bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Aged Humoral Immune Defense against Pneumococcal Bacteria by IgM Memory B Cell
Authors: Shi Yuhui , Yamazaki Takashi , Okubo Yoshio , Uehara Yoshio , Sugane Kazuo , Agematsu Kazunaga 
Published: April 2014

Abstract
Elderly persons have a high incidence of lethal infections by encapsulated bacteria. However, mechanisms involved in their poor defense and maintenance of immunological memory have been poorly understood. The present study characterized the population of B cells known as IgM memory B cell compartment and their response by pneumococcal vaccine in elderly people. CD27+ memory B cells, particularly IgD+IgM+CD27+ IgM memory B cells, had dramatically declined in the aged. Their Ig syntheses by B cells and the differentiation into plasma cells were diminished in vitro compared with those in adults. A rise of anti-pneumococcal IgM in sera of elderly persons was found with lower levels compared with those in adults after pneumococcal vaccination. Although diminished function itself of aged B cells surely exist, decline of the IgM memory B cell pool is expected to result in a poor humoral immunity against pneumococcal infection in elderly people.
In Vivo Depletion of CD11c+ Cells Delays the CD4+ T Cell Response to Mycobacterium tuberculosis and Exacerbates the Outcome of Infection
Authors: Tian Tian , Woodworth Joshua , Sköld Markus , Behar Samuel M. 
Published: April 2014

Abstract
Although dendritic cells (DC) are potent APC that prime T cells against many pathogens, there is no direct evidence that DC are required for immunity to Mycobacterium tuberculosis (Mtb) infection. The requirement for DC to prime the CD4+ T cell response following Mtb infection was investigated using pCD11c-diptheria toxin receptor/GFP transgenic mice, in which DC can be transiently ablated in vivo. We show a critical role for DC in initiation of the CD4+ T cell response to the mycobacterial Ag early secretory Ag of tuberculosis 6. The delay in initiating the Ag-specific T cell response led to impaired control of Mtb replication. Interestingly, DC were not required for the secondary CD4+ T cell response following Mtb infection in peptide-vaccinated mice. Thus, this study shows that DC are essential for the initiation of the adaptive T cell response to the human pathogen Mtb.
Monocyte-Astrocyte Networks and the Regulation of Chemokine Secretion in Neurocysticercosis
Authors: Uddin Jasim , Garcia Hector H. , Gilman Robert H. , Gonzalez Armando E. , Friedland Jon S. 
Published: April 2014

AbstractNeurocysticercosis, caused by infection with larval Taenia solium, is a major cause of epilepsy worldwide. Larval degeneration, which is symptomatic, results in inflammatory cell influx. Astrocytes, the most abundant cell type and major cytokine-producing cell within the CNS, may be important in orchestrating inflammatory responses after larval degeneration. We investigated the effects of direct stimulation and of conditioned medium from T. solium larval Ag (TsAg)-stimulated monocytes (CoMTsAg) on neutrophil and astrocyte chemokine release. CoMTsAg, but not control conditioned medium, stimulated astrocyte CCL2/MCP-1 (161.5 ± 16 ng/ml), CXCL8/IL-8 (416 ± 6.2 ng/ml), and CXCL10/IFN-γ-inducible protein (9.07 ± 0.6 ng/ml) secretion after 24 h, whereas direct astrocyte or neutrophil stimulation with TsAg had no effect. There was rapid accumulation of CCL2 and CXCL8 mRNA within 1 h, with somewhat delayed expression of CXCL10 mRNA initially detected 8 h poststimulation. Neutralizing anti-TNF-α inhibited CoMTsAg-induced CCL2 mRNA accumulation by up to 99%, causing total abolition of CXCL10 and up to 77% reduction in CXCL8 mRNA. CoMTsAg induced maximal nuclear binding of NF-κB p65 and p50 by 1 h, with IκBα and IκBβ decay within 15 min. In addition, CoMTsAg induced transient nuclear binding of AP-1, which peaked 4 h poststimulation. In NF-κB blocking experiments using pyrrolidine dithiocarbamate, CoMTsAg-induced CCL2 secretion was reduced by up to 80% (p = 0.0006), whereas CXCL8 was inhibited by up to 75% (p = 0.0003). In summary, the data show that astrocytes are an important source of chemokines following larval Ag stimulation. Such chemokine secretion is NF-κB dependent, likely to involve AP-1, and is regulated in a paracrine loop by monocyte-derived TNF-α.
CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis
Authors: Scumpia Philip O. , McAuliffe Priscilla F. , O’Malley Kerri A. , Ungaro Ricardo , Uchida Takefumi , Matsumoto Tadashi , Remick Daniel G. , Clare-Salzler Michael J. , Moldawer Lyle L. , Efron Philip A. 
Published: April 2014

