bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Commensal Bacteria in Development of Gut-Associated Lymphoid Tissues and Preimmune Antibody Repertoire
Authors: Rhee Ki-Jong , Sethupathi Periannan , Driks Adam , Lanning Dennis K. , Knight Katherine L. 
Published: April 2014

Abstract
Intestinal bacteria are required for development of gut-associated lymphoid tissues (GALT), which mediate a variety of host immune functions, such as mucosal immunity and oral tolerance. In rabbits, the intestinal microflora are also required for developing the preimmune Ab repertoire by promoting somatic diversification of Ig genes in B cells that have migrated to GALT. We studied the mechanism of bacteria-induced GALT development. Bacteria were introduced into rabbits in which the appendix had been rendered germfree by microsurgery (we refer to these rabbits as germfree-appendix rabbits). We then identified specific members of the intestinal flora that promote GALT development. The combination of Bacteroides fragilis and Bacillus subtilis consistently promoted GALT development and led to development of the preimmune Ab repertoire, as shown by an increase in somatic diversification of VDJ-Cμ genes in appendix B cells. Neither species alone consistently induced GALT development, nor did Clostridium subterminale, Escherichia coli, or Staphylococcus epidermidis. B. fragilis, which by itself is immunogenic, did not promote GALT development; hence, GALT development in rabbits does not appear to be the result of an Ag-specific immune response. To identify bacterial pathways required for GALT development, we introduced B. fragilis along with stress-response mutants of B. subtilis into germfree-appendix rabbits. We identified two Spo0A-controlled stress responses, sporulation and secretion of the protein YqxM, which are required for GALT development. We conclude that specific members of the commensal, intestinal flora drive GALT development through a specific subset of stress responses.
Identification of a Novel FcγRIIIaα-Associated Molecule That Contains Significant Homology to Porcine Cathelin
Authors: Sweeney Susan E. , Kim Yoon B. 
Published: April 2014

Abstract
The following studies are the first to demonstrate the association of porcine FcγRIIIaα with a molecule that contains significant homology to the cathelin family of antimicrobial proteins. We performed immunoprecipitation of the porcine FcγRIIIaα multisubunit complex from Brij 96 lysates of polymorphonuclear leukocytes using the G7 mAb, which binds to FcγRIIIaα on the surface of porcine NK cells and phagocytes. Previous results indicate that the transmembrane α subunit of the FcγRIIIa complex is associated with the γ subunit on the surface of porcine polymorphonuclear leukocytes and with several other unique proteins that surface iodinate and migrate at ∼15, 20, and 25 kDa when analyzed by reducing SDS-PAGE. Through characterization of the porcine FcγRIIIa complex, we identified the 15-kDa molecule as a unique FcγR-associated protein that has not been described in other systems. We now report an association between FcγRIIIaα and a 15-kDa molecule that shares homology to cathelin, a protein of undetermined function initially identified in porcine leukocytes. A domain with a high degree of homology to cathelin is found in the proregions of a family of antibiotic proteins referred to as cathelicidins. The results of our studies indicate the presence of a novel FcγRIIIa complex in the porcine system, and may provide new insights into the function of this antimicrobial protein homologue in relation to the variety of responses mediated through FcγRs.
Bone Marrow-Derived Progenitor Cells Are Important for Lung Repair after Lipopolysaccharide-Induced Lung Injury
Authors: Yamada Mitsuhiro , Kubo Hiroshi , Kobayashi Seiichi , Ishizawa Kota , Numasaki Muneo , Ueda Shinsaku , Suzuki Takashi , Sasaki Hidetada 
Published: April 2014

Abstract
Tissue repair often occurs in organs damaged by an inflammatory response. Inflammatory stimuli induce a rapid and massive release of inflammatory cells including neutrophils from the bone marrow. Recently, many studies suggested that bone marrow cells have the potential to differentiate into a variety of cell types. However, whether inflammatory stimuli induce release of bone marrow-derived progenitor cells (BMPCs), or how much impact the suppression of BMPCs has on the injured organ is not clear. Here we show that LPS, a component of Gram-negative bacterial cell walls, in the lung airways, induces a rapid mobilization of BMPCs into the circulation in mice. BMPCs accumulate within the inflammatory site and differentiate to become endothelial and epithelial cells. Moreover, the suppression of BMPCs by sublethal irradiation before intrapulmonary LPS leads to disruption of tissue structure and emphysema-like changes. Reconstitution of the bone marrow prevents these changes. These data suggest that BMPCs are important and required for lung repair after LPS-induced lung injury.
Potential Targets of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor for Multiple Sclerosis Therapy
Authors: Nath Narender , Giri Shailendra , Prasad Ratna , Singh Avtar K. , Singh Inderjit 
Published: April 2014

