bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mouse Lysozyme-M Knockout Mice Reveal How the Self-Determinant Hierarchy Shapes the T Cell Repertoire against This Circulating Self Antigen in Wild-Type Mice
Authors: Sinha Pratima , Chi Howard H. , Kim Hong R. , Clausen Björn E. , Pederson Brian , Sercarz Eli E. , Forster Irmgard , Moudgil Kamal D. 
Published: April 2014

AbstractWe have studied T cell tolerance to defined determinants within ML-M using wild-type (WT; ML-M+/+) and LysMcre (ML-M−/−) C3H (H-2k) mice to determine the relative contribution of ML-M-derived epitopes vs those from other self Ags in selection of the ML-M-specific T cell repertoire. ML-M was totally nonimmunogenic in WT mice, but was rendered immunogenic in LysMcre mice. Most of the response to ML-M in LysMcre mice was directed to the immunodominant determinant region 105–119. This determinant is spontaneously displayed (without adding exogenous ML-M) by macrophages of WT, but not LysMcre, mice and is stimulatory for peptide 105–119 (p105–119)-primed T cells. Moreover, neonatal tolerization of LysMcre mice with p105–119 or ML-M abrogated the T cell response to subsequent challenge with ML-M or p105–119. Furthermore, p95–109 and p110–125 of ML-M were immunogenic in LysMcre mice, but not in WT mice, thereby representing subdominant, tolerance-inducing epitopes of ML-M. As expected, the T cell repertoire to cryptic ML determinants in WT mice was also intact in LysMcre mice. Furthermore, the pattern of response to the related homologue of ML-M, hen eggwhite lysozyme, was similar in these two groups of mice. Thus, several codominant T cell determinants within ML-M contribute significantly to tolerance induction, and the anti-cryptic T cell repertoire to ML-M was positively selected on non-ML-M self ligands. These results reveal that the induction of self tolerance to a multideterminant protein follows the quantitative hierarchy of self-determinant expression and are of relevance in understanding the pathogenesis of autoimmunity.
Endogenous Expression of Activation-Induced Cytidine Deaminase in Cell Line WEHI-231
Authors: Spillmann Freia J. X. , Wabl Matthias 
Published: April 2014

Abstract
Because of its susceptibility to apoptosis on Ag receptor cross-linking, cells of the mouse cell line WEHI-231 have been classified as immature B cells. Surprisingly, however, the cell line expresses activation-induced cytidine deaminase, the enzyme that mediates hypermutation and Ig class switch recombination in activated B cells. Although both cDNA sequence and protein expression of activation-induced cytidine deaminase appear normal, the cell line does not hypermutate an indicator plasmid. For the readout, the indicator plasmid depends on the removal of deoxyuridine after transition from C to U and, therefore, on functional expression of uracil N-glycosylase 2, which is normal in WEHI-231. At the endogenous Ig locus, however, WEHI-231 does undergo the canonical hypermutation of G · C to A · T base pairs to some extent. The cell line also expresses the germline transcripts of the Ig γ2b, ε, and α loci, but it does not switch its IgM surface Ig.
Blockade of CXCR3 Receptor:Ligand Interactions Reduces Leukocyte Recruitment to the Lung and the Severity of Experimental Idiopathic Pneumonia Syndrome
Authors: Hildebrandt Gerhard C. , Corrion Leigh A. , Olkiewicz Krystyna M. , Lu Bao , Lowler Kathleen , Duffner Ulrich A. , Moore Bethany B. , Kuziel William A. , Liu Chen , Cooke Kenneth R. 
Published: April 2014

