bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rebuilding an Immune-Mediated Central Nervous System Disease: Weighing the Pathogenicity of Antigen-Specific versus Bystander T Cells
Authors: McGavern Dorian B. , Truong Phi 
Published: April 2014

Abstract
Although both self- and pathogen-specific T cells can participate in tissue destruction, recent studies have proposed that after viral infection, bystander T cells of an irrelevant specificity can bypass peptide-MHC restriction and contribute to undesired immunopathological consequences. To evaluate the importance of this mechanism of immunopathogenesis, we determined the relative contributions of Ag-specific and bystander CD8+ T cells to the development of CNS disease. Using lymphocytic choriomeningitis virus (LCMV) as a stimulus for T cell recruitment into the CNS, we demonstrate that bystander CD8+ T cells with an activated surface phenotype can indeed be recruited into the CNS over a chronic time window. These cells become anatomically positioned in the CNS parenchyma, and a fraction aberrantly acquires the capacity to produce the effector cytokine, IFN-γ. However, when directly compared with their virus-specific counterparts, the contribution of bystander T cells to CNS damage was insignificant in nature (even when specifically activated). Although bystander T cells alone failed to cause tissue injury, transferring as few as 1000 naive LCMV-specific CD8+ T cells into a restricted repertoire containing only bystander T cells was sufficient to induce immune-mediated pathology and reconstitute a fatal CNS disease. These studies underscore the importance of specific T cells in the development of immunopathology and subsequent disease. Because of highly restrictive constraints imposed by the host, it is more likely that specific, rather than nonspecific, bystander T cells are the active participants in T cell-mediated diseases that afflict humans.
A Novel Model for Lymphocytic Infiltration of the Thyroid Gland Generated by Transgenic Expression of the CC Chemokine CCL21
Authors: Martin Andrea P. , Coronel Elizabeth C. , Sano Gen-ichiro , Chen Shu-Cheng , Vassileva Galya , Canasto-Chibuque Claudia , Sedgwick Jonathon D. , Frenette Paul S. , Lipp Martin , Furtado Glaucia C. , Lira Sergio A. 
Published: April 2014

Abstract
Lymphocytic infiltrates and lymphoid follicles with germinal centers are often detected in autoimmune thyroid disease (AITD), but the mechanisms underlying lymphocyte entry and organization in the thyroid remain unknown. We tested the hypothesis that CCL21, a chemokine that regulates homeostatic lymphocyte trafficking, and whose expression has been detected in AITD, is involved in the migration of lymphocytes to the thyroid. We show that transgenic mice expressing CCL21 from the thyroglobulin promoter (TGCCL21 mice) have significant lymphocytic infiltrates, which are topologically segregated into B and T cell areas. Although high endothelial venules expressing peripheral lymph node addressin were frequently observed in the thyroid tissue, lymphocyte recruitment was independent of L-selectin or lymphotoxin-α but required CCR7 expression. Taken together, these results indicate that CCL21 is sufficient to drive lymphocyte recruitment to the thyroid, suggest that CCL21 is involved in AITD pathogenesis, and establish TGCCL21 transgenic mice as a novel model to study the formation and function of lymphoid follicles in the thyroid.
The Role of Dendritic Cells in Selection of Classical and Nonclassical CD8+ T Cells In Vivo
Authors: Cannarile Michael A. , Decanis Nadege , van Meerwijk Joost P. M. , Brocker Thomas 
Published: April 2014

Abstract
T cell development is determined by positive and negative selection events. An intriguing question is how signals through the TCR can induce thymocyte survival and maturation in some and programmed cell death in other thymocytes. This paradox can be explained by the hypothesis that different thymic cell types expressing self-MHC/peptide ligands mediate either positive or negative selection events. Using transgenic mice that express MHC class I (MHC-I) selectively on DC, we demonstrate a compartmentalization of thymic functions and reveal that DC induce CTL tolerance to MHC-I-positive hemopoietic targets in vivo. However, in normal and bone marrow chimeric mice, MHC-I+ DC are sufficient to positively select neither MHC-Ib (H2-M3)- nor MHC-Ia (H2-K)-restricted CD8+ T cells. Thus, thymic DC are specialized in tolerance induction, but cannot positively select the vast majority of MHC-I-restricted CD8+ T cells.
A-Kinase Anchoring Proteins Interact with Phosphodiesterases in T Lymphocyte Cell Lines
Authors: Asirvatham Angela L. , Galligan Sarah G. , Schillace Robynn V. , Davey Michael P. , Vasta Valeria , Beavo Joseph A. , Carr Daniel W. 
Published: April 2014