Abstract
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins are newly identified immunomodulators. In vivo treatment of SJL/J mice with lovastatin reduced the duration and clinical severity of active and passive experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Lovastatin induced the expression of GATA3 and the phosphorylation of STAT6, whereas it inhibited tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT4. Inhibition of the Janus kinase-STAT4 pathway by lovastatin modulated T0 to Th1 differentiation and reduced cytokine (IFN-γ and TNF-α) production, thus inducing Th2 cytokines (IL-4, IL-5, and IL-10). It inhibited T-bet (T box transcription factor) and NF-κB in activated T cells and significantly reduced infiltration of CD4- and MHC class II-positive cells to CNS. Further, it stabilized IL-4 production and GATA-3 expression in differentiated Th2 cells, whereas in differentiated Th1 cells it inhibited the expression of T-bet and reduced the production of IFN-γ. Moreover, lovastatin-exposed macrophage and BV2 (microglia) in allogeneic MLRs induced the production of the anti-inflammatory cytokine IL-10. These observations indicate that the anti-inflammatory effects of lovastatin are mediated via T cells as well as APCs, because it modulates the polarization patterns of naive T cell activation in an APC-independent system. Together, these findings reveal that lovastatin may have possible therapeutic value involving new targets (in both APCs and T cells) for the treatment of multiple sclerosis and other inflammatory diseases.
Cutting Edge: NF-κB2 Is a Negative Regulator of Dendritic Cell Function
Authors: Speirs Kendra , Lieberman Linda , Caamano Jorge , Hunter Christopher A. , Scott Phillip 
Published: April 2014

Abstract
RelB, a member of the NF-κB family of transcription factors, is essential for dendritic cell (DC) maturation. Recent findings indicate that RelB is exclusively regulated through its interaction with cytoplasmic NF-κB2/p100. The studies presented in this report show that DCs lacking NF-κB2 have dramatically enhanced RelB activity, associated with increased MHC class II and costimulatory molecule expression and an enhanced ability to induce CD4+ T cell responses. These studies identify a novel role for NF-κB2 in the negative regulation of RelB-induced DC maturation, with critical consequences for the regulation of adaptive immune responses.
Invariant Chain and the MHC Class II Cytoplasmic Domains Regulate Localization of MHC Class II Molecules to Lipid Rafts in Tumor Cell-Based Vaccines
Authors: Dolan Brian P. , Phelan Timothy P. , Ilkovitch Dan , Qi Ling , Wade William F. , Laufer Terri M. , Ostrand-Rosenberg Suzanne 
Published: April 2014

Abstract
Cell-based tumor vaccines, consisting of MHC class I+ tumor cells engineered to express MHC class II molecules, stimulate tumor-specific CD4+ T cells to mediate rejection of established, poorly immunogenic tumors. Previous experiments have demonstrated that these vaccines induce immunity by functioning as APCs for endogenously synthesized, tumor-encoded Ags. However, coexpression of the MHC class II accessory molecule invariant chain (Ii), or deletion of the MHC class II cytoplasmic domain abrogates vaccine immunogenicity. Recent reports have highlighted the role of lipid microdomains in Ag presentation. To determine whether Ii expression and/or truncation of MHC class II molecules impact vaccine efficacy by altering MHC class II localization to lipid microdomains, we examined the lipid raft affinity of MHC class II molecules in mouse M12.C3 B cell lymphomas and SaI/Ak sarcoma vaccine cells. Functional MHC class II heterodimers were detected in lipid rafts of both cell types. Interestingly, expression of Ii in M12.C3 cells or SaI/Ak cells blocked the MHC class II interactions with cell surface lipid rafts. In both cell types, truncation of either the α- or β-chain decreased the affinity of class II molecules for lipid rafts. Simultaneous deletion of both cytoplasmic domains further reduced localization of class II molecules to lipid rafts. Collectively, these data suggest that coexpression of Ii or deletion of the cytoplasmic domains of MHC class II molecules may reduce vaccine efficacy by blocking the constitutive association of MHC class II molecules with plasma membrane lipid rafts.
Regulation of Autoimmune Diabetes by Complete Freund’s Adjuvant Is Mediated by NK Cells
Authors: Lee I-Fang , Qin Huilian , Trudeau Jacqueline , Dutz Jan , Tan Rusung 
Published: April 2014