Abstract
Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication after allogeneic stem cell transplantation (allo-SCT) that responds poorly to standard immunosuppressive therapy. The pathophysiology of IPS involves the secretion of inflammatory cytokines including IFN-γ and TNF-α along with the recruitment of donor T cells to the lung. CXCR3 is a chemokine receptor that is expressed on activated Th1/Tc1 T cell subsets and the expression of its ligands CXCL9 (monokine induced by IFN-γ (Mig)) and CXCL10 (IFN-γ-inducible protein 10 (IP-10)) can be induced in a variety of cell types by IFN-γ alone or in combination with TNF-α. We used a lethally irradiated murine SCT model (B6 → bm1) to evaluate the role of CXCR3 receptor:ligand interactions in the development of IPS. We found that Mig and IP-10 protein levels were significantly elevated in the bronchoalveolar lavage fluid of allo-SCT recipients compared with syngeneic controls and correlated with the infiltration of IFN-γ-secreting CXCR3+ donor T cells into the lung. The in vivo neutralization of either Mig or IP-10 significantly reduced the severity of IPS compared with control-treated animals, and an additive effect was observed when both ligands were blocked simultaneously. Complementary experiments using CXCR3−/− mice as SCT donors also resulted in a significant decrease in IPS. These data demonstrate that interactions involving CXCR3 and its primary ligands Mig and IP-10 significantly contribute to donor T cell recruitment to the lung after allo-SCT. Therefore, approaches focusing on the abrogation of these interactions may prove successful in preventing or treating lung injury that occurs in this setting.
A Stable Aspirin-Triggered Lipoxin A4 Analog Blocks Phosphorylation of Leukocyte-Specific Protein 1 in Human Neutrophils
Authors: Ohira Taisuke , Bannenberg Gerard , Arita Makoto , Takahashi Minoru , Ge Qingyuan , Van Dyke Thomas E. , Stahl Gregory L. , Serhan Charles N. , Badwey John A. 
Published: April 2014

Abstract
Lipoxins and their aspirin-triggered 15-epimers are endogenous anti-inflammatory agents that block neutrophil chemotaxis in vitro and inhibit neutrophil influx in several models of acute inflammation. In this study, we examined the effects of 15-epi-16-(p-fluoro)-phenoxy-lipoxin A4 methyl ester, an aspirin-triggered lipoxin A4-stable analog (ATLa), on the protein phosphorylation pattern of human neutrophils. Neutrophils stimulated with the chemoattractant fMLP were found to exhibit intense phosphorylation of a 55-kDa protein that was blocked by ATLa (10–50 nM). This 55-kDa protein was identified as leukocyte-specific protein 1, a downstream component of the p38-MAPK cascade in neutrophils, by mass spectrometry, Western blotting, and immunoprecipitation experiments. ATLa (50 nM) also reduced phosphorylation/activation of several components of the p38-MAPK pathway in these cells (MAPK kinase 3/MAPK kinase 6, p38-MAPK, MAPK-activated protein kinase-2). These results indicate that ATLa exerts its anti-inflammatory effects, at least in part, by blocking activation of the p38-MAPK cascade in neutrophils, which is known to promote chemotaxis and other proinflammatory responses by these cells.
Protective Role of Arginase in a Mouse Model of Colitis
Authors: Gobert Alain P. , Cheng Yulan , Akhtar Mahmood , Mersey Benjamin D. , Blumberg Darren R. , Cross Raymond K. , Chaturvedi Rupesh , Drachenberg Cinthia B. , Boucher Jean-Luc , Hacker Amy , Casero Robert A. , Wilson Keith T. 
Published: April 2014

