bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3+CD25+ and Foxp3−CD25− CD4+ Regulatory T Cells
Authors: Sun Jia-Bin , Raghavan Sukanya , Sjöling Åsa , Lundin Samuel , Holmgren Jan 
Published: April 2014

Abstract
Oral administration of Ag coupled to cholera toxin B subunit (CTB) efficiently induces peripheral immunological tolerance. We investigated the extent to which this oral tolerance is mediated by CD25+CD4+ regulatory T cells (Treg). We found that total Treg, KJ1–26+ Treg and CTLA-4+ Treg were all increased in Peyer’s patches, mesenteric lymph nodes, and, to a lesser extent, in spleen of mice after intragastric administration of OVA/CTB conjugate, which also increased TGF-β in serum. This could be abolished by coadministering cholera toxin or by treatment with anti-TGF-β mAb. CD25+ Treg, but also CD25−CD4+ T cells from OVA/CTB-treated BALB/c or DO11.10 mice efficiently suppressed effector T cell proliferation and IL-2 production in vitro. Following adoptive transfer, both T cell populations also suppressed OVA-specific T cell and delayed-type hypersensitivity responses in vivo. Foxp3 was strongly expressed by CD25+ Treg from OVA/CTB-treated mice, and treatment also markedly expanded CD25+Foxp3+ Treg. Furthermore, in Rag1−/− mice that had adoptively received highly purified Foxp3−CD25−CD4+ OT-II T cells OVA/CTB feeding efficiently induced CD25+ Treg cells, which expressed Foxp3 more strongly than naturally developing Treg and also had stronger ability to suppress effector OT-II T cell proliferation. A remaining CD25− T cell population, which also became suppressive in response to OVA/CTB treatment, did not express Foxp3. Our results demonstrate that oral tolerance induced by CTB-conjugated Ag is associated with increase in TGF-β and in both the frequency and suppressive capacity of Foxp3+ and CTLA-4+ CD25+ Treg together with the generation of both Foxp3+ and Foxp3−CD25− CD4+ Treg.
Microenvironment-Dependent Requirement of STAT4 for the Induction of P-Selectin Ligands and Effector Cytokines on CD4+ T Cells in Healthy and Parasite-Infected Mice
Authors: Syrbe Uta , Hoffmann Ute , Schlawe Kerstin , Liesenfeld Oliver , Erb Klaus , Hamann Alf 
Published: April 2014

Abstract
T effector cells require selectin ligands to migrate into inflamed regions. In vitro, IL-12 promotes induction of these ligands as well as differentiation of CD4+ T cells into IFN-γ-producing Th1 but not Th2 cells. STAT4 is strongly involved in these processes. However, the presence of selectin ligands on various T effector cell subsets in vivo points to more complex regulatory pathways. To clarify the role of the IL-12/STAT4 signaling pathway, we analyzed the impact of STAT4 deficiency on the expression of P-selectin ligands (P-lig) on CD4+ T cells in vitro and in vivo, including conditions of infection. In vitro, we found significant expression of P-lig upon activation not only in the presence, but also in the absence, of IL-12, which was independent of STAT4. TGF-β, an alternative inducer of selectin ligands in human T cells, was not effective in murine CD4+ T cells, suggesting a role of additional signaling pathways. In vivo, a significant impact of STAT4 for the generation of P-lig+CD4+ T cells was observed for cells from peripheral lymph nodes, but not for those from spleen or lung. However, upon infection with the Th2-inducing parasite Nippostrongylus brasiliensis, P-lig expression became dependent on STAT4 signaling. Interestingly, also the frequency of IL-4-producing cells was greatly diminished in absence of STAT4. These data reveal a hitherto unknown contribution of STAT4 to the generation of Th2 cells in parasite infection and suggest that signals inducing inflammation-seeking properties in vivo vary depending on environmental conditions, such as type of organ and infection.
Immunoproteasome Subunit Deficiencies Impact Differentially on Two Immunodominant Influenza Virus-Specific CD8+ T Cell Responses
Authors: Pang Ken C. , Sanders Megan T. , Monaco John J. , Doherty Peter C. , Turner Stephen J. , Chen Weisan 
Published: April 2014

