bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Experimental Autoimmune Encephalomyelitis by a Tyrosine Kinase Inhibitor
Authors: Constantin Gabriela , Laudanna Carlo , Brocke Stefan , Butcher Eugene C. 
Published: December 2022

AbstractMigration of lymphocytes from the blood into the brain is a critical event in the pathogenesis of experimental autoimmune encephalomyelitis. Lymphocyte adhesion to brain endothelium is the first step in lymphocyte entry into the central nervous system, leading subsequently to myelin damage and paralysis. In this paper we show that the tyrosine kinase inhibitor, tyrphostin AG490, prevents binding of freshly isolated mouse lymph node cells and of in vivo activated lymphocytes to endothelium of inflamed brain in Stamper-Woodruff adhesion assays. Moreover, AG490 inhibits adhesion of encephalitogenic T cell lines to purified ICAM-1 and VCAM-1, molecules implicated in T cell recruitment into the central nervous system. In contrast, 2-h treatment of T cell lines with high doses of tyrphostin AG490 have no effect on the viability, intracellular calcium elevation induced by Con A or TCR cross-linking, proliferation, or TNF production by Ag-stimulated T cell lines. Systemic administration of AG490 prevents the accumulation of leukocytes in the brain and the development of experimental autoimmune encephalomyelitis induced by proteolipid protein, peptide 139–151-specific T cell lines in SJL/J mice. Blood leukocytes isolated from mice treated with tyrphostin AG490 are less adhesive on purified very late Ag-4 ligands compared with adhesion of leukocytes from control animals. Our results suggest that inhibition of signaling pathways involved in lymphocyte adhesion may represent a novel therapeutic approach for demyelinating diseases.
Identification of HLA-A3 and -B7-Restricted CTL Response to Hepatitis C Virus in Patients with Acute and Chronic Hepatitis C
Authors: Chang Kyong-Mi , Gruener Norbert H. , Southwood Scott , Sidney John , Pape Gerd R. , Chisari Francis V. , Sette Alessandro 
Published: December 2022

AbstractThe inverse relationship between peripheral blood CTL responsiveness to multiple hepatitis C virus (HCV) epitopes and viral titer in patients with persistent HCV infection suggests that enhancement of the CTL response might result in viral clearance. Since several HLA-A2-restricted HCV CTL epitopes are already known, we aimed to identify CTL epitopes restricted by other HLA types in an effort to expand the epitope repertoire available for T cell-mediated therapeutic vaccine development. Scanning of 14 different HCV genome sequences for the presence of conserved peptides containing the HLA-A3 and -B7 motifs revealed 9- to 10-mer peptides that were synthesized and assayed for binding to HLA-A3, -B7 supertype molecules. Peptides with good HLA-binding affinities and cross-reactivities with at least three of five most common molecules of each supertype were tested for the ability to stimulate a memory CTL response in the peripheral blood from selected HCV-infected patients and normal seronegative donors in vitro. We identified eight HLA-A3 supertype-restricted CTL epitopes and one HLA-B7 supertype-restricted CTL epitope that were recognized by infected patients but not by healthy seronegative donors. HLA class I serotyping of 158 chronically infected patients revealed that 80% expressed one or more of HLA molecules belong to either the A2, A3, or B7 supertypes. In conclusion, the epitopes, herein identified combined with previously defined HLA-A2-restricted CTL epitopes, should be useful for the design of an ethnically unbiased, therapeutic CTL vaccine for the treatment of patients with chronic HCV infection.
Maturation of CD4+ Lymphocytes in the Aged Microenvironment Results in a Memory-Enriched Population
Authors: Timm Jenna A. , Thoman Marilyn L. 
Published: December 2022