AbstractArginase is the endogenous inhibitor of inducible NO synthase (iNOS), because both enzymes use the same substrate, l-arginase (Arg). Importantly, arginase synthesizes ornithine, which is metabolized by the enzyme ornithine decarboxylase (ODC) to produce polyamines. We investigated the role of these enzymes in the Citrobacter rodentium model of colitis. Arginase I, iNOS, and ODC were induced in the colon during the infection, while arginase II was not up-regulated. l-Arg supplementation of wild-type mice or iNOS deletion significantly improved colitis, and l-Arg treatment of iNOS−/− mice led to an additive improvement. There was a significant induction of IFN-γ, IL-1, and TNF-α mRNA expression in colitis tissues that was markedly attenuated with l-Arg treatment or iNOS deletion. Treatment with the arginase inhibitor S-(2-boronoethyl)-l-cysteine worsened colitis in both wild-type and iNOS−/− mice. Polyamine levels were increased in colitis tissues, and were further increased by l-Arg. In addition, in vivo inhibition of ODC with α-difluoromethylornithine also exacerbated the colitis. Taken together, these data indicate that arginase is protective in C. rodentium colitis by enhancing the generation of polyamines in addition to competitive inhibition of iNOS. Modulation of the balance of iNOS and arginase, and of the arginase-ODC metabolic pathway may represent a new strategy for regulating intestinal inflammation.
Central Memory CD4+ T Cell Responses in Chronic HIV Infection Are Not Restored by Antiretroviral Therapy
Authors: Elrefaei Mohamed , McElroy Michael D. , Preas Christopher P. , Hoh Rebecca , Deeks Steven , Martin Jeffrey , Cao Huyen 
Published: April 2014

Abstract
A strong CD4+ T cell response has been correlated with better control of HIV infection. However, the effect of HIV on the maintenance of Ag-specific memory CD4+ T cells is not fully understood. We characterized the function and phenotype of memory CD4+ T cells generated by mumps and influenza A or B viruses in HIV-infected individuals receiving highly active antiretroviral therapy (n = 21), HIV-infected long-term nonprogressors (n = 10), and HIV-seronegative volunteers (n = 10). We observed significantly decreased proliferation of the Ag-specific central memory CD4+ T cell population (CD28+/CCR7+/CD45RA−) in the antiretroviral treated HIV-infected individuals compared with the seronegative controls. Restored CD4+ T cell count and decreased HIV viral load while on highly active antiretroviral therapy did not result in increased proliferation, whereas nadir CD4+ T cell count predicted the presence of Ag-specific proliferation. Our results indicate that HIV infection leads to impaired maintenance of virus-induced or vaccine-generated central memory CD4+ T cells that is not restored by HAART.
Induction of Human T Cell Leukemia Virus Type I Receptors on Quiescent Naive T Lymphocytes by TGF-β
Authors: Jones Kathryn S. , Akel Salem , Petrow-Sadowski Cari , Huang Ying , Bertolette Daniel C. , Ruscetti Francis W. 
Published: April 2014

Abstract
The retrovirus human T cell leukemia virus (HTLV) type I (HTLV-I) is primarily transmitted by breast-feeding or sexual contact, by cell-to-cell contact between T cells. TGF-β, which has been shown to enhance transmission of HTLV-I in vitro, is found at high levels in breast milk and semen. In this study, the ability of TGF-β to regulate expression of molecules involved in HTLV-I binding and entry was examined. Previous studies using a soluble form of the HTLV-I envelope protein SU have shown that quiescent human T cells do not express cell surface molecules that specifically bind SU. After T cell activation, HTLV SU binding proteins are rapidly induced. In this study, we report that TGF-β induces expression of proteins that bind soluble HTLV SU and HTLV virions on naive CD4+ T lymphocytes. The induction of these proteins occurred without cell cycle entry or expression of activation markers, involved TGF-β-induced intracellular signaling, and required de novo transcription and translation. Treatment of naive CD4+ T lymphocytes with TGF-β induced expression of GLUT-1, which has recently been reported to function as a receptor for HTLV. Treatment of a TGF-β-sensitive human myeloid cell line increased the titer of both HTLV-I- and HTLV-II-pseudotyped viruses. Although earlier studies suggested that HTLV SU binding proteins might be an early marker of T cell activation and/or cell proliferation, we report in this study that TGF-β induces binding of HTLV virions and expression of glucose transporter type 1 in primary CD4+ T lymphocytes that remain quiescent.
Identification of a Macrophage-Specific Chromatin Signature in the IL-10 Locus
Authors: Saraiva Margarida , Christensen Jillian R. , Tsytsykova Alla V. , Goldfeld Anne E. , Ley Steven C. , Kioussis Dimitris , O′Garra Anne 
Published: April 2014