Abstract
CD11c+ dendritic cells (DCs) are APCs that link innate and adaptive immunity. Although DCs are lost from spleen and lymph nodes in sepsis, their role in outcome remains unclear. Transgenic mice (B6.FVB-Tg.Itgax-DTR/EGFP.57Lan/J) expressing the diphtheria toxin (DT) receptor on the CD11c promoter (DCKO mice) received 4 ng/kg DT, which resulted in depletion of 88–95% of mature myeloid and lymphoid DCs, with less depletion (75%) of plasmacytoid DCs. Pretreatment of DCKO mice with DT resulted in reduced survival in sepsis compared with saline-pretreated DCKO mice (0 vs 54%; p &lt; 0.05) or DT-treated wild-type littermates (0 vs 54%; p &lt; 0.05). This increased mortality was not associated with either increased bacteremia or plasma cytokine concentrations. Intravenous injection of 107 wild-type DCs improved survival in DCKO mice (42 vs 0%; p = 0.05). These data confirm that DCs are essential in the septic response and suggest that strategies to maintain DC numbers or function may improve outcome.
Monocytes Stimulated by 110-kDa Fibronectin Fragments Suppress Proliferation of Anti-CD3-Activated T Cells
Authors: Birdsall Holly H. , Porter Wendy J. , Trial JoAnn , Rossen Roger D. 
Published: April 2014

Abstract
One hundred ten to 120-kDa fragments of fibronectin (FNf), generated by proteases released in the course of tissue injury and inflammation, stimulate monocytes to produce proinflammatory cytokines, promote mononuclear leukocytes (MNL) transendothelial migration, up-regulate monocyte CD11b and CD86 expression, and induce monocyte-derived dendritic cell differentiation. To investigate whether the proinflammatory consequences of FNf are offset by responses that can suppress proliferation of activated T lymphocytes, we investigated the effect of FNf-treated MNL on autologous T lymphocytes induced to proliferate by substrate-immobilized anti-CD3. FNf-stimulated MNL suppressed anti-CD3-induced T cell proliferation through both contact-dependent and contact-independent mechanisms. Contact-independent suppression was mediated, at least in part, by IL-10 and TGF-β released by the FNf-stimulated MNL. After 24–48 h exposure to FNf, activated T cells and monocytes formed clusters displaying CD25, CD14, CD3, and CD4 that were not dissociable by chelation of divalent cations. Killing monocytes with l-leucine methyl ester abolished these T cell-monocyte clusters and the ability of the FNf-stimulated MNL to suppress anti-CD3 induced T cell proliferation. Thus, in addition to activating MNL and causing them to migrate to sites of injury, FNf appears to induce suppressor monocytes.
Requirement of IL-17 Receptor Signaling in Radiation-Resistant Cells in the Joint for Full Progression of Destructive Synovitis
Authors: Lubberts Erik , Schwarzenberger Paul , Huang Weitao , Schurr Jill R. , Peschon Jacques J. , van den Berg Wim B. , Kolls Jay K. 
Published: April 2014

