bluuebunny/crossref_metadata_2025_split huggingface dataset:
Naive, Effector, and Memory T Lymphocytes Efficiently Scan Dendritic Cells In Vivo: Contact Frequency in T Cell Zones of Secondary Lymphoid Organs Does Not Depend on LFA-1 Expression and Facilitates Survival of Effector T Cells
Authors: Westermann Jürgen , Bode Ulrike , Sahle Andrea , Speck Uwe , Karin Nathan , Bell Eric B. , Kalies Kathrin , Gebert Andreas 
Published: April 2014

Abstract
Contact between T cells and dendritic cells (DCs) is required for their subsequent interaction leading to the induction of adaptive immune responses. Quantitative data regarding the contact frequencies of T cell subsets in different lymphoid organs and species are lacking. Therefore, naive, effector, and memory CD4 T cells were injected into rats in absence of the cognate Ag, and 0.5–96 h later, spleen, lymph nodes, and Peyer’s patches were removed. Cryosections were analyzed for contact between donor T cells and endogenous DCs in the T cell zone, and donor cell proliferation. More than 60% of injected naive CD4 T cells were in contact with endogenous DCs at all time points and in all organs analyzed. Surprisingly, we were unable to detect any differences between naive, effector, and memory CD4 T cells despite different expression levels of surface molecules. In addition, contact frequency was similar for T cells in lymphoid organs of rats, mice, and humans; it was unaffected by the absence of LFA-1 (CD11a/CD18), and sustained effector T cells in an activated state. Thus, the architecture of the T cell zone rather than expression patterns of surface molecules determines the contact efficiency between T cells and DCs in vivo.
Thymic Anlage Is Colonized by Progenitors Restricted to T, NK, and Dendritic Cell Lineages
Authors: Masuda Kyoko , Itoi Manami , Amagai Takashi , Minato Nagahiro , Katsura Yoshimoto , Kawamoto Hiroshi 
Published: April 2014

AbstractIt remains controversial whether the thymus-colonizing progenitors are committed to the T cell lineage. A major problem that has impeded the characterization of thymic immigrants has been that the earliest intrathymic progenitors thus far identified do not necessarily represent the genuine thymic immigrants, because their developmental potential should have been influenced by contact with the thymic microenvironment. In the present study, we examined the developmental potential of the ontogenically earliest thymic progenitors of day 11 murine fetus. These cells reside in the surrounding mesenchymal region and have not encountered thymic epithelial components. Flow cytometric and immunohistochemical analyses demonstrated that these cells are exclusively Lin−c-kit+IL-7R+. Limiting dilution analyses disclosed that the progenitors with T cell potential were abundant, while those with B cell potential were virtually absent in the region of day 11 thymic anlage. Clonal analyses reveled that they are restricted to T, NK, and dendritic cell lineages. Each progenitor was capable of forming a large number of precursors that may clonally accommodate highly diverse TCRβ chains. These results provide direct evidence that the progenitors restricted to the T/NK/dendritic cell lineage selectively immigrate into the thymus.
Antiangiogenic Drugs Synergize with a Membrane Macrophage Colony-Stimulating Factor-Based Tumor Vaccine to Therapeutically Treat Rats with an Established Malignant Intracranial Glioma
Authors: Jeffes Edward W. B. , Zhang Jian Gang , Hoa Neil , Petkar Animesh , Delgado Christina , Chong Samuel , Obenaus Andre , Sanchez Ramon , Khalaghizadeh Sakineh , Khomenko Tetyana , Knight Brandon A. , Alipanah Reza , Nguyen Tuong-Vi , Shah Chirag , Vohra Seema , Zhuang Jing-Li , Liu Jessie , Wepsic H. Terry , Jadus Martin R. 
Published: April 2014

