bluuebunny/crossref_metadata_2025_split huggingface dataset:
NF-κB Controls Cell Fate Specification, Survival, and Molecular Differentiation of Immunoregulatory Natural T Lymphocytes
Authors: Stanic Aleksandar K. , Bezbradica Jelena S. , Park Jang-June , Matsuki Naoto , Mora Ana L. , Van Kaer Luc , Boothby Mark R. , Joyce Sebastian 
Published: April 2014

Abstract
Ontogenetic, homeostatic, and functional deficiencies within immunoregulatory natural T (iNKT) lymphocytes underlie various inflammatory immune disorders including autoimmunity. Signaling events that control cell fate specification and molecular differentiation of iNKT cells are only partly understood. Here we demonstrate that these processes within iNKT cells require classical NF-κB signaling. Inhibition of NF-κB signaling blocks iNKT cell ontogeny at an immature stage and reveals an apparent, novel precursor in which negative selection occurs. Most importantly, this block occurs due to a lack of survival signals, as Bcl-xL overexpression rescues iNKT cell ontogeny. Maturation of immature iNKT cell precursors induces Bcl-2 expression, which is defective in the absence of NF-κB signaling. Bcl-xL overexpression also rescues this maturation-induced Bcl-2 expression. Thus, antiapoptotic signals relayed by NF-κB critically control cell fate specification and molecular differentiation of iNKT cells and, hence, reveal a novel role for such signals within the immune system.
Adjuvant Costimulation during Secondary Antigen Challenge Directs Qualitative Aspects of Oral Tolerance Induction, Particularly during the Neonatal Period
Authors: Tobagus Iriani T. , Thomas Wayne R. , Holt Patrick G. 
Published: April 2014

AbstractIn this report we demonstrate that although passive feeding of specific Ag to mice as neonates or adults can induce oral tolerance in both the cellular and humoral arms of the immune response, quantitative and, in particular, qualitative aspects of the tolerance process are determined by the nature of the inflammatory costimuli provided at the time of secondary Ag challenge. Moreover, this dependency upon nonspecific costimulation is more profound in Ag-fed neonates than in their adult counterparts. Thus, administration of Ag in the Th1-selective adjuvant CFA to prefed animals resulted in significant inhibition of IgG2a, IL-2, and IFN-γ responses, whereas IL-5 responses were increased. In contrast, rechallenge with Ag in the Th2-selective adjuvant aluminum hydroxide resulted in significant inhibition of IgG1, IgE, IL-2, and IL-5 responses, whereas IFN-γ responses were increased. Additionally, although soluble Ag challenge of prefed adults revealed marginal tolerogenic effects, the same challenge protocol in animals prefed as neonates elicited enhanced Th2-dependent IgG1 production. These results suggest that inflammatory stimulation at the time of Ag challenge is obligatory to trigger oral tolerance mechanisms, particularly in animals fed as neonates and also that the type of adjuvant used at the time of challenge selects for the type of Th cell population to be inhibited.
CD4+ T Cells Regulate CD8+ T Cell-Mediated Cutaneous Immune Responses by Restricting Effector T Cell Development through a Fas Ligand-Dependent Mechanism
Authors: Gorbachev Anton V. , Fairchild Robert L. 
Published: April 2014

AbstractThe magnitude and duration of CD8+ T cell-mediated responses in the skin to hapten sensitization and challenge, contact hypersensitivity (CHS), is negatively regulated by CD4+ T cells through an unknown mechanism. In this study we show that CD4+ T cells restrict the development and expansion of hapten-specific CD8+ T cells mediating CHS responses to 2,4-dinitrofluorobenzene. In the absence of CD4+ T cells, high numbers of hapten-specific CD8+ T cells producing IFN-γ were detected in the skin-draining lymph nodes on day 5 postsensitization, and these numbers decreased slightly, but were maintained through day 9, correlating with the increased magnitude and duration of CHS responses observed in these mice. In the presence of CD4+ T cells, the number of hapten-specific CD8+ T cells producing IFN-γ detected on day 5 postsensitization was lower and quickly fell to background levels by day 7. The limited development of effector CD8+ T cells was associated with decreased numbers of hapten-presenting dendritic cells in the lymphoid priming site. This form of immunoregulation was absent after sensitization of Fas ligand-defective gld mice. Transfer of wild-type CD4+ T cells to gld mice restored the negative regulation of CD8+ T cell priming and the immune response to hapten challenge in gld-recipient mice. These results indicate that CD4+ T cells restrict hapten-specific CD8+ T cell priming for CHS responses through a Fas ligand-dependent mechanism.
Reduced Thymocyte Development in Sonic Hedgehog Knockout Embryos
Authors: Shah Divya K. , Hager-Theodorides Ariadne L. , Outram Susan V. , Ross Susan E. , Varas Alberto , Crompton Tessa 
Published: April 2014