Abstract
Autoimmune (type 1) diabetes results from a loss of β cells that is mediated by self-reactive T cells. Previous studies have shown that a single injection of CFA prevents diabetes in nonobese diabetic (NOD) mice, but the mechanism(s) of protection remain unknown. We show here that NOD mice immunized with CFA have a markedly reduced incidence of diabetes and that this reduced incidence is associated with a decrease in the number of β cell-specific, autoreactive CTL. In addition, the adoptive transfer of diabetes into syngeneic NOD/SCID recipients was prevented by CFA immunization, and the protective effects of CFA were lost when cells expressing the NK cell marker, asialo GM1, were removed from both donor cells and recipient mice. Returning a population of CD3−DX5+ cells to the adoptive transfer restored the protective effects of CFA. Therefore, NK cells mediate the protective effects of CFA possibly through the down-regulation of autoreactive CTL and stimulation of NK cells represents a novel approach to the prevention of autoimmune diabetes.
IL-12p70-Dependent Th1 Induction by Human B Cells Requires Combined Activation with CD40 Ligand and CpG DNA
Authors: Wagner Moritz , Poeck Hendrik , Jahrsdoerfer Bernd , Rothenfusser Simon , Prell Domenik , Bohle Barbara , Tuma Evelyn , Giese Thomas , Ellwart Joachim W. , Endres Stefan , Hartmann Gunther 
Published: April 2014

Abstract
The detection of microbial molecules via Toll-like receptors (TLR) in B cells is not well characterized. In this study, we found that both naive and memory B cells lack TLR4 (receptor for LPS) but express TLR9 (receptor for CpG motifs) and produce IL-6, TNF-α, and IL-10 upon stimulation with CpG oligonucleotides (ODN), synthetic mimics of microbial DNA. Consistent with the lack of TLR4, purified B cells failed to respond to LPS. Similar to CpG ODN, CD40 ligand (CD40L) alone induced IL-6, TNF-α, and IL-10. Production of these cytokines as well as IgM synthesis was synergistically increased when both CpG ODN and CD40L were combined. Unlike IL-6, TNF-α, and IL-10, the Th1 cytokine IL-12p70 was detected only when both CpG ODN and CD40L were present, and its induction was independent of B cell receptor cross-linking. CpG ODN did not increase the capacity of CD40L-activated B cells to induce proliferation of naive T cells. However, B cells activated with CpG ODN and CD40L strongly enhanced IFN-γ production in developing CD4 T cells via IL-12. Together, these results demonstrate that IL-12p70 production in human B cells is under the dual control of microbial stimulation and T cell help. Our findings provide a molecular basis for the potent adjuvant activity of CpG ODN to support humoral immune responses observed in vivo, and for the limited value of LPS.
Early Growth Response Gene 3 Regulates Thymocyte Proliferation during the Transition from CD4−CD8− to CD4+CD8+1
Authors: Xi Hongkang , Kersh Gilbert J. 
Published: April 2014

Abstract
In thymocytes developing in the αβ lineage, the transition from CD4, CD8 double negative (DN) to CD4, CD8 double positive (DP) is associated with several rounds of cell division and changes in the expression of multiple genes. This transition is induced by the formation of a pre-TCR that includes a rearranged TCR β-chain and the pre-TCR α-chain. The mechanism by which the pre-TCR influences both gene expression and proliferation has not been defined. We have evaluated the role played by early growth response gene 3 (Egr3) in translating pre-TCR signals into differentiation and proliferation. Egr3 is a transcriptional regulator that contains a zinc-finger DNA binding domain. We find that Egr3-deficient mice have a reduced number of thymocytes compared with wild-type mice, and that this is due to poor proliferation during the DN to DP transition. Treatment of both Egr3+/+ and Egr3−/− mice on the Rag1−/− background with anti-CD3ε Ab in vivo results in similar differentiation events, but reduced cell recovery in the Egr3−/− mice. We have also generated transgenic mice that express high levels of Egr3 constitutively, and when these mice are bred onto a Rag1−/− background they exhibit increased proliferation in the absence of stimulation and have pre-TCR α-chain and CD25 down-regulation, as well as increased Cα expression. The results show that Egr3 is an important regulator of proliferation in response to pre-TCR signals, and that it also may regulate some specific aspects of differentiation.
Induction of Tumor Regression by Administration of B7-Ig Fusion Proteins: Mediation by Type 2 CD8+ T Cells and Dependence on IL-4 Production
Authors: Yamaguchi Nobuya , Hiraoka Shin-ichiro , Mukai Takao , Takeuchi Noritami , Zhou Xu-Yu , Ono Shiro , Kogo Mikihiko , Dunussi-Joannopoulos Kyriaki , Ling Vincent , Wolf Stanley , Fujiwara Hiromi 
Published: April 2014