AbstractCombining a T9/9L glioma vaccine, expressing the membrane form of M-CSF, with a systemic antiangiogenic drug-based therapy theoretically targeted toward growth factor receptors within the tumor’s vasculature successfully treated &gt;90% of the rats bearing 7-day-old intracranial T9/9L gliomas. The antiangiogenic drugs included (Z)-3-[4-(dimethylamino)benzylidenyl]indolin-2-one (a platelet-derived growth factor receptor β and a fibroblast growth factor receptor 1 kinase inhibitor) and oxindole (a vascular endothelial growth factor receptor 2 kinase inhibitor). A total of 20–40% of the animals treated with the antiangiogenic drugs alone survived, while all nontreated controls and tumor vaccine-treated rats died within 40 days. In vitro, these drugs inhibited endothelial cells from proliferating in response to the angiogenic factors produced by T9/9L glioma cells and prevented endothelial cell tubulogenesis. FITC-labeled tomato lectin staining demonstrated fewer and constricted blood vessels within the intracranial tumor after drug therapy. Magnetic resonance imaging demonstrated that the intracranial T9 glioma grew much slower in the presence of these antiangiogenic drugs. These drugs did not affect in vitro glioma cell growth nor T cell mitogenesis. Histological analysis revealed that the tumor destruction occurred at the margins of the tumor, where there was a heavy lymphocytic infiltrate. Real-time PCR showed more IL-2-specific mRNA was present within the gliomas in the vaccinated rats treated with the drugs. Animals that rejected the established T9/9L glioma by the combination therapy proved immune against an intracranial rechallenge by T9/9L glioma, but showed no resistance to an unrelated MADB106 breast cancer.
Regulated Folding of Tyrosinase in the Endoplasmic Reticulum Demonstrates That Misfolded Full-Length Proteins Are Efficient Substrates for Class I Processing and Presentation
Authors: Ostankovitch Marina , Robila Valentina , Engelhard Victor H. 
Published: April 2014

AbstractShort-lived protein translation products have been proposed to be the principal substrates that enter the class I MHC processing and presentation pathway. However, the biochemical nature of these substrates is poorly defined. Whether the major processing substrates are misfolded full-length proteins, or alternatively, aberrantly initiated or truncated polypeptides still remains to be addressed. To examine this, we used melanoma in which one-third of wild-type tyrosinase molecules were correctly folded and localized beyond the Golgi, while the remainder were present in the endoplasmic reticulum in an unfolded/misfolded state. Increasing the efficiency of tyrosinase folding using chemical chaperones led to a reduction in the level of substrate available to the proteasome and decreased the expression of a tyrosinase-derived epitope. Conversely, in transfectants expressing tyrosinase mutants that are completely misfolded, both proteasome substrate and epitope presentation were significantly enhanced. Proteasome substrate availability was a consequence of misfolding and not simply due to retention in the endoplasmic reticulum. Thus, the extent of folding/misfolding of a full-length protein is an important determinant of the level of epitope presentation.
Progressive and Controlled Development of Mouse Dendritic Cells from Flt3+CD11b+ Progenitors In Vitro
Authors: Hieronymus Thomas , Gust Tatjana C. , Kirsch Ralf D. , Jorgas Thorsten , Blendinger Gitta , Goncharenko Mykola , Supplitt Kamilla , Rose-John Stefan , Müller Albrecht M. , Zenke Martin 
Published: April 2014