Abstract
The Hedgehog family of secreted intercellular signaling molecules are regulators of patterning and organogenesis during animal development. In this study we provide genetic evidence that Sonic Hedgehog (Shh) has a role in the control of murine T cell development. Analysis of Shh−/− mouse embryos revealed that Shh regulates fetal thymus cellularity and thymocyte differentiation. Shh is necessary for expansion of CD4−CD8− double-negative (DN) thymocytes and for efficient transition from the earliest CD44+CD25− DN population to the subsequent CD44+CD25+ DN population and from DN to CD4+CD8+ double-positive cells.
The Impact of Self-Tolerance on the Polyclonal CD8+ T Cell Repertoire
Authors: Kessels Helmut W. H. G. , de Visser Karin E. , Tirion Felicia H. , Coccoris Miriam , Kruisbeek Ada M. , Schumacher Ton N. M. 
Published: April 2014

Abstract
TCRs possess considerable cross-reactivity toward structurally related Ags. Because the signaling threshold for negative selection is lower than that required for activation of mature T cells, the question arises as to which extent thymic deletion of self-specific T cells affects T cell responsiveness toward foreign peptides. In this study we show, in three different mouse models systems, that the polyclonal CD8+ T cell repertoire has a marked ability to react against the majority of Ags related to self despite self-tolerance, even in cases where self and foreign differ only marginally at a single TCR-contact residue. Thus, while individual T cells are markedly cross-reactive, the ability to distinguish between closely related Ags is introduced at the polyclonal T cell level.
Immunosuppressive Activity of Endovanilloids:N-Arachidonoyl-Dopamine Inhibits Activation of the NF-κB, NFAT, and Activator Protein 1 Signaling Pathways
Authors: Sancho Rocío , Macho Antonio , de La Vega Laureano , Calzado Marco A. , Fiebich Bernd L. , Appendino Giovanni , Muñoz Eduardo 
Published: April 2014

AbstractEndogenous N-acyl dopamines such as N-arachidonoyldopamine (NADA) and N-oleoyldopamine have been recently identified as a new class of brain neurotransmitters sharing endocannabinoid and endovanilloid biological activities. As endocannabinoids show immunomodulatory activity, and T cells play a key role in the onset of several diseases that affect the CNS, we have evaluated the immunosuppressive activity of NADA and N-oleoyldopamine in human T cells, discovering that both compounds are potent inhibitors of early and late events in TCR-mediated T cell activation. Moreover, we found that NADA specifically inhibited both IL-2 and TNF-α gene transcription in stimulated Jurkat T cells. To further characterize the inhibitory mechanisms of NADA at the transcriptional level, we examined the DNA binding and transcriptional activities of NF-κB, NF-AT, and AP-1 transcription factors in Jurkat cells. We found that NADA inhibited NF-κB-dependent transcriptional activity without affecting either degradation of the cytoplasmic NF-κB inhibitory protein, IκBα, or DNA binding activity. However, phosphorylation of the p65/RelA subunit was clearly inhibited by NADA in stimulated cells. In addition, NADA inhibited both binding to DNA and the transcriptional activity of NF-AT and AP-1, as expected from the inhibition of NF-AT1 dephosphorylation and c-Jun N-terminal kinase activation in stimulated T cells. Finally, overexpression of a constitutively active form of calcineurin demonstrated that this phosphatase may represent one of the main targets of NADA. These findings provide new mechanistic insights into the anti-inflammatory activities of NADA and highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.
Biases in Ig λ Light Chain Rearrangements in Human Intestinal Plasma Cells
Authors: Su Wen , Boursier Laurent , Padala Archana , Sanderson Jeremy D. , Spencer Jo 
Published: April 2014