Abstract
The cAMP protein kinase A (PKA) pathway in T cells conveys an inhibitory signal to suppress inflammation. This study was performed to understand the mechanisms involved in cAMP-mediated signaling in T lymphocytes. A-kinase anchoring proteins (AKAPs) bind and target PKA to various subcellular locations. AKAPs also bind other signaling molecules such as cyclic nucleotide phosphodiesterases (PDEs) that hydrolyze cAMP in the cell. PDE4 and PDE7 have important roles in T cell activation. Based on this information, we hypothesized that AKAPs associate with PDEs in T lymphocytes. Immunoprecipitation of Jurkat cell lysates with Abs against both the regulatory subunit of PKA (RIIα) and specific AKAPs resulted in increased PDE activity associated with RIIα and AKAP95, AKAP149, and myeloid translocation gene (MTG) compared with control (IgG). Immunoprecipitation and pull-down analyses demonstrate that PDE4A binds to AKAP149, AKAP95, and MTG, but not AKAP79, whereas PDE7A was found to bind only MTG. Further analysis of MTG/PDE association illustrated that PDE4A and PDE7A bind residues 1–344 of MTG16b. Confocal analysis of HuT 78 cells stained with anti-PDE7A showed overlapping staining patterns with the Golgi marker GM130, suggesting that PDE7A is located in the Golgi. The staining pattern of PDE7A also showed similarity to the staining pattern of MTG, supporting the immunoprecipitation data and suggesting that MTG may interact with PDE7A in the Golgi. In summary, these data suggest that AKAPs interact with both PKA and PDE in T lymphocytes and thus are a key component of the signaling complex regulating T cell activation.
Localization of Marginal Zone Macrophages Is Regulated by C-C Chemokine Ligands 21/19
Authors: Ato Manabu , Nakano Hideki , Kakiuchi Terutaka , Kaye Paul M. 
Published: April 2014

AbstractThe marginal zone (MZ) of the spleen is an important site for the capture of blood-borne pathogens and a gateway for lymphocytes entering the white pulp. We have recently reported that Leishmania donovani infection results in a remarkably selective loss of MZ macrophages (MZM) from the MZ. To understand the basis of this observation, we have investigated how MZM maintain their anatomical distribution in the steady state in uninfected mice. We now report that plt/plt mice, which lack functional CCL19 and CCL21, have significantly reduced numbers of MZM compared with normal C57BL/6 (B6) mice. Similarly, in B6.CD45.1→plt/plt chimeras, donor-derived MZM were rare compared with the number observed in reciprocal plt/plt→B6.CD45.1 chimeras. Moreover, we show that administration of pertussis toxin, an inhibitor of chemokine receptor signaling, to B6 mice results in exit of MZM from the MZ, that MZM can migrate in response to CCL19 and CCL21 in vitro, and that MZM colocalize with CD31+CCL21+ endothelial cells. Collectively, these data indicate that CCL21 and, to a lesser extent, CCL19 play significant roles in the distinctive localization of MZM within the splenic MZ. Deficiency of CCL19 and CCL21, as also previously observed in mice infected with L. donovani, may thus account for the selective loss of MZM seen during this infection.
Th2 Response of Human Peripheral Monocytes Involves Isoform-Specific Induction of Monoamine Oxidase-A
Authors: Chaitidis Pavlos , Billett Ellen E. , O’Donnell Valerie B. , Fajardo Alexandra Bermudez , Fitzgerald Julia , Kuban Ralf J. , Ungethuem Ute , Kühn Hartmut 
Published: April 2014

Abstract
Monocyte/macrophage function is critically regulated by specific cytokines and growth factors that they are exposed to at inflammatory sites. IL-4 and IL-13 are multifunctional cytokines generated mainly by Th2 lymphocytes that have important biological activities in allergy and inflammation. The Th2 response of human peripheral monocytes is characterized by complex alterations in the gene expression pattern, which involves dominant expression of CD23 cell surface Ag and lipid-peroxidizing 15-lipoxygenase-1 (15-LOX1). In this study, we report that the classical Th2 cytokines IL-4 and IL-13 strongly up-regulate expression of monoamine oxidase A (MAO-A) with no induction of the closely related isozyme, MAO-B. Real-time PCR indicated a &gt;2000-fold up-regulation of the MAO-A transcripts, and immunohistochemistry revealed coexpression of the enzyme with 15-LOX1 in a major subpopulation of monocytes. MAO-A was also induced in lung carcinoma A549 cells by IL-4 in parallel with 15-LOX1. In promyelomonocytic U937 cells, which neither express 15-LOX1 nor MAO-A in response to IL-4 stimulation, expression of MAO-A was up-regulated following transfection with 15-LOX1. This is the first report indicating expression of MAO-A in human monocytes. Its isoform-specific up-regulation in response to Th2 cytokines suggests involvement of the enzyme in modulation of innate and/or acquired immune system.
Marrow Stromal Cells and Osteoclast Precursors Differentially Contribute to TNF-α-Induced Osteoclastogenesis In Vivo
Authors: Kitaura Hideki , Sands Mark S. , Aya Kunihiko , Zhou Ping , Hirayama Teruhisa , Uthgenannt Brian , Wei Shi , Takeshita Sunao , Novack Deborah Veis , Silva Matthew J. , Abu-Amer Yousef , Ross F. Patrick , Teitelbaum Steven L. 
Published: April 2014