Abstract
IL-17 is a proinflammatory cytokine suspected to be involved in inflammatory and autoimmune diseases such as rheumatoid arthritis. In the present study, we report that IL-17R signaling is required in radiation-resistant cells in the joint for full progression of chronic synovitis and bone erosion. Repeated injections of Gram-positive bacterial cell wall fragments (streptococcal cell wall) directly into the knee joint of naive IL-17R-deficient (IL-17R−/−) mice had no effect on the acute phase of arthritis but prevented progression to chronic destructive synovitis as was noted in wild-type (wt) mice. Microarray analysis revealed significant down-regulation of leukocyte-specific chemokines, selectins, cytokines, and collagenase-3 in the synovium of IL-17R−/− mice. Bone marrow (BM) chimeric mice revealed the need for IL-17R expression on radiation-resistant joint cells for destructive inflammation. Chimeric mice of host wt and donor IL-17R−/− BM cells developed destructive synovitis in this chronic reactivated streptococcal cell wall arthritis model similar to wt→wt chimeras. In contrast, chimeric mice of host IL-17R−/− and donor wt BM cells were protected from chronic destructive arthritis similar as IL-17R−/−→IL-17R−/− chimeras. These data strongly indicate that IL-17R signaling in radiation-resistant cells in the joint is required for turning an acute macrophage-mediated inflammation into a chronic destructive synovitis.
Gene Expression Profiling Reveals Multiple Protective Influences of the Peptide α-Melanocyte-Stimulating Hormone in Experimental Heart Transplantation
Authors: Colombo Gualtiero , Gatti Stefano , Turcatti Flavia , Sordi Andrea , Fassati Luigi R. , Bonino Ferruccio , Lipton James M. , Catania Anna 
Published: April 2014

Abstract
Novel therapies are sought to increase efficiency and survival of transplanted organs. Previous research on experimental heart transplantation showed that treatment with the anti-inflammatory peptide α-melanocyte-stimulating hormone (α-MSH) prolongs allograft survival. The aim of the present research was to determine the molecular mechanism of this protective activity. Gene expression profile was examined in heart grafts removed on postoperative days 1 and 4 from rats treated with saline or the synthetic α-MSH analog Nle4DPhe7 (NDP)-α-MSH. On postoperative day 1, the peptide induced expression of cytoskeleton proteins, intracellular kinases, transcription regulators, metallopeptidases, and protease inhibitors. Conversely, NDP-α-MSH repressed immune, inflammatory, cell cycle, and protein turnover mediators. Later effects of α-MSH treatment included down-regulation of oxidative stress response and up-regulation of ion channels, calcium regulation proteins, phosphatidylinositol signaling system, and glycolipidic metabolism. NDP-α-MSH exerted its effects on both Ag-dependent and -independent injury. The results indicate that NDP-α-MSH preserves heart function through a broad effect on multiple pathways and suggest that the peptide could improve the outcome of organ transplantation in combination with immunosuppressive treatments.
Cutting Edge: CD8 T Cells Specific for Lymphocytic Choriomeningitis Virus Require Type I IFN Receptor for Clonal Expansion
Authors: Aichele Peter , Unsoeld Heike , Koschella Marie , Schweier Oliver , Kalinke Ulrich , Vucikuja Smiljka 
Published: April 2014

Abstract
The role of type I IFN signaling in CD8 T cells was analyzed in an adoptive transfer model using P14 TCR transgenic CD8 T cells specific for lymphocytic choriomeningitis virus (LCMV) but deficient in type I IFNR. In the present study, we demonstrate severe impairment in the capacity of P14 T cells lacking type I IFNR to expand in normal type I IFNR wild-type C57BL/6 hosts after LCMV infection. In contrast, following infection of recipient mice with recombinant vaccinia virus expressing LCMV glycoprotein, P14 T cell expansion was considerably less dependent on type I IFNR expression. Lack of type I IFNR expression by P14 T cells did not affect cell division after LCMV infection but interfered with clonal expansion. Thus, direct type I IFN signaling is essential for CD8 T cell survival in certain viral infections.
Cutting Edge: Insufficient Perforin Expression in CD8+ T Cells in Response to Hemagglutinin from Avian Influenza (H5N1) Virus
Authors: Hsieh Szu-Min , Chang Shan-Chwen 
Published: April 2014