AbstractWith advancing age the CD4+ T lymphocyte compartment becomes enriched for memory cells in both humans and experimental animals. Although it has been assumed that the shift from a naive to a memory-dominant population is due to a lifetime of antigenic exposure and selection as well as a loss of naive cell input due to reduced thymopoiesis, the present data suggest that the aged microenvironment influences the maturation of newly produced CD4+ T cells. In two models, aged and young mice were compared for the ability to reconstitute their peripheral CD4+ T cell pools following depletion, and both age groups were found to be competent to renew this population. However, the phenotype and lymphokine profile of populations arising in aged animals were distinctly different from those in the young mice. In contrast to the expectation that depletion and reconstitution might give rise to a naive-dominant T cell pool, aged mice reconstituted a population nearly indistinguishable from that found in control age-matched individuals. The majority of the CD4+ pool were CD44high CD45RBlow Mel-14low and upon activation with anti-CD3 these CD4+ T cells produced mRNA for IL-2, IL-4, IL-5, and IFN-γ. In aged bone marrow-transplanted mice, the same phenotypic profile and cytokine mRNA pattern were found in CD4+ T cells of host and donor origin. In contrast, the majority of CD4+ T cells in young reconstituted mice were CD44low CD45RBhigh Mel-14high. These lymphocytes, when activated, produced high levels of mRNA for IL-2, with little or no IL-4, IL-5, or IFN-γ mRNA.
Critical Requirement for Aspartic Acid at Position 82 of Myelin Basic Protein 73–86 for Recruitment of Vβ8.2+ T Cells and Encephalitogenicity in the Lewis Rat
Authors: Smeltz Ronald B. , Wauben Marca H. M. , Wolf Norbert A. , Swanborg Robert H. 
Published: December 2022

AbstractWe synthesized single amino acid-substituted peptide analogues of guinea pig myelin basic protein (MBP) 73–86 to study the importance of aspartic acid at residue 82 (QKSQRSQDENPV), which previous reports have suggested is a critical TCR contact residue. Whereas the wild-type 73–86 peptide elicited severe experimental autoimmune encephalomyelitis (EAE) in the Lewis rat, none of the peptide analogues with substitutions at position 82 were capable of inducing EAE. The inability to cause EAE was not due to a failure to bind MHC or to elicit T cell proliferation and cytokine secretion. T cells specific for MBP73–86 did not cross-react with any of the analogues tested, further indicating the importance of this residue in T cell responses to 73–86. Analysis by flow cytometry showed that only the wild-type 73–86 peptide was capable of recruiting Vβ8.2+ T cells, which have been shown previously to be important for disease induction. Reduced expression of the Vβ8.2 TCR was also seen in Lewis rats protected from EAE by coimmunization of MBP73–86 with 73–86(82D→A), despite an increase in cytokine production when both peptides were present during in vitro culture. The data indicate that aspartic acid 82 is a critical TCR contact residue and is required for the recruitment of Vβ8.2+ T cells and the encephalitogenic activity of MBP73–86.
Conserved Residues Amino-Terminal of Cytoplasmic Tyrosines Contribute to the SHP-1-Mediated Inhibitory Function of Killer Cell Ig-Like Receptors
Authors: Burshtyn Deborah N. , Lam Alan S. , Weston Margaret , Gupta Neetu , Warmerdam Petra A. M. , Long Eric O. 
Published: December 2022

Abstract
The sequence I/VxYxxL, often referred to as an immunoreceptor tyrosine-based inhibition motif (ITIM), binds to the C-terminal Src homology 2 domain of the tyrosine phosphatase SHP-1. Conserved residues N-terminal of the tyrosine are not ordinarily found in other Src homology 2 domain binding motifs. The inhibitory forms of killer cell Ig-like receptors (KIR) contain two ITIMs. The role of each ITIM, and of the conserved residues upstream of the tyrosine, in the inhibition of NK cells was tested by vaccinia virus-mediated expression of mutant KIRs. Substitution of the tyrosine in the membrane-proximal ITIM abrogated the ability of KIR to block Ab-dependent cellular cytotoxicity, whereas mutation of the membrane-distal ITIM tyrosine had little effect. Substitution of the conserved hydrophobic amino acid that was located two residues N-terminal to the tyrosine weakened, but did not eliminate, the function of the receptor. In contrast, these substitutions drastically reduced the amount of SHP-1 immunoprecipitated with KIR, suggesting that weak interactions with SHP-1 may be sufficient for inhibition.
IL-4 Selectively Inhibits IL-2-Triggered Stat5 Activation, But Not Proliferation, in Human T Cells
Authors: Castro Aaron , Sengupta Tapas K. , Ruiz Donna C. , Yang Edward , Ivashkiv Lionel B. 
Published: December 2022

