycosylation changes were occurring on activated T cells. There was also an increase in the PNAhighCD4 T cell population in virally infected mice. Increased PNA binding to activated CD8 T cells correlated with higher endogenous neuraminidase levels in these cells. This higher neuraminidase activity most likely contributed to the PNAhigh phenotype by cleaving sialic acid residues off the core-1 O-glycans or glycoproteins destined for the cell surface. A PNAhighCD8 T cell population persisted in immune mice that had cleared the LCMV infection. When spleen cells from immune mice were sorted into PNAhigh and PNAlow populations, &gt;95% of the LCMV-specific memory CD8 T cells segregated with the PNAhigh population. This shows that virus-specific memory CD8 T cells remain hyposialylated and can be distinguished from naive CD8 T cells based on PNA binding. Thus, PNA can be used as a marker for Ag-experienced T cells.
HIV-Tat Protein Activates c-Jun N-Terminal Kinase and Activator Protein-1
Authors: Kumar Ashok , Manna Sunil K. , Dhawan Subhash , Aggarwal Bharat B. 
Published: December 2022

Abstract
Human immunodeficiency virus-1 tat (HIV-tat) protein, like other proinflammatory cytokines (such as TNF), activates a wide variety of cellular responses, some of which play a critical role in progression of HIV infection. Whether HIV-tat, like TNF, also activates c-Jun N-terminal kinase (JNK) and the transcription factor activator protein (AP)-1 is not known. We show that treatment of human histiocytic lymphoma U937 cells with the HIV-tat protein causes activation of JNK and AP-1 in a time- and dose-dependent manner. Transfection of a T cell line, H9 cells with the HIV-tat gene also resulted in an activation of JNK that was not further increased by treatment of cells with exogenous HIV-tat protein. Neutralizing Ab against HIV-tat inhibited the HIV-tat-mediated JNK activation. The activation of JNK by HIV-tat appears to be mediated through generation of free radical species, since pretreatment of cells with N-acetylcysteine (NAC) abolished the effect. Overall our results demonstrate that HIV-tat activates JNK and AP-1, which may contribute to the pathogenesis of AIDS.
Regulatory Elements in the Promoter of a MurineTCRD VGene Segment
Authors: Kienker Laura J. , Ghosh Maya R. , Tucker Philip W. 
Published: December 2022

AbstractTCRD V segments rearrange in an ordered fashion during human and murine thymic development. Recombination requires the accessibility of substrate gene segments, and transcriptional enhancers and promoters have been shown to regulate the accessible chromatin configuration. We therefore investigated the regulation of TCRD V rearrangements by characterizing the promoter of the first TCRD V segment to be rearranged, DV101S1, under the influence of its own enhancer. Sequences required for full promoter activity were identified by transient transfections of normal and mutated promoters into a human γδ lymphoma, and necessary elements fall between −86 and +66 nt, relative to the major transcription start site. They include a cAMP responsive element (CRE) at −62, an Ets site at −39, a TATA box at −26, the major transcriptional start site sequence (−8 to −5 and −2 to +11), and a downstream sequence (+12 to +33). Gel shift analyses and in vitro DNase I footprinting showed that nuclear proteins bind to the functionally relevant CRE, Ets, +1 to +10 sequence, and the +17 to +21 sequence. Nuclear proteins also bind to an E box at −52, and GATA-3 binds to a GATA motif at −5, as shown by Ab ablation-supershift experiments, but mutations that abrogated protein binding to these sites failed to affect DV101S1 promoter activity. We conclude that not all protein-binding sites within the DV101S1 minimal promoter are important for enhancer driven TCRD gene transcription. Further, the possibility remains that the GATA and E box sites function in enhancer independent DV101S1 germline transcription.
Use of Complete Eluted Peptide Sequence Data from HLA-DR and -DQ Molecules to Predict T Cell Epitopes, and the Influence of the Nonbinding Terminal Regions of Ligands in Epitope Selection
Authors: Godkin Andrew J. , Davenport Miles P. , Willis Anthony , Jewell Derek P. , Hill Adrian V. S. 
Published: December 2022