AbstractCD28 signals contribute to either type 1 or type 2 T cell differentiation. Here, we show that administration of B7.2-Ig fusion proteins to tumor-bearing mice induces tumor regression by promoting the differentiation of antitumor type 2 CD8+ effector T cells along with IL-4 production. B7.2-Ig-mediated regression was not induced in IL-4−/− and STAT6−/− mice. However, it was elicited in IFN-γ−/− and STAT4−/− mice. By contrast, IL-12-induced tumor regression occurred in IL-4−/− and STAT6−/− mice, but not in IFN-γ−/− and STAT4−/− mice. Moreover, B7.2-Ig treatment was effective in a tumor model not responsive to IL-12. B7.2-Ig administration elicited elevated levels of IL-4 production. Tumor regression was predominantly mediated by CD8+ T cells, although the induction of these effector cells required CD4+ T cells. Tumor regression induced by CD8+ T cells alone was inhibited by neutralizing the IL-4 produced during B7.2-Ig treatment. Thus, these results indicate that stimulation in vivo of CD28 with B7.2-Ig in tumor-bearing mice results in enhanced induction of antitumor type 2 CD8+ T cells (Tc2) leading to Tc2-mediated tumor regression.
Characterization of Defective CD4−CD8− T Cells in Murine Tumors Generated Independent of Antigen Specificity
Authors: Prins Robert M. , Incardona Francesca , Lau Regan , Lee Paul , Claus Sarah , Zhang Wenxuan , Black Keith L. , Wheeler Christopher J. 
Published: April 2014

AbstractImmune-based therapy confers limited benefits to hosts bearing late-stage tumors. Mounting evidence points to local suppression of T cell function as the most substantial barrier to effective antitumor immunity in hosts with large tumor burdens. Despite this, events responsible for locally defective T cells and immune suppression in tumors remain unclear. We describe in this study a predominant T cell population localized within two murine tumors that is characterized by expression of apoptotic markers and TCRαβ/CD3, but not CD4, CD8, or NK-associated markers. These defective cells resembled double negative (DN) T cells in lpr mice, harbored defects in the expression of T cell signaling molecules, and produced the anti-inflammatory cytokine, IL-10. Conditions known to increase or decrease the accumulation of lpr DN T cells had corresponding effects on local DN tumor infiltrating lymphocyte (TIL) levels and inversely impacted host survival. Adoptive transfer into s.c. tumors demonstrated that naive CD8+ T cells were highly susceptible to becoming DN TIL, and local supplementation of tumors with nontumor Ag-bearing MHC class I-expressing fibroblasts decreased both this susceptibility and endogenous DN TIL levels. These findings identify a major defective T cell population with suppressive potential within tumors. The data also suggest that local T cell defectiveness is controlled by the tumor environment independent of cognate Ag specificity per se. Decreasing defective DN TIL levels by increasing noncognate peptide MHC class I availability, or modulating TCR or cytokine signaling may facilitate host survival by bolstering endogenous immunity to late-stage tumors, and may help improve therapeutic tumor vaccines.
Nucleotide Sequencing of Psoriatic Arthritis Tissue before and during Methotrexate Administration Reveals a Complex Inflammatory T Cell Infiltrate with Very Few Clones Exhibiting Features That Suggest They Drive the Inflammatory Process by Recognizing Autoantigens
Authors: Curran Shane A. , FitzGerald Oliver M. , Costello Patrick J. , Selby Jeanette M. , Kane David J. , Bresnihan Barry , Winchester Robert 
Published: April 2014

AbstractPsoriatic arthritis is an interesting MHC class I allele associated autoimmune disease where injury is likely mediated exclusively by T cells. We used TCR β-chain nucleotide sequencing to gain insight into the adaptive immune events responsible for this injury and determine whether the numerous oligoclonal expansions of this disease represent extreme determinant spreading among driving clones that recognize autoantigen or were non-Ag-driven, inflammation-related expansions. Because methotrexate suppresses but does not eliminate this inflammation, we hypothesized that clones persisting during methotrexate treatment would likely drive the inflammation. Seventy-six percent of the T cell clones in active tissue were polyclonal and unexpanded, accounting for 31% of transcripts. They were decreased greatly by methotrexate. Strikingly, most expanded clones in the inflamed joint did not persist during methotrexate treatment, were found only in inflammatory sites, exhibited no structural homology to one another, and were either CD4 or CD8 in lineage, suggesting they were non-autoantigen-driven, inflammation-related expansions. Only 12% of the expanded clones could be grouped into clonal sets distinguished by structurally homologous CDR3 β-chain amino acid motifs suggesting Ag drive. These were exclusively CD8 in lineage, persisted during methotrexate administration, and were present in both joint fluid and blood implying they were candidate driver clones that recognized an autoantigen. However, a major set of putative driver clones exhibited a previously described EBV-specific β-chain motif, emphasizing that the dominant feature of the disease was activation of multiple clones apparently lacking specificity for an inciting autoantigen.
CD86 and CD80 Differentially Modulate the Suppressive Function of Human Regulatory T Cells
Authors: Zheng Yong , Manzotti Claire N. , Liu Michael , Burke Fiona , Mead Karen I. , Sansom David M. 
Published: April 2014