AbstractIL-2 activates several distinct signaling pathways that are important for T cell activation, proliferation, and differentiation into both Th1 and Th2 phenotypes. IL-4, the major cytokine that promotes differentiation of Th2 cells, has been shown to block signaling of the Th1-promoting cytokine IL-12. As IL-2 synergizes with IL-12 in promoting Th1 differentiation, the effects of IL-4 on IL-2 signal transduction were investigated. IL-4 suppressed activation of DNA binding and tyrosine phosphorylation of the transcription factor Stat5 by IL-2, and suppressed the expression of the IL-2-inducible genes CD25, CIS, the PGE2 receptor, and cytokine responsive (CR) genes CR1 and CR8. Activation of Stat5 by cytokines that share a common γ receptor subunit, IL-2, IL-7, and IL-15, was suppressed by preculture in IL-4. Activation of the Jak1 and Jak3 kinases that are proximal to Stat5 in the IL-2-Jak-STAT signaling pathway was suppressed, and this correlated with inhibition of IL-2Rβ subunit expression. In contrast to suppression of Stat5, proliferative responses to IL-2 were augmented in IL-4-cultured cells, and activation of proliferative pathways leading to activation of mitogen activated protein kinases, induction of expression of Myc, Fos, Pim-1, and cyclin D3, and decreased levels of the cyclin-dependent kinase inhibitor p27 were intact. These results identify molecular mechanisms underlying interactions between IL-4 and IL-2 in T cells and demonstrate that one mechanism of regulation of IL-2 activity is selective and differential modulation of signaling pathways.
Comparison of Lung Dendritic Cells and B Cells in Stimulating Naive Antigen-Specific T Cells
Authors: Masten Barbara J. , Lipscomb Mary F. 
Published: December 2022

AbstractDendritic cells (DCs) are specialized APCs that are important in priming naive T cells and can be manipulated in vitro and in vivo to enhance immunizations against microorganisms and tumors. A limitation in the development of suitable immunotherapeutic vaccines for the lung is incomplete information on the role of DCs and other potential APCs in the lung in priming naive T cells. In the current study, we analyzed the relative contributions of murine lung DCs and B cells to process and present OVA to naive CD4+ OVA323–339-specific (DO11.10) T cells in vitro. We also examined their expression of MHC class II and accessory molecules before and after maturation in culture. Similar to DCs from other sites, freshly isolated lung DCs can process OVA, spontaneously up-regulate MHC class II and accessory molecules during overnight culture, and stimulate naive T cells in an Ag-specific manner. In contrast, freshly isolated lung B cells were unable to both process and present native OVA. Furthermore, under conditions of limited OVA323–339 peptide exposure, B cells had a significantly diminished capacity to stimulate T cells, and this correlated with a decreased density of both MHC class II and important costimulatory molecules as compared with lung DCs.
Specificity of the SH2 Domains of SHP-1 in the Interaction with the Immunoreceptor Tyrosine-Based Inhibitory Motif-Bearing Receptor gp49B
Authors: Wang Lawrence L. , Blasioli Julie , Plas David R. , Thomas Matthew L. , Yokoyama Wayne M. 
Published: December 2022

Abstract
Inhibitory receptors on hemopoietic cells critically regulate cellular function. Despite their expression on a variety of cell types, these inhibitory receptors signal through a common mechanism involving tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM), which engages Src homology 2 (SH2) domain-containing cytoplasmic tyrosine or inositol phosphatases. In this study, we have investigated the proximal signal-transduction pathway of an ITIM-bearing receptor, gp49B, a member of a newly described family of murine NK and mast cell receptors. We demonstrate that the tyrosine residues within the ITIMs are phosphorylated and serve for the association and activation of the cytoplasmic tyrosine phosphatase SHP-1. Furthermore, we demonstrate a physiologic association between gp49B and SHP-1 by coimmunoprecipitation studies from NK cells. To address the mechanism of binding between gp49B and SHP-1, binding studies involving glutathione S-transferase SHP-1 mutants were performed. Utilizing the tandem SH2 domains of SHP-1, we show that either SH2 domain can interact with phosphorylated gp49B. Full-length SHP-1, with an inactivated amino SH2 domain, also retained gp49B binding. However, binding to gp49B was disrupted by inactivation of the carboxyl SH2 domain of full-length SHP-1, suggesting that in the presence of the phosphatase domain, the carboxyl SH2 domain is required for the recruitment of phosphorylated gp49B. Thus, gp49B signaling involves SHP-1, and this association is dependent on tyrosine phosphorylation of the gp49B ITIMs, and an intact SHP-1 carboxyl SH2 domain.
Tpm1,a Locus Controlling IL-12 Responsiveness, Acts by a Cell-Autonomous Mechanism
Authors: Guler Mehmet L. , Gorham James D. , Dietrich William F. , Murphy Theresa L. , Steen Robert G. , Parvin Curtis A. , Fenoglio Dominic , Grupe Andrew , Peltz Gary , Murphy Kenneth M. 
Published: December 2022