Abstract
Hypercytokinemia has been considered to be responsible for hemophagocytosis and multiorgan failure in severe human cases of H5N1 viral infection. In this study, we show a recombinant hemagglutinin (H5) from a H5N1 virus may suppress the perforin expression and reduce cytotoxicity of human CD8+ T cells to kill H5-bearing cells. The persistence of H5-presenting cells provides sustained stimulation and leads to a marked lymphoproliferation and IFN-γ hyperproduction. We propose the IFN-γ hyperproduction may explain macrophage overactivation and subsequent hypercytokinemia and hemophagocytosis in severe human cases of avian influenza.
Limited Infiltration of Exogenous Dendritic Cells and Naive T Cells Restricts Immune Responses in Peripheral Lymph Nodes
Authors: Mullins David W. , Engelhard Victor H. 
Published: April 2014

AbstractPrimary CD8 T cell responses in lymph nodes (LN) and protective immunological tumor control are quantitatively limited following immunization with exogenous peptide-pulsed dendritic cells (DC). This arises from two constraints. First, LN are saturated by relatively small quantities of exogenous DC. Second, circulation of new naive T cells into DC-infiltrated LN during the functional lifespan of the DC is negligible. Limits on DC and T cellularity in, and flux through, LN constrain the magnitude of both primary and subsequent recall responses. Enhanced immune responses and tumor control can be achieved using maneuvers to augment LN retention of DC or availability of naive T cells to Ag-presenting DC. These data offer an increased understanding of LN function in general and provide a practical basis for improvements in tumor immunotherapy.
Bruton’s Tyrosine Kinase and SLP-65 Regulate Pre-B Cell Differentiation and the Induction of Ig Light Chain Gene Rearrangement
Authors: Kersseboom Rogier , Ta Van B. T. , Zijlstra A. J. Esther , Middendorp Sabine , Jumaa Hassan , Fokko van Loo Pieter , Hendriks Rudolf W. 
Published: April 2014

AbstractBruton’s tyrosine kinase (Btk) and the adapter protein SLP-65 (Src homology 2 domain-containing leukocyte-specific phosphoprotein of 65 kDa) transmit precursor BCR (pre-BCR) signals that are essential for efficient developmental progression of large cycling into small resting pre-B cells. We show that Btk- and SLP-65-deficient pre-B cells have a specific defect in Ig λ L chain germline transcription. In Btk/SLP-65 double-deficient pre-B cells, both κ and λ germline transcripts are severely reduced. Although these observations point to an important role for Btk and SLP-65 in the initiation of L chain gene rearrangement, the possibility remained that these signaling molecules are only required for termination of pre-B cell proliferation or for pre-B cell survival, whereby differentiation and L chain rearrangement is subsequently initiated in a Btk/SLP-65-independent fashion. Because transgenic expression of the antiapoptotic protein Bcl-2 did not rescue the developmental arrest of Btk/SLP-65 double-deficient pre-B cells, we conclude that defective L chain opening in Btk/SLP-65-deficient small resting pre-B cells is not due to their reduced survival. Next, we analyzed transgenic mice expressing the constitutively active Btk mutant E41K. The expression of E41K-Btk in Ig H chain-negative pro-B cells induced 1) surface marker changes that signify cellular differentiation, including down-regulation of surrogate L chain and up-regulation of CD2, CD25, and MHC class II; and 2) premature rearrangement and expression of κ and λ light chains. These findings demonstrate that Btk and SLP-65 transmit signals that induce cellular maturation and Ig L chain rearrangement independently of their role in termination of pre-B cell expansion.
Insufficient APC Capacities of Dendritic Cells in Gene Gun-Mediated DNA Vaccination
Authors: Lauterbach Henning , Gruber Anton , Ried Christine , Cheminay Cedric , Brocker Thomas 
Published: April 2014