Abstract
Regulatory T cells (Treg) are important in maintaining tolerance to self tissues. As both CD28 and CTLA-4 molecules are implicated in the function of Treg, we investigated the ability of their two natural ligands, CD80 and CD86, to influence the Treg-suppressive capacity. During T cell responses to alloantigens expressed on dendritic cells, we observed that Abs against CD86 potently enhanced suppression by CD4+CD25+ Treg. In contrast, blocking CD80 enhanced proliferative responses by impairing Treg suppression. Intriguingly, the relative expression levels of CD80 and CD86 on dendritic cells are modulated during progression from an immature to a mature state, and this correlates with the ability of Treg to suppress responses. Our data show that CD80 and CD86 have opposing functions through CD28 and CTLA-4 on Treg, an observation that has significant implications for manipulation of immune responses and tolerance in vivo.
In Vivo VL-Targeted Activation-Induced Apoptotic Supraclonal Deletion by a Microbial B Cell Toxin
Authors: Goodyear Carl S. , Narita Masami , Silverman Gregg J. 
Published: April 2014

Abstract
To interfere with host immune responses, some microbial pathogens produce proteins with the properties of superantigens, which can interact via conserved V region framework subdomains of the Ag receptors of lymphocytes rather than the complementarity-determining region involved in the binding of conventional Ags. In recent studies, we have elucidated how a model B cell superantigen affects the host immune system by targeting a conserved VH site on the Ag receptors of B lymphocytes. To determine whether these findings represent a general paradigm, we investigated the in vivo immunobiologic properties of protein L of Peptostreptococcus magnus (PpL), a microbial Ig-binding protein specific for a V region site on Ig L chains. Our studies confirmed that PpL binding is restricted to a subset of murine Vκ-expressing B cells, and found that B cells with stronger PpL-binding activity are associated with certain B cell subsets: splenic marginal zone (CD21high CD23low), splenic CD1+, peritoneal B-1a (IgDlow CD5+), and CD21high CD24high B cells in peripheral lymph nodes, mesenteric lymph nodes, and Peyer’s patches. Infusion of PpL triggered a sequence of events in B cell receptor (BCR)-targeted B cells, with rapid down-regulation of BCR, the induction of an activation phenotype, and limited rounds of proliferation. Apoptosis followed through a process heralded by the dissipation of mitochondrial membrane potential, the induction of the caspase pathway, DNA fragmentation, and the deposition of B cell apoptotic bodies. These studies define a common pathway by which microbial toxins that target V region-associated BCR sites induce programmed cell death.
Targeting of Secretory IgA to Peyer’s Patch Dendritic and T Cells after Transport by Intestinal M Cells
Authors: Rey Jacques , Garin Nathalie , Spertini François , Corthésy Blaise 
Published: April 2014

AbstractIn addition to being instrumental to the protection of mucosal epithelia, secretory IgA (SIgA) adheres to and is transported by intestinal Peyer’s patch (PP) M cells. The possible functional reason for this transport is unknown. We have thus examined in mice the outcome of SIgA delivered from the intestinal lumen to the cells present in the underlying organized mucosa-associated lymphoreticular tissue. We show selective association of SIgA with dendritic cells and CD4+ T and B lymphocytes recovered from PP in vitro. In vivo, exogenously delivered SIgA is able to enter into multiple PP lining the intestine. In PP, SIgA associates with and is internalized by dendritic cells in the subepithelial dome region, whereas the interaction with CD4+ T cells is limited to surface binding. Interaction between cells and SIgA is mediated by the IgA moiety and occurs for polymeric and monomeric molecular forms. Thus, although immune exclusion represents the main function of SIgA, transport of the Ab by M cells might promote Ag sampling under neutralizing conditions essential to the homeostasis of mucosal surfaces.