Abstract
Human intestinal lamina propria plasma cells are considered to be the progeny of chronically stimulated germinal centers located in organized gut-associated lymphoid tissues such as Peyer’s patches and isolated lymphoid follicles. We have sampled human colonic lamina propria plasma cells and naive and memory B cell subsets from human Peyer’s patches by microdissection of immunohistochemically stained tissue sections and used PCR methods and sequence analysis to compare IgVλJλ rearrangements in the plasma cell and B cell populations. Rearrangements that were either in-frame or out-of-frame between V and J were compared. Usage of IgVλ families in the in-frame rearrangements from the plasma cells resembled that observed in the mantle cells, suggesting that antigenic selection for cellular specificity does not dramatically favor any particular Vλ segment. However, in marked contrast, out-of-frame rearrangements involving Vλ1 and Vλ2 families are rarely observed in intestinal plasma cells, whereas rearrangements involving Vλ5 are increased. This resulted in significantly biased ratios of in-frame:out-of-frame rearrangements in these Vλ families. Out-of-frame rearrangements of IgVλJλ from plasma cells, including those involving the Vλ5 family, have a significant tendency not to involve Jλ1, consistent with the hypothesis that this population includes rearrangements generated by secondary recombination events. We propose that modification of out-of-frame rearrangements of IgVλJλ exists, probably a consequence of secondary rearrangements. This may be a mechanism to avoid translocations to susceptible out-of-frame IgVλJλ rearrangements during somatic hypermutation.
Conformation and Glycosylation of a Megalin Fragment Correlate with Nephritogenicity in Heymann Nephritis
Authors: Tramontano Alfonso , Makker Sudesh P. 
Published: April 2014

Abstract
Active Heymann nephritis (AHN), a rat model of autoimmune glomerulonephritis, is induced by immunization with autologous megalin, a 600-kDa cell surface glycoprotein isolated from crude renal extracts. Recombinant proteins containing a 563-residue N-terminal sequence of megalin were obtained from Escherichia coli and baculovirus-insect cell expression systems. Rats immunized with the soluble, secreted protein encoded by a baculovirus construct elicited high titer anti-megalin autoantibodies and developed glomerular immune deposits and elevated proteinuria consistent with AHN. Rats treated with the bacterial or nonsecreted insect cell proteins produced a milder anti-megalin response and did not develop the disease. Nephritogenicity appeared to correlate with conformational or other structural features of native megalin. All three recombinant proteins were reactive in Western blots with rabbit anti-megalin antiserum, whereas the insect cell-derived proteins reacted preferentially in Western blot and ELISA with anti-megalin autoantibodies from rats with AHN induced by native megalin. Only the secreted insect cell product was stained in a lectin blot, suggesting its specific glycosylation. These observations provide evidence that a megalin N-terminal domain includes B and T cell epitopes sufficient for a pathogenic autoimmune response and that a native-like conformation and glycosylation are essential for the induction of disease. The importance of conformational B cell epitopes for pathogenic autoantibodies recapitulates observations made in other models of organ-specific autoimmune disease. Glycosidic modifications could influence the presentation of either B or T cell epitopes in AHN, consistent with emerging evidence of the role of post-translational modifications in pathogenic autoimmune responses.
The Crystal Structure of Human CD1b with a Bound Bacterial Glycolipid
Authors: Batuwangala Thil , Shepherd Dawn , Gadola Stephan D. , Gibson Kevin J. C. , Zaccai Nathan R. , Fersht Alan R. , Besra Gurdyal S. , Cerundolo Vincenzo , Jones E. Yvonne 
Published: April 2014

Abstract
The human MHC class I-like molecule CD1b is distinctive among CD1 alleles in that it is capable of presenting a set of glycolipid species that show a very broad range of variation in the lengths of their acyl chains. A structure of CD1b complexed with relatively short acyl chain glycolipids plus detergent suggested how an interlinked network of channels within the Ag-binding groove could accommodate acyl chain lengths of up to 80 carbons. The structure of CD1b complexed with glucose monomycolate, reported in this study, confirms this hypothesis and illustrates how the distinctive substituents of intracellular bacterial glycolipids can be accommodated. The Ag-binding groove of CD1b is, uniquely among CD1 alleles, partitioned into channels suitable for the compact accommodation of lengthy acyl chains. The current crystal structure illustrates for the first time the binding of a natural bacterial lipid Ag to CD1b and shows how its novel structural features fit this molecule for its role in the immune response to intracellular bacteria.
Macrophages, CD4+ or CD8+ Cells Are Each Sufficient for Protection against Chlamydia pneumoniae Infection through their Ability to Secrete IFN-γ
Authors: Rothfuchs Antonio Gigliotti , Kreuger Maria Regina , Wigzell Hans , Rottenberg Martin E. 
Published: April 2014