AbstractGene gun-mediated DNA immunization is a powerful mode of vaccination against infectious diseases and tumors. Many studies have identified dendritic cells (DC) as the central players in inducing immunity upon biolistic DNA vaccination; however, none of these studies directly quantify DC-mediated responses in comparison with immunity triggered by all Ag- and MHC-expressing cells. In this study we use two different approaches to decipher the relative role of DC vs other cell types in gene gun-induced immunity. First, we directly compared the immunization efficacy of different DNA constructs, which allow Ag expression ubiquitously (CMV promoter) or specifically in DC (CD11c promoter) and would encode either for soluble or membrane bound forms of Ag. Second, we immunized transgenic mice in which only DC can present MHC-restricted Ag, and directly compared the magnitudes of CTL activation with those obtained in wild-type mice. Surprisingly, our combined data suggest that, although DC-specific Ag expression is sufficient to induce humoral responses, DC alone cannot trigger optimal CD4 and CD8 T cell responses upon gene gun vaccination. Therefore, we conclude that DC alone are insufficient to mediate optimal induction of T cell immunity upon gene gun DNA vaccination and that broad Ag expression rather than DC-restricted approaches are necessary for induction of complete immune responses.
MHC Class II Expression Identifies Functionally Distinct Human Regulatory T Cells
Authors: Baecher-Allan Clare , Wolf Elizabeth , Hafler David A. 
Published: April 2014

AbstractIt has been known for decades that circulating human CD4 cells can express functional MHC class II molecules that induce T cell nonresponsiveness with Ag presentation. Because there is significant expression of MHC class II (MHC-II) determinants (DR) on a subpopulation CD4+CD25high regulatory T cells (Treg), we examined the function of CD4 cells expressing MHC-DR. We demonstrate that MHC-II expression on human CD4+CD25high T cells identifies a functionally distinct population of Treg that induces early contact-dependent suppression that is associated with high Foxp3 expression. In striking contrast, MHC-II− CD4+CD25high Treg induce early IL-4 and IL-10 secretion and a late Foxp3-associated contact-dependent suppression. The DR expressing CD25high Treg express higher levels of Foxp3 message and protein, compared with the DR−CD25high Treg population. Direct single-cell cloning of CD4+CD25high Treg revealed that, regardless of initial DR expression, ex vivo expression of CD25high, and not DR, predicted which clones would exhibit contact-dependent suppression, high levels of Foxp3 message, and an increased propensity to become constitutive for DR expression. Thus, the direct ex vivo expression of MHC-II in the context of CD25high identifies a mature, functionally distinct regulatory T cell population involved in contact-dependent in vitro suppression.
DOCK2 Is Required in T Cell Precursors for Development of Vα14 NK T Cells
Authors: Kunisaki Yuya , Tanaka Yoshihiko , Sanui Terukazu , Inayoshi Ayumi , Noda Mayuko , Nakayama Toshinori , Harada Michishige , Taniguchi Masaru , Sasazuki Takehiko , Fukui Yoshinori 
Published: April 2014