Abstract
In diseases with a strong association with an HLA haplotype, identification of relevant T cell epitopes may allow alteration of the pathologic process. In this report we use a reverse immunogenetic approach to predict possible HLA class II-restricted T cell epitopes by using complete pool sequencing data. Data from HLA-DR2(B1*1501), -DR3(B1*0301), -DQ2(A1*0501, B1*0201), and -DQ8(A1*0301, B1*0302) alleles were used by a computer program that searches a candidate protein to predict ligands with a relatively high probability of being processed and presented. This approach successfully identified both known T cell epitopes and eluted single peptides from the parent protein. Furthermore, the program identified ligands from proteins in which the binding motif of the HLA molecule was unable to do so. When the information from the nonbinding N- and C-terminal regions in the pool sequence was removed, the ability to predict several ligands was markedly reduced, particularly for the HLA-DQ alleles. This suggests a possible role for these regions in determining ligands for HLA class II molecules. Thus, the use of complete eluted peptide sequence data offers a powerful approach to the prediction of HLA-DQ and -DR peptide ligands and T cell epitopes.
The CXC Chemokines IP-10 and Mig Are Necessary for IL-12-Mediated Regression of the Mouse RENCA Tumor
Authors: Tannenbaum Charles S. , Tubbs Raymond , Armstrong David , Finke James H. , Bukowski Ronald M. , Hamilton Thomas A. 
Published: December 2022

AbstractThe role of the non-ELR-containing CXC chemokines IP-10 and Mig in antitumor activity induced by systemic treatment with IL-12 was examined in mice bearing the murine renal adenocarcinoma RENCA. IL-12 treatment produces a potent antitumor effect that is associated with tumor infiltration by CD8+ T lymphocytes. The regression of tumor is associated with the elevated expression of the IFN-γ-inducible chemokines IP-10 and Mig within the tumor tissue. IP-10 and Mig have been shown to function as chemoattractants for activated T lymphocytes. In animals treated with rabbit polyclonal Abs specific for IP-10 and for Mig, the IL-12-induced regression of RENCA tumors was partially abrogated. This effect was associated with a dramatic inhibition of T cell infiltration. Thus, it appears that IL-12-dependent, T cell-mediated antitumor activity requires the intermediate expression of IP-10 and Mig to recruit antitumor effector T cells to the tumor site.
Cutting Edge: A Conditionally Active Form of STAT6 Can Mimic Certain Effects of IL-4
Authors: Kamogawa Yumiko , Lee Hyun Jun , Johnston James A. , McMahon Martin , O’Garra Anne , Arai Naoko 
Published: December 2022

Abstract
Binding of IL-4 to its cognate receptor leads to the activation of a number of signaling pathways within the cell. Activation of the transcription factor STAT6 by JAK family protein tyrosine kinases has been shown to be essential for the full response of cells to IL-4. To elucidate the role of STAT6 in IL-4 signaling, we have constructed and expressed in cells a conditionally active form of the protein (STAT6:ER*) by fusing STAT6 to a modified form of the hormone-binding domain of the estrogen receptor. Activation of STAT6:ER* by 4-hydroxytamoxifen leads to specific activation of STAT6-regulated gene expression including the activation of a STAT6 reporter construct and induction of CD23 in B cell lines. Interestingly, in contrast to native STAT6, activation of STAT6:ER* occurs in the absence of detectable tyrosine phosphorylation of the fusion protein. This type of conditional system will be helpful in dissecting the mechanisms and specificity of transcriptional regulation by the STAT family of transcription factors.
Kinetics of Expression of Costimulatory Molecules and Their Ligands in Murine Relapsing Experimental Autoimmune Encephalomyelitis In Vivo
Authors: Issazadeh Shohreh , Navikas Vaidrius , Schaub Meike , Sayegh Mohamed , Khoury Samia 
Published: December 2022

AbstractWe studied the kinetics of expression of costimulatory molecules and cytokines in the central nervous system (CNS) in murine relapsing experimental autoimmune encephalomyelitis (EAE). During the natural course of EAE, B7-2 expression in the CNS correlated with clinical signs, while B7-1 was exclusively expressed during remissions. Interestingly, B7-1 was expressed on infiltrating mononuclear cells as well as neuronal cells in the CNS. In the periphery, B7-1 expression on APCs peaked with clinical disease but decreased on T cells. CD28 and CTLA4 molecules, the two known ligands for B7-1 and B7-2, had distinct expression patterns in the CNS; CD28 was highly expressed and correlated with B7-2 expression on APCs (macrophages/microglia as well as astrocytes) and with the clinical signs of EAE. CTLA4, on the other hand, was expressed by substantially fewer cells during the effector phase of disease and peaked during remission, which is consistent with the emerging role of this molecule in the termination of immune responses. The expression of CD40 and CD40L in the CNS was increased during clinical attacks. The expression of IL-12, IFN-γ, and TNF-α correlated with disease activity and severity, while TGF-β was the only factor that was up-regulated during the recovery phase. Interestingly, TGF-β was also expressed by neurons during remission. This is the first study demonstrating the kinetics of the in vivo expression of costimulatory molecules, their ligands, and cytokines in an autoimmune disease model characterized by remissions and relapses. Our data suggest that the targeting of costimulatory molecules to block an immune response must take into account the expression patterns in the target organ.