Abstract
The molecular mechanisms that regulate expression of the immunosuppressive cytokine IL-10 remain poorly understood. In this study, by measuring sensitivity to DNase I digestion, we show that production of IL-10 by primary mouse bone marrow-derived macrophages stimulated through pattern recognition receptors was associated with chromatin remodeling of the IL-10 locus. We also demonstrate that the IL-10 locus is remodeled in primary Th2 cells and IL-10-producing regulatory T cells that have been differentiated in vitro. Strikingly, a novel DNase I-hypersensitive site (HSS-4.5) was identified in stimulated macrophages, but not in T cells. We show that hyperacetylated histones were recruited to this site in stimulated macrophages. Furthermore, HSS-4.5 is highly conserved and contains a putative NF-κB binding site. In support of a function for this site, NF-κB p65/RelA was recruited to HSS-4.5 in vivo and its activation was required for optimal IL-10 gene expression in LPS-stimulated macrophages.
A Critical Role for Sialylation in Cryoglobulin Activity of Murine IgG3 Monoclonal Antibodies
Authors: Kuroda Yasuhiro , Kuroki Aki , Kikuchi Shuichi , Funase Takaaki , Nakata Munehiro , Izui Shozo 
Published: April 2014

AbstractCryoprecipitating IgG3 autoantibodies have been shown to play a significant role in the development of murine lupus-like autoimmune syndrome. However, the structural basis of IgG3 cryoprecipitation still remains to be defined. In view of the implication of positively charged amino acid residues present in variable regions in IgG3 cryoglobulin activity, we explored the role of terminal sialic acids in oligosaccharide side chains for the cryogenic activity of IgG3 mAb. Comparative oligosaccharide structural analysis of different cryogenic and non-cryogenic IgG3 mAb showed an inverse correlation between the extent of sialylation and cryogenic activity. The inhibitory role of sialylation was further confirmed by the demonstration of enrichment of less and more sialylated IgG3 in cryoprecipitated and noncryoprecipitated fractions, respectively, separated from four different cryogenic IgG3 mAb. Significantly, the sialic acid contents of the latter fraction became comparable to those of non-cryogenic IgG3 mAb. Finally, we observed that highly sialylated non-cryogenic IgG3 mAb was more potent in the inhibition of cryoprecipitation of cryogenic IgG3 mAb. Our results thus suggest that the content of negatively charged sialic acids in oligosaccharide side chains is one of the critical factors to determine IgG3 cryoglobulin activity, along with amino acid sequences of the IgG3 variable regions.
Influence of β1 Integrin Intracytoplasmic Domains in the Regulation of VLA-4-Mediated Adhesion of Human T Cells to VCAM-1 under Flow Conditions
Authors: Rosenthal-Allieri Maria Alessandra , Ticchioni Michel , Breittmayer Jean Philippe , Shimizu Yoji , Bernard Alain 
Published: April 2014