Abstract
By using a T, B, or NK cell-deficient mouse strain (recombinase-activating gene (RAG)-1−/−/common cytokine receptor γ-chain (γCR)), and T and B cell and IFN-γ-deficient (RAG-1−/−/IFN-γ−/−) mice, we have studied the generation of immunity against infection by Chlamydia pneumoniae. We found that IFN-γ secreted by innate-cell populations protect against C. pneumoniae infection. However, NK cells were not needed for such IFN-γ-dependent innate immune protection. Inoculation of wild type, but not IFN-γ−/− bone marrow-derived macrophages protected RAG-1−/−/IFN-γ−/− mice against C. pneumoniae infection. In line, pulmonary macrophages from RAG-1−/− C. pneumoniae-infected mice expressed IFN-γ mRNA. Reconstitution of RAG-1−/−/γcR−/− or RAG-1−/−/IFN-γ−/− mice with CD4+ or CD8+ cells by i.v. transfer of FACS sorted wild type spleen cells (SC) increased resistance to C. pneumoniae infection. On the contrary, no protection was observed upon transfer of IFN-γ−/− CD4+ or IFN-γ−/− CD8+ SC. T cell-dependent protection against C. pneumoniae was weaker when IFN-γR−/− CD4+ or IFN-γR−/− CD8+ SC were inoculated into RAG-1−/−/IFN-γ−/− mice. Thus both nonlymphoid and T cell-derived IFN-γ can play a central and complementary role in protection against C. pneumoniae. IFN-γ secreted by nonlymphoid cells was not required for T cell-mediated protection against C. pneumoniae; however, IFN-γ regulated T cell protective functions.
Recognition of Homo- and Heterosubtypic Variants of Influenza A Viruses by Human CD8+ T Lymphocytes
Authors: Boon Adrianus C. M. , de Mutsert Gerrie , van Baarle Debbie , Smith Derek J. , Lapedes Alan S. , Fouchier Ron A. M. , Sintnicolaas Kees , Osterhaus Albert D. M. E. , Rimmelzwaan Guus F. 
Published: April 2014

Abstract
In the present study, the recognition of epitope variants of influenza A viruses by human CTL was investigated. To this end, human CD8+ CTL clones, specific for natural variants of the HLA-B*3501-restricted epitope in the nucleoprotein (NP418–426), were generated. As determined in 51Cr release assays and by flow cytometry with HLA-B*3501-peptide tetrameric complexes, CTL clones were found to be specific for epitopes within one subtype or cross-reactive with heterosubtypic variants of the epitope. Using eight natural variants of the epitope, positions in the 9-mer important for T cell recognition and involved in escape from CTL immunity were identified and visualized using multidimensional scaling. It was shown that positions 4 and 5 in the 9-mer epitope were important determinants of T cell specificity. The in vivo existence of CD8+ cells cross-reactive with homo- and heterosubtypic variants of the epitope was further confirmed using polyclonal T cell populations obtained after stimulation of PBMC with different influenza A viruses. Based on the observed recognition patterns of the clonal and polyclonal T cell populations and serology, it is hypothesized that consecutive infections with influenza viruses containing different variants of the epitope select for cross-reactive T cells in vivo.
Protective Immunization against Group B Meningococci Using Anti-Idiotypic Mimics of the Capsular Polysaccharide
Authors: Beninati Concetta , Arseni Simona , Mancuso Giuseppe , Magliani Walter , Conti Stefania , Midiri Angelina , Biondo Carmelo , Polonelli Luciano , Teti Giuseppe 
Published: April 2014