AbstractMouse CD1d-restricted Vα14 NKT cells are a unique subset of lymphocytes, which play important roles in immune regulation, tumor surveillance and host defense against pathogens. DOCK2, a mammalian homolog of Caenorhabditis elegans CED-5 and Drosophila melanogaster myoblast city, is critical for lymphocyte migration and regulates T cell responsiveness through immunological synapse formation, yet its role in Vα14 NKT cells remains unknown. We found that DOCK2 deficiency causes marked reduction of Vα14 NKT cells in the thymus, liver, and spleen. When α-galactosylceramide (α-GalCer), a ligand for Vα14 NKT cells, was administrated, cytokine production was scarcely detected in DOCK2-deficient mice, suggesting that DOCK2 deficiency primarily affects generation of Vα14 NKT cells. Supporting this idea, staining with CD1d/α-GalCer tetramers revealed that CD44−NK1.1− Vα14 NKT cell precursors are severely reduced in the thymuses of DOCK2-deficient mice. In addition, studies using bone marrow chimeras indicated that development of Vα14 NKT cells requires DOCK2 expression in T cell precursors, but not in APCs. These results indicate that DOCK2 is required for positive selection of Vα14 NKT cells in a cell-autonomous manner, thereby suggesting that avidity-based selection also governs development of this unique subset of lymphocytes in the thymus.
Direct Stimulation of T Cells by Type I IFN Enhances the CD8+ T Cell Response during Cross-Priming
Authors: Le Bon Agnes , Durand Vanessa , Kamphuis Elisabeth , Thompson Clare , Bulfone-Paus Silvia , Rossmann Cornelia , Kalinke Ulrich , Tough David F. 
Published: April 2014

Abstract
Type I IFN (IFN-αβ), which is produced rapidly in response to infection, plays a key role in innate immunity and also acts as a stimulus for the adaptive immune response. We have investigated how IFN-αβ induces cross-priming, comparing CD8+ T cell responses generated against soluble protein Ags in the presence or absence of IFN-αβ. Injection of IFN-α was found to prolong the proliferation and expansion of Ag-specific CD8+ T cells, which was associated with marked up-regulation of IL-2 and IL-15 receptors on Ag-specific cells and expression of IL-15 in the draining lymph node. Surprisingly, neither IL-2 nor IL-15 was required for IFN-α-induced cross-priming. Conversely, expression of the IFN-αβR by T cells was shown to be necessary for effective stimulation of the response by IFN-α. The finding that T cells represent direct targets of IFN-αβ-mediated stimulation reveals an additional mechanism by which the innate response to infection promotes adaptive immunity.
Identification of Memory B Cells Using a Novel Transgenic Mouse Model
Authors: Chappell Craig P. , Jacob Joshy 
Published: April 2014

AbstractMemory B cells help to protect the host from invading pathogens by maintaining persistent levels of Ag-specific serum Ab and generating rapid Ab responses upon re-exposure to Ag. Unambiguous identification of memory B cells has been a major obstacle to furthering our knowledge concerning both the development of B cell memory and secondary Ab responses due to an absence of specific cell surface markers. Germinal centers (GCs) are thought to be the major site of Ig hypermutation and Ag-driven selection of memory B cells. To develop a model that would identify GC-derived memory B cells, we generated transgenic mice that expressed cre recombinase in a GC-specific fashion. Interbreeding these mice with the cre-reporter strain, ROSA26R, produced progeny in which β-galactosidase (β-gal) was permanently expressed in B cells of the GC-memory pathway. Analysis following immunization with (4-hydroxy-3-nitrophenyl)acetyl coupled to chicken γ globulin showed that long-lived β-gal+ B cells exclusively contained somatically mutated λ1 V regions and were capable of producing Ag-specific Ab-forming cell (AFC) responses that were &gt;100-fold higher than those afforded by β-gal− B cells following adoptive transfer to naive hosts. Secondary challenge of immune mice showed that only ∼20% of secondary AFCs expressed β-gal. Interestingly, we found that somatic hypermutation of rearranged λ1 V regions within secondary AFCs showed a strong correlation with β-gal expression, suggesting that nonmutated B cells contribute significantly to secondary Ab responses. This model should provide useful insights into memory B cell development, maintenance, and differentiation following immunization or pathogenic infection.