Abstract
The marrow stromal cell is the principal source of the key osteoclastogenic cytokine receptor activator of NF-κB (RANK) ligand (RANKL). To individualize the role of marrow stromal cells in varying states of TNF-α-driven osteoclast formation in vivo, we generated chimeric mice in which wild-type (WT) marrow, immunodepleted of T cells and stromal cells, is transplanted into lethally irradiated mice deleted of both the p55 and p75 TNFR. As control, similarly treated WT marrow was transplanted into WT mice. Each group was administered increasing doses of TNF-α. Exposure to high-dose cytokine ex vivo induces exuberant osteoclastogenesis irrespective of in vivo TNF-α treatment or whether the recipient animals possess TNF-α-responsive stromal cells. In contrast, the osteoclastogenic capacity of marrow treated with lower-dose TNF-α requires priming by TNFR-bearing stromal cells in vivo. Importantly, the osteoclastogenic contribution of cytokine responsive stromal cells in vivo diminishes as the dose of TNF-α increases. In keeping with this conclusion, mice with severe inflammatory arthritis develop profound osteoclastogenesis and bone erosion independent of stromal cell expression of TNFR. The direct induction of osteoclast recruitment by TNF-α is characterized by enhanced RANK expression and sensitization of precursor cells to RANKL. Thus, osteolysis attending relatively modest elevations in ambient TNF-α depends upon responsive stromal cells. Alternatively, in states of severe periarticular inflammation, TNF-α may fully exert its bone erosive effects by directly promoting the differentiation of osteoclast precursors independent of cytokine-responsive stromal cells and T lymphocytes.
TCR- and CD28-Mediated Recruitment of Phosphodiesterase 4 to Lipid Rafts Potentiates TCR Signaling
Authors: Abrahamsen Hilde , Baillie George , Ngai Jacob , Vang Torkel , Nika Konstantina , Ruppelt Anja , Mustelin Tomas , Zaccolo Manuela , Houslay Miles , Taskén Kjetil 
Published: April 2014

AbstractLigation of the TCR along with the coreceptor CD28 is necessary to elicit T cell activation in vivo, whereas TCR triggering alone does not allow a full T cell response. Upon T cell activation of human peripheral blood T cells, we found that the majority of cAMP was generated in T cell lipid rafts followed by activation of protein kinase A. However, upon TCR and CD28 coligation, β-arrestin in complex with cAMP-specific phosphodiesterase 4 (PDE4) was recruited to lipid rafts which down-regulated cAMP levels. Whereas inhibition of protein kinase A increased TCR-induced immune responses, inhibition of PDE4 blunted T cell cytokine production. Conversely, overexpression of either PDE4 or β-arrestin augmented TCR/CD28-stimulated cytokine production. We show here for the first time that the T cell immune response is potentiated by TCR/CD28-mediated recruitment of PDE4 to lipid rafts, which counteracts the local, TCR-induced production of cAMP. The specific recruitment of PDE4 thus serves to abrogate the negative feedback by cAMP which is elicited in the absence of a coreceptor stimulus.
Identification of Novel Human Aggrecan T Cell Epitopes in HLA-B27 Transgenic Mice Associated with Spondyloarthropathy
Authors: Kuon Wolfgang , Kuhne Maren , Busch Dirk H. , Atagunduz Pamir , Seipel Martina , Wu Peihua , Morawietz Lars , Fernahl Gabriele , Appel Heiner , Weiss Elisabeth H. , Krenn Veit , Sieper Joachim 
Published: April 2014