AbstractTh phenotype development is controlled not only by cytokines but also by other parameters including genetic background. One site of genetic variation between murine strains that has direct impact on Th development is the expression of the IL-12 receptor. T cells from B10.D2 and BALB/c mice show distinct control of IL-12 receptor expression. When activated by Ag, B10.D2 T cells express functional IL-12 receptors and maintain IL-12 responsiveness. In contrast, under the same conditions, BALB/c T cells fail to express IL-12 receptors and become unresponsive to IL-12, precluding any Th1-inducing effects if subsequently exposed to IL-12. Previously, we identified a locus, which we termed T cell phenotype modifier 1 (Tpm1), on murine chromosome 11 that controls this differential maintenance of IL-12 responsiveness. In this study, we have produced a higher resolution map around Tpm1. We produced and analyzed a series of recombinants from a first-generation backcross that significantly narrows the genetic boundaries of Tpm1. This allowed us to exclude from consideration certain previous candidates for Tpm1, including IFN-regulatory factor-1. Also, cellular analysis of F1(B10.D2 × BALB/c) T cells demonstrates that Tpm1 exerts its effect on IL-12 receptor expression in a cell-autonomous manner, rather than through influencing the extracellular milieu. This result strongly implies that despite the proximity of our locus to the IL-13/IL-4 gene cluster, these cytokines are not candidates for Tpm1.
Evidence for Immune Regulation in the Induction of Transplantation Tolerance: A Conditional but Limited Role for IL-4
Authors: Bushell Andrew , Niimi Masanori , Morris Peter J. , Wood Kathryn J. 
Published: December 2022

AbstractMost experimental models of allograft tolerance depend on manipulation of immune responses at the time of transplant. In such systems, the graft itself probably plays an important role in the induction of unresponsiveness but as a consequence may suffer immune mediated damage. Ideally, recipients would be made specifically unresponsive before transplant such that the graft is protected from the outset. In this report, we demonstrate that CBA mice pretreated with donor-specific transfusion plus anti-CD4 Ab 28 days before transplant accept cardiac allografts indefinitely without further intervention. Adoptive transfer of spleen cells from mice with long term surviving grafts results in donor-specific graft acceptance in naive secondary recipients, indicating that tolerance in this system involves immuneregulation. Regulation develops as a result of the pretreatment protocol alone, since transfer of cells from pretreated but untransplanted mice to naive recipients also leads to prolonged allograft survival without additional therapy. Neutralizing IL-4 at the time of tolerance induction had no effect on graft outcome in primary recipients. However, removal of IL-4 from the adoptive transfer donors at the time of tolerance induction prevented long term engraftment in the majority of secondary recipients. Our data demonstrate that pretreatment of transplant recipients can establish immune regulation powerful enough to override the responses of an intact immune repertoire and that under stringent conditions at least, development of this regulatory population may in part be dependent on IL-4.
Induction of Specific T Cell Tolerance by Fas Ligand- Expressing Antigen-Presenting Cells
Authors: Zhang Huang-ge , Su Xiao , Liu Di , Liu Weimin , Yang Pingar , Wang Zheng , Edwards Carl K. , Bluethmann Horst , Mountz John D. , Zhou Tong 
Published: December 2022

AbstractAutocrine interaction of Fas and Fas ligand leads to apoptosis of activated T cells, a process that is critical for the maintenance of peripheral T cell tolerance. Paracrine interactions of Fas ligand with T cells also may play an important role in the maintenance of tolerance, as Fas ligand can create immune-privileged sites and prevent graft rejection by inducing apoptosis in T cells. We surmised that APCs that express Fas ligand might directly induce apoptosis of T cells during presentation of Ag to the T cells, thus inducing Ag-specific, systemic T cell tolerance. Here, we show that profound, specific T cell unresponsiveness to alloantigen was induced by treatment of H-2k mice with H-2b APCs that expressed Fas ligand and that profound T cell unresponsiveness specific for the H-Y Ag was induced by treatment of H-2Db/H-Y TCR transgenic female mice with H-2Db/H-Y APCs that expressed Fas ligand. The induction of this systemic T cell tolerance required the expression of Fas ligand on the APCs as well as the expression of Fas on the T cells. The tolerance was restricted to the Ag presented by the APCs. The rapid and profound clonal deletion of the Ag-specific, peripheral T cells mediated by the Fas ligand-expressing APCs contributed to the induction of tolerance. These findings demonstrate that Ag-specific T cell tolerance can be induced by APCs that express Fas ligand and suggest a novel function for APCs in the induction of T cell apoptosis. Furthermore, they indicate a novel immunointervention strategy for treatment of graft rejection and autoantigen-specific autoimmune diseases.
Evidence for Repression of IL-2 Gene Activation in Anergic T Cells
Authors: Telander David G. , Malvey Erika-Nell , Mueller Daniel L. 
Published: December 2022