Abstract
Primary CD8+ T cell (TCD8+) responses to viruses are directed toward multiple Ags and shaped by both the level of Ag presentation and the underlying Ag-specific TCD8+ repertoire. The relative importance of these factors in deciding the hierarchy of TCD8+ responses and how they are influenced by the immunoproteasome are not well understood. Using an influenza infection model in mice deficient in various immunoproteasome subunits, we observe that Ag presentation and TCD8+ repertoire are altered in an epitope-specific and immunoproteasome subunit-dependent manner. More importantly, we find that the level of Ag presentation and the extent of the underlying repertoire can work either alone or in concert to determine definitively the magnitude of the individual TCD8+ responses and hence the overall TCD8+ hierarchy. Together, these results provide a clearer understanding of how immunodominance hierarchies are established.
B Cell-Mediated Antigen Presentation Is Required for the Pathogenesis of Acute Cardiac Allograft Rejection
Authors: Noorchashm Hooman , Reed Amy J. , Rostami Susan Y. , Mozaffari Raha , Zekavat Ghazal , Koeberlein Brigitte , Caton Andrew J. , Naji Ali 
Published: April 2014

Abstract
Acute allograft rejection requires the activation of alloreactive CD4 T cells. Despite the capacity of B cells to act as potent APCs capable of activating CD4 T cells in vivo, their role in the progression of acute allograft rejection was unclear. To determine the contribution of B cell APC function in alloimmunity, we engineered mice with a targeted deficiency of MHC class II-mediated Ag presentation confined to the B cell compartment. Cardiac allograft survival was markedly prolonged in these mice as compared to control counterparts (median survival time, &gt;70 vs 9.5 days). Mechanistically, deficient B cell-mediated Ag presentation disrupted both alloantibody production and the progression of CD4 T cell activation following heart transplantation. These findings demonstrate that indirect alloantigen presentation by recipients’ B cells plays an important role in the efficient progression of acute vascularized allograft rejection.
Imprinting the Fate of Antigen-Reactive B Cells through the Affinity of the B Cell Receptor
Authors: O’Connor Brian P. , Vogel Laura A. , Zhang Weijun , Loo William , Shnider Danielle , Lind Evan F. , Ratliff Michelle , Noelle Randolph J. , Erickson Loren D. 
Published: April 2014

Abstract
Long-lived plasma cells (PCs) and memory B cells (Bmem) constitute the cellular components of enduring humoral immunity, whereas short-lived PCs that rapidly produce Ig correspond to the host’s need for immediate protection against pathogens. In this study we show that the innate affinity of the BCR for Ag imprints upon naive B cells their differentiation fate to become short- or long-lived PCs and Bmem. Using BCR transgenic mice with varying affinities for Ag, naive B cells with high affinity lose their capacity to form germinal centers (GCs), develop neither Bmem nor long-lived PCs, and are destined to a short-lived PC fate. Moderate affinity interactions result in hastened GC responses, and differentiation to long-lived PCs, but Bmem remain extinct. In contrast, lower affinity interactions show tempered GCs, producing Bmem and affinity-matured, long-lived PCs. Thus, a continuum of elementary to comprehensive humoral immune responses exists that is controlled by inherent BCR affinity.
Dendritic Cells Amplify T Cell-Mediated Immune Responses in the Central Nervous System
Authors: Karman Jozsef , Chu Hamlet H. , Co Dominic O. , Seroogy Christine M. , Sandor Matyas , Fabry Zsuzsanna 
Published: April 2014

Abstract
Neuroinflammation often starts with the invasion of T lymphocytes into the CNS leading to recruitment of macrophages and amplification of inflammation. In this study, we show that dendritic cells (DCs) facilitate T-T cell help in the CNS and contribute to the amplification of local neuroinflammation. We adoptively transferred defined amounts of naive TCR-transgenic (TCR) recombination-activating gene-1-deficient T cells into another TCR-transgenic mouse strain expressing different Ag specificity. Following adoptive transfers, we coinjected DCs that presented one or multiple Ags into the brain and followed the activation of T cells with defined specificities simultaneously. Injection of DCs presenting both Ags simultaneously led to significantly higher infiltration of T cells into the brain compared with injection of a mixture of DCs pulsed with two Ags separately. DCs mediated either cooperative or competitive interactions between T cell populations with different specificities depending upon their MHC-restricting element usage. These results suggest that DC-mediated cooperation between brain-infiltrating T cells of different Ag specificities in the CNS plays an important role in regulation of neuroinflammation. This work also implies that blocking Ag-specific responses may block not only the targeted specificities, but may also effectively block their cooperative assistance to other T cells. Therefore, these data justify more attention to Ag-specific therapeutic approaches for neuroinflammation.
Gut IgA Class Switch Recombination in the Absence of CD40 Does Not Occur in the Lamina Propria and Is Independent of Germinal Centers
Authors: Bergqvist Peter , Gärdby Eva , Stensson Anneli , Bemark Mats , Lycke Nils Y. 
Published: April 2014