AbstractThe pathology of ankylosing spondylitis, reactive arthritis, and other spondyloarthropathies (SpA) is closely associated with the human leukocyte class I Ag HLA-B27. A characteristic finding in SpA is inflammation of cartilage structures of the joint, in particular at the site of ligament/tendon and bone junction (enthesitis). In this study, we investigated the role of CD8+ T cells in response to the cartilage proteoglycan aggrecan as a potential candidate autoantigen in BALB/c-B27 transgenic mice. We identified four new HLA-B27-restricted nonamer peptides, one of them (no. 67) with a particularly strong T cell immunogenicity. Peptide no. 67 immunization was capable of stimulating HLA-B27-restricted, CD8+ T cells in BALB/c-B27 transgenic animals, but not in wild-type BALB/c mice. The peptide was specifically recognized on P815-B27 transfectants by HLA-B27-restricted CTLs, which were also detectable by HLA tetramer staining ex vivo as well as in situ. Most importantly, analysis of the joints from peptide no. 67-immunized mice induced typical histological signs of SpA. Our data indicate that HLA-B27-restricted epitopes derived from human aggrecan are involved in the induction of inflammation (tenosynovitis), underlining the importance of HLA-B27 in the pathogenesis of SpA.
IL-7 Gene Therapy in Aging Restores Early Thymopoiesis without Reversing Involution
Authors: Phillips Joy A. , Brondstetter Theresa I. , English Chauca A. , Lee Heidi E. , Virts Elizabeth L. , Thoman Marilyn L. 
Published: April 2014

Abstract
Thymic involution begins early in life and continues throughout adulthood, resulting in a decreased population of naive T cells in the periphery and a reduced ability to fight off newly encountered infectious diseases. We have previously shown that the first step of thymopoiesis is specifically blocked in aging. This block at the DN1 to DN2 transition and the subsequent loss of thymic output in old age mirrors the changes seen in IL-7-deficient mice, and it is hypothesized that decreased intrathymic IL-7 is involved in age-related thymic involution. To separate the effect of IL-7 on thymic involution from its function as a peripheral lymphocyte growth cofactor, we injected IL-7-secreting stromal cells into the thymi of recipient mice. The increased local concentration of IL-7 maintained the first step of thymopoiesis at a level far higher than was seen in age-matched controls. However, despite this success, there was no decrease in thymic involution or increase in T cell output. The inability of IL-7 to prevent involution led us to the discovery of an additional age-sensitive step in thymopoiesis, proliferation of the DN4 population, which is unaffected by IL-7 expression.
Flt3-Ligand, IL-4, GM-CSF, and Adherence-Mediated Isolation of Murine Lung Dendritic Cells: Assessment of Isolation Technique on Phenotype and Function
Authors: Swanson Kena A. , Zheng Yan , Heidler Kathleen M. , Zhang Zhen-Du , Webb Tonya J. , Wilkes David S. 
Published: April 2014

AbstractLung dendritic cells (DCs) are difficult to study due to their limited quantities and the complexities required for isolation. Although many procedures have been used to overcome this challenge, the effects of isolation techniques on lung DCs have not been reported. The current study shows that freshly isolated DCs (CD11c+) have limited ability to induce proliferation in allogeneic T cells, and are immature as indicated by low cell surface expression of costimulatory molecules compared with liver or splenic DCs. DCs isolated after overnight culture or from mice treated with Flt3L are phenotypically mature and potent stimulators of allogeneic T cells. DCs could not be propagated from lung mononuclear cells in response to IL-4 and GM-CSF. Contrary to data reported for nonpulmonary DCs, expression of CCR6 was decreased on mature lung DCs, and only a subset of mature DCs expressed higher levels of CCR7. Absence of CD8α expression indicates that freshly isolated DCs are myeloid-type, whereas mature DCs induced by overnight culture are both “lymphoid” (CD8α+) and “myeloid” (CD8α−). DCs from mice genetically deficient in CD8α expression were strong simulators of allogeneic T cells which was consistent with data showing that CD8α− DCs from CD8α-sufficient mice are better APCs compared with CD8α+ DCs from the same mice. These data show that freshly isolated lung DCs are phenotypically and functionally distinct, and that the isolation technique alters the biology of these cells. Therefore, lung DC phenotype and function must be interpreted relative to the technique used for isolation.
Initiation of Cellular Organization in Lymph Nodes Is Regulated by Non-B Cell-Derived Signals and Is Not Dependent on CXC Chemokine Ligand 13
Authors: Cupedo Tom , Lund Frances E. , Ngo Vu N. , Randall Troy D. , Jansen Wendy , Greuter Mascha J. , de Waal-Malefyt Rene , Kraal Georg , Cyster Jason G. , Mebius Reina E. 
Published: April 2014