Abstract
The VLA-4 integrin supports static cell-cell, cell-matrix adhesion, and dynamic interactions with VCAM-1. Although functions for well-conserved β1 integrin cytoplasmic domains in regulating static cell adhesion has been established, the molecular basis for β1 integrin-dependent arrest on VCAM-1 under flow conditions remains poorly understood. We have transfected the β1 integrin-deficient A1 Jurkat T cell line with β1 cDNA constructs with deletions of the NPXY motifs and specific mutations of tyrosine residues. Deletion of either NPXY motif impaired static adhesion induced by CD2 or CD47 triggering or direct β1 integrin stimulation. In contrast, PMA-induced adhesion to VCAM-1 was unaffected by deletion of the NPIY motif and only slightly impaired by deletion of NPKY. Moreover, deletion of the NPIY motif resulted in enhanced rolling and reduced arrest on VCAM-1 under shear flow conditions. In contrast, deletion of the NPKY motif did not alter arrest under flow. Although tyrosine to phenylalanine substitutions within two NPXY motifs did not alter static adhesion to VCAM-1, these mutations enhanced arrest on VCAM-1 under flow conditions. Furthermore, although deletion of the C′-terminal 5 AA of the β1 cytoplasmic domain dramatically impaired activation-dependent static adhesion, it did not impair arrest on VCAM-1 under flow conditions. Thus, our results demonstrate distinct structural requirements for VLA-4 function under static and shear flow conditions. This may be relevant for VLA-4 activity regulation in different anatomic compartments, such as when circulating cells arrest on inflamed endothelium under shear flow and when resident cells in bone marrow interact with VCAM-1- positive stromal cells.
Genetic Dissection of Systemic Lupus Erythematosus Pathogenesis: Partial Functional Complementation betweenSle1andSle3/5Demonstrates Requirement for Intracellular Coexpression for Full Phenotypic Expression of Lupus
Authors: Wakui Masatoshi , Morel Laurence , Butfiloski Edward J. , Kim Chunsun , Sobel Eric S. 
Published: April 2014

AbstractSle1 on chromosome 1 and Sle3/5 on chromosome 7 are two of the most critical lupus susceptibility loci of the New Zealand Black/White-derived NZM2410 mouse strain. In contrast to C57BL/6 mice congenic for either Sle1 (B6.Sle1) or Sle3/5 (B6.Sle3/5), strains that express only a modest lupus-related phenotype, the bicongenic B6.Sle1.Sle3/5 strain has a robust phenotype, suggesting a critical role for epistatic interactions in lupus pathogenesis. Mixed chimera experiments indicated that the two loci are functionally expressed by different cell populations and predicted that phenotypic expression of the phenotypic features of the B6.Sle1.Sle3/5 strain could be fully reproduced with a combination of B6.Sle1 and B6.Sle3/5 bone marrow. Contrary to our expectations, there was only a partial functional complementation in these mixed chimeras. Spleen enlargement, CD4:CD8 ratio elevation, and epitope spreading of autoantibodies were fully developed in B6+B6.Sle1.Sle3/5 but not in B6.Sle1+B6.Sle3/5 mixed chimeras. This study is the first to present evidence that the pathways mediated by two critical lupus susceptibility loci derived from the New Zealand White strain must be integrated intracellularly for epistatic interactions to occur. Our mixed chimera approach continues to provide novel insights into the functional genetic pathways underlying this important murine model of systemic autoimmunity.
Inefficient Cross-Presentation Limits the CD8+ T Cell Response to a Subdominant Tumor Antigen Epitope
Authors: Otahal Pavel , Hutchinson Sandra C. , Mylin Lawrence M. , Tevethia M. Judith , Tevethia Satvir S. , Schell Todd D. 
Published: April 2014