Abstract
Use of the serogroup B meningococcal capsular polysaccharide (MenB CP) as a vaccine is hampered by the presence of epitopes that cross-react with human polysialic acid. As non-cross-reactive, protective capsular epitopes have also been described, we set out to develop protein mimics of one of such epitopes using as a template a highly protective mAb (mAb Seam 3) raised against a chemically modified form of the MenB CP (N-Pr MenB CP). Using phage display, anti-idiotypic single-chain Ab fragments (scFvs) were obtained from spleen cells of mice immunized with the Seam 3 mAb. Two Seam 3-specific scFvs competed with N-Pr MenB CP for binding to either mAb Seam 3 or rabbit Abs present in typing sera. Moreover, in mice and rabbits the scFvs elicited the production of Abs reacting with both N-Pr MenB CP and whole meningococci, but not with human polysialic acid. These scFv-induced Ab responses were boostable and of the Th1 type, as shown by a predominance of IgG2a. In addition, passive immunization with sera from scFv-immunized animals partially protected neonatal mice from experimental infection with group B meningococci. In conclusion, we have produced anti-idiotypic scFvs that mimic a protective MenB CP epitope and may be useful in the development of an alternative group B meningococcal vaccine.
Cyclooxygenase-2-Mediated Prostaglandin E2 Production in Mesenteric Lymph Nodes and in Cultured Macrophages and Dendritic Cells after Infection with Salmonella
Authors: Bowman Christal C. , Bost Kenneth L. 
Published: April 2014

Abstract
Although numerous studies have demonstrated the ability of intestinal epithelial cells to produce PGs after infection with wild-type strains of Salmonella, few studies have focused on Salmonella-induced prostanoids in mucosal lymphoid tissues. This is surprising in view of the profound effects PGs can have on the host response. To begin to address PG production at mucosal sites, mice were orally inoculated with Salmonella, and at varying times postinfection cyclooxygenase-2 (COX-2) mRNA expression and PGE2 synthesis were investigated. COX-2 mRNA expression was highly inducible in the mesenteric lymph nodes, whereas COX-1 mRNA levels were constitutive. PGE2 production also increased significantly in the mesenteric lymph nodes following exposure to viable Salmonella, but not after exposure to killed bacteria. This increased PGE2 response could be blocked by treatment of mice with the selective COX-2 inhibitor, celecoxib. Treatment of mice with celecoxib during salmonellosis resulted in increased viable bacteria in the mesenteric lymph nodes by day 3 postinfection. However, celecoxib treatment prolonged the survival of lethally infected animals. In vitro studies demonstrated Salmonella-induced up-regulation of COX-2 mRNA expression and PGE2 secretion by both macrophages and dendritic cells, which could also be blocked in the presence of celecoxib. Interestingly, exposure of these cultured APCs to viable Salmonella was a much greater stimulus for induction of PGE2 synthesis than exposure to Salmonella-derived LPS. The present study demonstrates induction of PGE2 synthesis in mesenteric lymph nodes, macrophages, and dendritic cells after infection with wild-type Salmonella.
HIV-1-Specific Memory CD4+ T Cells Are Phenotypically Less Mature Than Cytomegalovirus-Specific Memory CD4+ T Cells
Authors: Yue Feng Yun , Kovacs Colin M. , Dimayuga Rowena C. , Parks Paul , Ostrowski Mario A. 
Published: April 2014

Abstract
HIV-1-specific CD4+ T cells are qualitatively dysfunctional in the majority of HIV-1-infected individuals and are thus unable to effectively control viral replication. The current study extensively details the maturational phenotype of memory CD4+ T cells directed against HIV-1 and CMV. We find that HIV-1-specific CD4+ T cells are skewed to an early central memory phenotype, whereas CMV-specific CD4+ T cells generally display a late effector memory phenotype. These differences hold true for both IFN-γ- and IL-2-producing virus-specific CD4+ T cells, are present during all disease stages, and persist even after highly active antiretroviral therapy (HAART). In addition, after HAART, HIV-1-specific CD4+ T cells are enriched for CD27+CD28−-expressing cells, a rare phenotype, reflecting an early intermediate stage of differentiation. We found no correlation between differentiation phenotype of HIV-1-specific CD4+ T cells and HIV-1 plasma viral load or HIV-1 disease progression. Surprisingly, HIV-1 viral load affected the maturational phenotype of CMV-specific CD4+ T cells toward an earlier, less-differentiated state. In summary, our data indicate that the maturational state of HIV-1-specific CD4+ T cells cannot be a sole explanation for loss of containment of HIV-1. However, HIV-1 replication can affect the phenotype of CD4+ T cells of other specificities, which might adversely affect their ability to control those pathogens. The role for HIV-1-specific CD4+ T cells expressing CD27+CD28− after HAART remains to be determined.