Abstract
The molecular and cellular events that initiate the formation of T and B cell areas in developing lymph nodes are poorly understood. In this study we show that formation of the lymphoid architecture in murine neonatal lymph nodes evolves through a series of distinct stages. The initial segregation of T and B cells is regulated in a CXCL13-independent manner, characterized by the localization of B cells in a ring-like pattern in the outer cortex on day 4. However, during this CXCL13-independent phase of lymph node modeling, CXCL13 is expressed and regulated in a lymphotoxin-α1β2 (LTα1β2)-dependent manner. Surprisingly, neonatal B cells are unable to respond to this chemokine and also lack surface LTα1β2 expression. At this time, CD45+CD4+CD3− cells are the predominant LTα1β2-expressing cells and are also capable of responding to CXCL13. From day 4 on, architectural changes become CXCL13 dependent, and B cells become fully CXCL13 responsive, express LTα1β2, and cluster in anatomically distinct follicles. Because the initial induction of CXCL13 is dependent on LTα1β2, a role for CD45+CD4+CD3− cells in inducing chemokine expression in the developing lymph nodes is proposed and, as such, a role in initiation of the shaping of the microenvironment.
E2f1Mutation Induces Early Onset of Diabetes and Sjögren’s Syndrome in Nonobese Diabetic Mice
Authors: Salam Mohammad Abdus , Matin Khairul , Matsumoto Naoko , Tsuha Yuzo , Hanada Nobuhiro , Senpuku Hidenobu 
Published: April 2014

AbstractE2f1 is an important regulator of T cell proliferation, differentiation, and apoptosis that controls the transcription of a group of genes that are normally regulated at the G1 to S phase transition in the cell cycle. Insulin-dependent diabetes mellitus (IDDM) and Sjögren’s syndrome (SS) are highly regulated autoimmune diseases that develop spontaneously in NOD mice. The aim of the present in vivo study was to explore the functional importance of the E2f1 molecule in IDDM and SS, in the context of whole animal physiology and pathophysiology, using E2f1-deficient NOD mice. For the experiment, we produced NOD mice homozygous for a nonfunctional E2f1 allele onto a NOD background. E2f1-deficient NOD mice developed an early and increased onset of diabetes as compared with their littermates. These mice also exhibited a defect in T lymphocyte development, leading to excessive numbers of mature T cells (CD4+ and CD8+), due to a maturation stage-specific defect in the apoptosis of thymocytes and peripheral T cells. We also found that they also exhibited a more rapid and increased entry into the S phase following antigenic stimulation of spleen cells and thymocytes in vitro. Furthermore, E2f1-deficient mice showed a profound decrease of immunoregulatory CD4+CD25+ T cells, while the spleen cells of NOD mice lacking E2f1 showed a significant increase of the proinflammatory cytokine IFN-γ following antigenic stimulation in vitro. Consistent with these observations, E2f1 homozygous mutant NOD mice were highly predisposed to the development of IDDM and SS.
Restriction of De Novo Nucleotide Biosynthesis Interferes with Clonal Expansion and Differentiation into Effector and Memory CD8 T Cells
Authors: Quéméneur Laurence , Beloeil Laurent , Michallet Marie-Cécile , Angelov Georgi , Tomkowiak Martine , Revillard Jean-Pierre , Marvel Jacqueline 
Published: April 2014

AbstractNucleotide synthesis inhibitors are currently used in neoplastic diseases or as immunosuppressive agents for the prevention of acute rejection in organ transplantation and the treatment of autoimmune disorders. We have previously described that these inhibitors interfere with proliferation and survival of primary T cells in vitro. However, the precise effects of nucleotide restriction on effector and memory functions have not been elucidated. In this study, we investigated the impact of nucleotide synthesis inhibition on CD8 T cell differentiation by using TCR transgenic mice (F5) specific for the influenza virus nucleoprotein 68 peptide presented on the H-2Db molecule. Our results show that methotrexate and 5-fluorouracil prevent the acquisition of effector functions, such as IFN-γ, granzyme B expression, and cytotoxic function following antigenic stimulation of naive cells. Surprisingly, in the presence of mycophenolate mofetil, activated F5 cells are still able to produce granzyme B and to kill target cells but to a lesser extent compared with control. All three inhibitors interfere with the differentiation of naive cells into memory CD8 T cells. In contrast, the drugs are unable to inhibit the development of improved cytotoxic functions displayed by memory CD8 T cells.