AbstractCD8+ T lymphocytes (TCD8) responding to subdominant epitopes provide alternate targets for the immunotherapy of cancer, particularly when self-tolerance limits the response to immunodominant epitopes. However, the mechanisms that promote TCD8 subdominance to tumor Ags remain obscure. We investigated the basis for the lack of priming against a subdominant tumor epitope following immunization of C57BL/6 (B6) mice with SV40 large tumor Ag (T Ag)-transformed cells. Immunization of B6 mice with wild-type T Ag-transformed cells primes TCD8 specific for three immunodominant T Ag epitopes (epitopes I, II/III, and IV) but fails to induce TCD8 specific for the subdominant T Ag epitope V. Using adoptively transferred TCD8 from epitope V-specific TCR transgenic mice and immunization with T Ag-transformed cells, we demonstrate that the subdominant epitope V is weakly cross-presented relative to immunodominant epitopes derived from the same protein Ag. Priming of naive epitope V-specific TCR transgenic TCD8 in B6 mice required cross-presentation by host APC. However, robust expansion of these TCD8 required additional direct presentation of the subdominant epitope by T Ag-transformed cells and was only significant following immunization with T Ag-expressing cells lacking the immunodominant epitopes. These results indicate that limited cross-presentation coupled with competition by immunodominant epitope-specific TCD8 contributes to the subdominant nature of a tumor-specific epitope. This finding has implications for vaccination strategies targeting TCD8 responses to cancer.
Phenotype and Homing of CD4 Tumor-Specific T Cells Is Modulated by Tumor Bulk
Authors: Benigni Fabio , Zimmermann Valérie S. , Hugues Stephanie , Caserta Stefano , Basso Veronica , Rivino Laura , Ingulli Elizabeth , Malherbe Laurent , Glaichenhaus Nicolas , Mondino Anna 
Published: April 2014

AbstractTechnical difficulties in tracking endogenous CD4 T lymphocytes have limited the characterization of tumor-specific CD4 T cell responses. Using fluorescent MHC class II/peptide multimers, we defined the fate of endogenous Leishmania receptor for activated C kinase (LACK)-specific CD4 T cells in mice bearing LACK-expressing TS/A tumors. LACK-specific CD44highCD62Llow CD4 T cells accumulated in the draining lymph nodes and had characteristics of effector cells, secreting IL-2 and IFN-γ upon Ag restimulation. Increased frequencies of CD44highCD62Llow LACK-experienced cells were also detected in the spleen, lung, liver, and tumor itself, but not in nondraining lymph nodes, where the cells maintained a naive phenotype. The absence of systemic redistribution of LACK-specific memory T cells correlated with the presence of tumor. Indeed, LACK-specific CD4 T cells with central memory features (IL-2+IFN-γ−CD44highCD62Lhigh cells) accumulated in all peripheral lymph nodes of mice immunized with LACK-pulsed dendritic cells and after tumor resection. Together, our data demonstrate that although tumor-specific CD4 effector T cells producing IFN-γ are continuously generated in the presence of tumor, central memory CD4 T cells accumulate only after tumor resection. Thus, the continuous stimulation of tumor-specific CD4 T cells in tumor-bearing mice appears to hinder the systemic accumulation of central memory CD4 T lymphocytes.
Nitric Oxide Inhibits IFN-α Production of Human Plasmacytoid Dendritic Cells Partly via a Guanosine 3′,5′-Cyclic Monophosphate-Dependent Pathway
Authors: Morita Rimpei , Uchiyama Takashi , Hori Toshiyuki 
Published: April 2014

Abstract
NO, a free radical gas, is known to be critically involved not only in vascular relaxation but also in host defense. Besides direct bactericidal effects, NO has been shown to inhibit Th1 responses and modulate immune responses in vivo, although the precise mechanism is unclear. In this study, we examined the effect of NO on human plasmacytoid dendritic cells (pDCs) to explore the possibility that NO might affect innate as well as adaptive immunity through pDCs. We found that NO suppressed IFN-α production of pDCs partly via a cGMP-dependent mechanism, which was accompanied by down-regulation of IFN regulatory factor 7 expression. Furthermore, treatment of pDCs with NO decreased production of IL-6 and TNF-α and up-regulated OX40 ligand expression. In accordance with these changes, pDCs treated with NO plus CpG-oligodeoxynucleotide AAC-30 promoted differentiation of naive CD4+ T cells into a Th2 phenotype. Moreover, pDCs did not express inducible NO synthase even after treatment with AAC-30, LPS, and several cytokines. These results suggest that exogenous NO and its second messenger, cGMP, alter innate as well as adaptive immune response through modulating the functions of pDCs and may be involved in the pathogenesis of certain Th2-dominant allergic diseases.