AbstractDendritic cells (DC) represent key regulators of the immune system, yet their development from hemopoietic precursors is poorly defined. In this study, we describe an in vitro system for amplification of a Flt3+CD11b+ progenitor from mouse bone marrow with specific cytokines. Such progenitor cells develop into both CD11b+ and CD11b− DC, and CD8α+ and CD8α− DC in vivo. Furthermore, with GM-CSF, these progenitors synchronously differentiated into fully functional DC in vitro. This two-step culture system yields homogeneous populations of Flt3+CD11b+ progenitor cells in high numbers and allows monitoring the consecutive steps of DC development in vitro under well-defined conditions. We used phenotypic and functional markers and transcriptional profiling by DNA microarrays to study the Flt3+CD11b+ progenitor and differentiated DC. We report here on an extensive analysis of the surface Ag expression of Flt3+CD11b+ progenitor cells and relate that to surface Ag expression of hemopoietic stem cells. Flt3+CD11b+ progenitors studied exhibit a broad overlap of surface Ags with stem cells and express several stem cell Ags such as Flt3, IL-6R, c-kit/SCF receptor, and CD93/AA4.1, CD133/AC133, and CD49f/integrin α6. Thus, Flt3+CD11b+ progenitors express several stem cell surface Ags and develop into both CD11b+ and CD11b− DC, and CD8α+ and CD8α− DC in vivo, and thus into both of the main conventional DC subtypes.
The Fate of Low Affinity Tumor-Specific CD8+ T Cells in Tumor-Bearing Mice
Authors: Lyman Michael A. , Nugent C. Thomas , Marquardt Kristi L. , Biggs Judith A. , Pamer Eric G. , Sherman Linda A. 
Published: April 2014

AbstractA major challenge in tumor immunology is how best to activate the relatively low avidity self-specific and tumor-specific T cells that are available in the self-tolerant repertoire. To address this issue, we produced a TCR transgenic mouse expressing a class I-restricted hemagglutinin (HA)-specific TCR (clone 1 TCR) derived from a mouse that expressed HA as a self-Ag in the insulin-producing β cells of the pancreatic islets (InsHA) mice. Upon transfer of clone 1 TCR CD8+ T cells into InsHA mice, very few cells were activated by cross-presented HA, indicating that the cells were retained in InsHA mice because they ignored the presence of Ag, and not because they were functionally inactivated by anergy or tuning. Upon transfer into recipient mice in which HA is expressed at high concentrations as a tumor-associated Ag in spontaneously arising insulinomas (RIP-Tag2-HA mice), a high proportion of clone 1 cells were activated when they encountered cross-presented tumor Ag in the pancreatic lymph nodes. However, the activated cells exhibited very weak effector function and were soon tolerized. The few activated cells that did migrate to the tumor were unable to delay tumor progression. However, when HA-specific CD4 helper cells were cotransferred with clone 1 cells into RIP-Tag2-HA recipients and the mice were vaccinated with influenza, clone 1 cells were found to exert a significant level of effector function and could delay tumor growth. This tumor model should prove of great value in identifying protocols that can optimize the function of low avidity tumor-specific T cells.
IFN Regulatory Factor-4 and -8 Govern Dendritic Cell Subset Development and Their Functional Diversity
Authors: Tamura Tomohiko , Tailor Prafullakumar , Yamaoka Kunihiro , Kong Hee Jeong , Tsujimura Hideki , O’Shea John J. , Singh Harinder , Ozato Keiko 
Published: April 2014

AbstractDendritic cells (DCs) are bone marrow (BM)-derived APCs central to both innate and adaptive immunity. DCs are a heterogeneous cell population composed of multiple subsets with diverse functions. The mechanism governing the generation of multiple DC subsets is, however, poorly understood. In this study we investigated the roles of closely related transcription factors, IFN regulatory factor (IRF)-4 and IRF-8, in DC development by analyzing IRF-4−/−, IRF-8−/−, and IRF-4−/−IRF-8−/− (double-knockout) mice. We found that IRF-4 is required for the generation of CD4+ DCs, whereas IRF-8 is, as reported previously, essential for CD8α+ DCs. Both IRFs support the development of CD4−CD8α− DCs. IRF-8 and, to a lesser degree, IRF-4 contribute to plasmacytoid DC (PDC) development. Thus, the two IRFs together regulate the development of all conventional DCs as well as PDCs. Consistent with these findings, IRF-4, but not IRF-8, was expressed in CD4+ DCs, whereas only IRF-8 was expressed in CD8α+ DCs. CD4−CD8α− DCs and PDCs expressed both IRFs. We also demonstrate in vitro that GM-CSF-mediated DC differentiation depends on IRF-4, whereas Fms-like tyrosine kinase 3 ligand-mediated differentiation depends mainly on IRF-8. Gene transfer experiments with double-knockout BM cells showed that both IRFs have an overlapping activity and stimulate a common process of DC development. Nonetheless, each IRF also possesses a distinct activity to stimulate subset-specific gene expression, leading to the generation of functionally divergent DCs. Together, IRF-4 and IRF-8 serve as a backbone of the molecular program regulating DC subset development and their functional diversity.
CXC Chemokine Ligand 12-Induced Focal Adhesion Kinase Activation and Segregation into Membrane Domains Is Modulated by Regulator of G Protein Signaling 1 in Pro-B Cells
Authors: Le Yi , Honczarenko Marek , Glodek Aleksandra M. , Ho Daniel K. , Silberstein Leslie E. 
Published: April 2014