AbstractThe induction of clonal anergy in a T cell inhibits IL-2 secretion because of the development of a proximal signal transduction defect. Fusion of anergic murine T cells to human Jurkat T leukemia cells and formation of heterokaryons failed to result in a complementation of this signaling defect and restoration of murine IL-2 mRNA inducibility. Instead, signal transduction to the human IL-2 gene became disrupted. Heterokaryons formed by the fusion of anergic murine T cells to normal murine T cells also failed to accumulate intracellular IL-2 protein in response to stimulation either with the combination of CD3 and CD28 mAbs or with ionomycin plus a protein kinase C-activating phorbol ester. The results argue against a loss-of-function signaling defect as the sole basis for clonal anergy induction and document the presence of a dominant-acting repressor molecule that inhibits signal transduction to the IL-2 gene within viable anergic T cells.
Structure and Genomic Organization of a Second Cluster of Immunoglobulin Heavy Chain Gene Segments in the Channel Catfish
Authors: Ghaffari Seyed H. , Lobb Craig J. 
Published: December 2022

Abstract
The structure, organization, and partial sequence of a 25-kb genomic region containing a second cluster of H chain gene segments in the channel catfish (Ictalurus punctatus) has been determined. Multiple VH gene segments, representing different VH families, are located upstream of a germline-joined VDJ. The VDJ segment has a split leader sequence and a single open reading consistent with that expressed in members of the VH1 family. Downstream of the germline-joined VDJ is a single JH segment and two pseudogene exons structurally similar to the Cμ1 and Cμ2 exons of the functional gene. Both pseudogene exons are multiply crippled with RNA splice sites destroyed, and open reading frames are interrupted by termination codons, insertions, and/or deletions. Sequence alignment of a 10.8-kb region within the second H chain cluster with the genomic sequence of the nine JH segments and the functional Cμ within the first H chain gene cluster indicates that the second H chain gene cluster probably arose by a massive duplication event. The JH region of the VDJ, the coding and flanking regions of the single JH segment, and the pseudogene Cμ exons were readily aligned with homologous segments in the first gene cluster. This duplication event may have extended to include the upstream VH segments. A member of the Tc1 mariner family of transposable elements is located downstream of the pseudogene Cμ2, which suggests that the transposition may have contributed to the evolution of the duplicated Cμ.
MHC Class II-Dependent NK1.1+ γδ T Cells Are Induced in Mice bySalmonellaInfection
Authors: Nishimura Hitoshi , Washizu Junji , Naiki Yoshikazu , Hara Toru , Fukui Yoshinori , Sasazuki Takehiko , Yoshikai Yasunobu 
Published: December 2022

AbstractWe observed the emergence of a novel population of γδ T cells expressing NK1.1 Ag in the peritoneal cavity of mice infected with Salmonella choleraesuis. The NK1.1+γδ T cells accounted for approximately 20% of all γδ T cells emerging in the peritoneal cavity of C57BL/6 mice and expressed preferentially rearranged Vγ4-Jγ1 and Vδ6.3-Dδ1-Dδ2-Jδ1 genes with N diversity. The γδ T cells proliferated vigorously in response to PHA-treated spleen cells and produced IFN-γ in the culture supernatant. However, spleen cells from Aβb-deficient mice were unable to stimulate the γδ T cells. Furthermore, the NK1.1+γδ T cells were stimulated not only by Chinese hamster ovary (CHO) cells expressing wild-type IAb but also by those expressing IAb/Eα52-68 or IAb/pigeon cytochrome c-derived analogue peptide complex. These proliferation activities were inhibited by mAb specific for IAb chain. Consistent with these findings, the emergence of NK1.1+γδ T cells was reduced in the peritoneal cavity of Aβb-deficient mice after Salmonella infection, whereas NK1.1+γδ T cells were rather abundant in the peritoneal cavity of Salmonella-infected β2m-deficient mice. Moreover, the NK1.1+γδ T cells were easily identified in the thymus of β2m-deficient but not Aβb-deficient mice. Our results indicated that MHC class II expression is essential for development and activation of NK1.1+γδ T cells in the thymus and the periphery.