Abstract
CXCL12-induced chemotaxis and adhesion to VCAM-1 decrease as B cells differentiate in the bone marrow. However, the mechanisms that regulate CXCL12/CXCR4-mediated signaling are poorly understood. We report that after CXCL12 stimulation of progenitor B cells, focal adhesion kinase (FAK) and PI3K are inducibly recruited to raft-associated membrane domains. After CXCL12 stimulation, phosphorylated FAK is also localized in membrane domains. The CXCL12/CXCR4-FAK pathway is membrane cholesterol dependent and impaired by metabolic inhibitors of Gi, Src family, and the GTPase-activating protein, regulator of G protein signaling 1 (RGS1). In the bone marrow, RGS1 mRNA expression is low in progenitor B cells and high in mature B cells, implying developmental regulation of CXCL12/CXCR4 signaling by RGS1. CXCL12-induced chemotaxis and adhesion are impaired when FAK recruitment and phosphorylation are inhibited by either membrane cholesterol depletion or overexpression of RGS1 in progenitor B cells. We conclude that the recruitment of signaling molecules to specific membrane domains plays an important role in CXCL12/CXCR4-induced cellular responses.
CD8+ T Cell Immunity Against a Tumor/Self-Antigen Is Augmented by CD4+ T Helper Cells and Hindered by Naturally Occurring T Regulatory Cells
Authors: Antony Paul A. , Piccirillo Ciriaco A. , Akpinarli Akgül , Finkelstein Steven E. , Speiss Paul J. , Surman Deborah R. , Palmer Douglas C. , Chan Chi-Chao , Klebanoff Christopher A. , Overwijk Willem W. , Rosenberg Steven A. , Restifo Nicholas P. 
Published: April 2014

Abstract
CD4+ T cells control the effector function, memory, and maintenance of CD8+ T cells. Paradoxically, we found that absence of CD4+ T cells enhanced adoptive immunotherapy of cancer when using CD8+ T cells directed against a persisting tumor/self-Ag. However, adoptive transfer of CD4+CD25− Th cells (Th cells) with tumor/self-reactive CD8+ T cells and vaccination into CD4+ T cell-deficient hosts induced autoimmunity and regression of established melanoma. Transfer of CD4+ T cells that contained a mixture of Th and CD4+CD25+ T regulatory cells (Treg cells) or Treg cells alone prevented effective adoptive immunotherapy. Maintenance of CD8+ T cell numbers and function was dependent on Th cells that were capable of IL-2 production because therapy failed when Th cells were derived from IL-2−/− mice. These findings reveal that Th cells can help break tolerance to a persisting self-Ag and treat established tumors through an IL-2-dependent mechanism, but requires simultaneous absence of naturally occurring Treg cells to be effective.
The Wiskott-Aldrich Syndrome Protein Regulates Nuclear Translocation of NFAT2 and NF-κB (RelA) Independently of Its Role in Filamentous Actin Polymerization and Actin Cytoskeletal Rearrangement
Authors: Huang Winifred , Ochs Hans D. , Dupont Bo , Vyas Yatin M. 
Published: April 2014

Abstract
Effector functions mediated by NK cells involve cytotoxicity and transcription-dependent production and release of cytokines and chemokines. Although the JAK/STAT pathway mediates lymphokine-induced transcriptional regulation in NK cells, very little is known about transcriptional regulation induced during cell-cell contact. We demonstrate that the Wiskott-Aldrich syndrome protein (WASp) is an important component for integration of signals leading to nuclear translocation of NFAT2 and NF-κB (RelA) during cell-cell contact and NKp46-dependent signaling. This WASp function is independent of its known role in F-actin polymerization and cytoskeletal rearrangement. Absence of WASp results in decreased accumulation of calcineurin, WASp-interacting protein, and molecules upstream of calcium mobilization, i.e., activated ZAP70 and phospholipase C-γ1, in the disorganized NK cell immune synapse. Production of GM-CSF, but not IFN-γ, is decreased, while natural cytotoxicity of Wiskott-Aldrich syndrome-NK cells is maintained. Our results indicate that WASp independently regulates its dual functions, i.e., actin cytoskeletal remodeling and transcription in NK cells.
Natural Killer Dendritic Cells Have Both Antigen Presenting and Lytic Function and in Response to CpG Produce IFN-γ via Autocrine IL-12
Authors: Pillarisetty Venu G. , Katz Steven C. , Bleier Joshua I. , Shah Alaap B. , DeMatteo Ronald P. 
Published: April 2014

Abstract
We have isolated rare cells bearing the NK cell surface marker NK1.1, as well as the dendritic cell (DC) marker CD11c, from the spleen, liver, lymph nodes, and thymus of normal mice. These cells possess both NK cell and DC function because they can lyse tumor cells and subsequently present Ags to naive Ag-specific T cells. Interestingly, in response to IL-4 plus either IL-2 or CpG, NKDC produce more IFN-γ than do DC, or even NK cells. We determined that CpG, but not IL-2, induces NKDC to secrete IFN-γ via the autocrine effects of IL-12. In vivo, CpG dramatically increases the number of NKDC. Furthermore, NKDC induce greater Ag-specific T cell activation than do DC after adoptive transfer. Their unique ability to lyse tumor cells, present Ags, and secrete inflammatory cytokines suggests that NKDC may play a crucial role in linking innate and adaptive immunity.
Activated Human B Lymphocytes Express Cyclooxygenase-2 and Cyclooxygenase Inhibitors Attenuate Antibody Production
Authors: Ryan Elizabeth P. , Pollack Stephen J. , Murant Thomas I. , Bernstein Steven H. , Felgar Raymond E. , Phipps Richard P. 
Published: April 2014

AbstractNonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory diseases and target cyclooxygenases 1 and 2 (Cox-1, Cox-2) that are responsible for PG production. Newer Cox-2-selective drugs have been heavily prescribed to quench inflammation. Little is known about whether or not these drugs influence human B lymphocytes and their ability to produce Ab. We report herein that activated human B cells not only highly express Cox-2 and produce PGs, but that the NSAID indomethacin and Cox-2-selective drugs profoundly inhibit the ability of human B cells to produce IgG and IgM in vitro. Human blood B cells highly express Cox-2 mRNA and protein and produce PGs after activation with CD40L, pansorbin, or CD40L plus BCR engagement. Cox-2 is also highly expressed by human tonsil B cells, as shown by immunohistochemistry. Cox-inhibiting drugs modestly affect purified B cell proliferation but profoundly reduce Ab production. The ability of whole blood to produce IgM and IgG following stimulation is also strongly inhibited. In support that Cox-2 plays a seminal role in B lymphocyte Ab production, Cox-2 knockout mice have 64% less IgM and 35% less IgG than normal littermate controls. These findings support that NSAIDs and the new Cox-2-selective drugs have an unsuspected target, the B cell, and attenuate Ab production in humans. Use of NSAIDs may therefore influence autoantibody production in autoimmune diseases and may dampen humoral immunity in response to antigenic challenge/vaccination.
Overexpression of the Runx3 Transcription Factor Increases the Proportion of Mature Thymocytes of the CD8 Single-Positive Lineage
Authors: Kohu Kazuyoshi , Sato Takehito , Ohno Shin-ichiro , Hayashi Keitaro , Uchino Ryuji , Abe Natsumi , Nakazato Megumi , Yoshida Naomi , Kikuchi Toshiaki , Iwakura Yoichiro , Inoue Yoshihiro , Watanabe Toshio , Habu Sonoko , Satake Masanobu 
Published: April 2014

Abstract
The Runx family of transcription factors is thought to regulate the differentiation of thymocytes. Runx3 protein is detected mainly in the CD4−8+ subset of T lymphocytes. In the thymus of Runx3-deficient mice, CD4 expression is de-repressed and CD4−8+ thymocytes do not develop. This clearly implicates Runx3 in CD4 silencing, but does not necessarily prove its role in the differentiation of CD4−8+ thymocytes per se. In the present study, we created transgenic mice that overexpress Runx3 and analyzed the development of thymocytes in these animals. In the Runx3-transgenic thymus, the number of CD4−8+ cells was greatly increased, whereas the numbers of CD4+8+ and CD4+8− cells were reduced. The CD4−8+ transgenic thymocytes contained mature cells with a TCRhighHSAlow phenotype. These cells were released from the thymus and contributed to the elevated level of CD4−8+ cells relative to CD4+8− cells in the spleen. Runx3 overexpression also increased the number of mature CD4−8+ thymocytes in mice with class II-restricted, transgenic TCR and in mice with a class I-deficient background, both of which are favorable for CD4+8− lineage selection. Thus, Runx3 can drive thymocytes to select the CD4−8+ lineage. This activity is likely to be due to more than a simple silencing of CD4 gene expression.
The Human CD1-Restricted T Cell Repertoire Is Limited to Cross-Reactive Antigens: Implications for Host Responses against Immunologically Related Pathogens
Authors: Sieling Peter A. , Torrelles Jordi B. , Stenger Steffen , Chung Woosin , Burdick Anne E. , Rea Thomas H. , Brennan Patrick J. , Belisle John T. , Porcelli Steven A. , Modlin Robert L. 
Published: April 2014

AbstractThe repertoires of CD1- and MHC-restricted T cells are complementary, permitting the immune recognition of both lipid and peptide Ags, respectively. To compare the breadth of the CD1-restricted and MHC-restricted T cell repertoires, we evaluated T cell responses against lipid and peptide Ags of mycobacteria in leprosy, comparing tuberculoid patients, who are able to restrict the pathogen, and lepromatous patients, who have disseminated infection. The striking finding was that in lepromatous leprosy, T cells did not efficiently recognize lipid Ags from the leprosy pathogen, Mycobacterium leprae, or the related species, Mycobacterium tuberculosis, yet were able to efficiently recognize peptide Ags from M. tuberculosis, but not M. leprae. To identify a mechanism for T cell unresponsiveness against mycobacterial lipid Ags in lepromatous patients, we used T cell clones to probe the species specificity of the Ags recognized. We found that the majority of M. leprae-reactive CD1-restricted T cell clones (92%) were cross-reactive for multiple mycobacterial species, whereas the majority of M. leprae-reactive MHC-restricted T cells were species specific (66%), with a limited number of T cell clones cross-reactive (34%) with M. tuberculosis. In comparison with the MHC class II-restricted T cell repertoire, the CD1-restricted T cell repertoire is limited to recognition of cross-reactive Ags, imparting a distinct role in the host response to immunologically related pathogens.