AbstractConflicting findings have recently been presented as to the sites and sources of B cells that undergo class switch recombination (CSR) to IgA in the gut. In this study we provide compelling evidence in CD40−/− mice demonstrating that IgA CSR can be independent of CD40 signaling and germinal center formation and does not occur in the gut lamina propria (LP) itself. We found that CD40−/− mice had near normal levels of gut total IgA despite lacking germinal centers and completely failing to raise specific responses against the T cell-dependent Ags cholera toxin and keyhole limpet hemocyanin. The Peyer’s patches in CD40−/− mice expressed unexpectedly high levels of activation-induced cytidine deaminase mRNA and germline α transcripts, but few postswitch circular DNA transcripts, arguing against significant IgA CSR. Moreover and more surprisingly, wild-type mice exhibited no to low IgA CSR in mesenteric lymph nodes or isolated lymphoid follicles. Importantly, both strains failed to demonstrate any of the molecular markers for IgA CSR in the gut LP itself. Whereas all of the classical sites for IgA CSR in the GALT in CD40−/− mice appeared severely compromised for IgA CSR, B cells in the peritoneal cavity demonstrated the expression of activation-induced cytidine deaminase mRNA comparable to that of wild-type mice. However, peritoneal cavity B cells in both strains expressed intermediate levels of the germinal center marker GL7 and exhibited no germline α transcripts, and only three of 51 mice analyzed showed the presence of postswitch circular DNA transcripts. Taken together, these findings strongly argue for alternative inductive sites for gut IgA CSR against T cell-independent Ags outside of the GALT and the nonorganized LP.
Cyclooxygenase-2 Inhibition Attenuates Antibody Responses against Human Papillomavirus-Like Particles
Authors: Ryan Elizabeth P. , Malboeuf Christine M. , Bernard Matthew , Rose Robert C. , Phipps Richard P. 
Published: April 2014

Abstract
Vaccination to generate protective humoral immunity against infectious disease is becoming increasingly important due to emerging strains of virus, poorly immunogenic vaccines, and the threat of bioterrorism. We demonstrate that cyclooxygenase-2 (Cox-2) is crucial for optimal Ab responses to a model vaccine, human papillomavirus type 16 virus-like particles (HPV 16 VLPs). Cox-2-deficient mice produce 70% less IgG, 50% fewer Ab-secreting cells, and 10-fold less neutralizing Ab to HPV 16 VLP vaccination compared with wild-type mice. The reduction in Ab production by Cox-2−/− mice was partially due to a decrease in class switching. SC-58125, a structural analog of the Cox-2-selective inhibitor Celebrex reduced by ∼70% human memory B cell differentiation to HPV 16 VLP IgG-secreting cells. The widespread use of nonsteroidal anti-inflammatory drugs and Cox-2-selective inhibitory drugs may therefore reduce vaccine efficacy, especially when vaccines are poorly immunogenic or the target population is poorly responsive to immunization.
IFN-β-Mediated Up-Regulation of CD1d in Bacteria-Infected APCs
Authors: Raghuraman Gayatri , Geng Yanbiao , Wang Chyung-Ru 
Published: April 2014

Abstract
The expression of CD1d molecules is essential for the selection and activation of a unique subset of T cells, invariant NKT cells, which express limited TCR diversity and have been demonstrated to function in both regulatory and antimicrobial immune responses. Although it has been reported that the levels of CD1d expression can be modulated during infection, the mechanisms that mediate this effect are poorly defined. In this study, we show that infection of dendritic cells and macrophages both in vitro and in vivo with the intracellular pathogen Listeria monocytogenes leads to up-regulation of CD1d. IFN-β is required to mediate this up-regulation in L. monocytogenes infection, as well as being sufficient to up-regulate CD1d expression in vitro. Unlike MHC class I molecules, the increased surface expression of CD1d by IFN-β is not regulated at the transcriptional level. Confocal microscopy and metabolic labeling experiments show that the total pool of CD1d protein is increased in IFN-β-treated cells and that increased surface expression of CD1d is not due to the redistribution of the intracellular pool of CD1d. IFN-β treatment increases the de novo synthesis of CD1d. This change in surface CD1d expression was functionally relevant, as IFN-β-treated dendritic cells are more efficient in stimulating invariant NKT cells than untreated controls. Taken together, these data support a role for early IFN-β-mediated up-regulation of CD1d in NKT cell activation during infection.
Allergy-Driven Alternative Splicing of IL-13 Receptor α2 Yields Distinct Membrane and Soluble Forms
Authors: Tabata Yasuhiro , Chen Weiguo , Warrier Manoj R. , Gibson Aaron M. , Daines Michael O. , Hershey Gurjit K. Khurana 
Published: April 2014

Abstract
IL-13 is a key mediator of allergic inflammation. Its diverse functions are mediated by a complex receptor system including IL-4Rα, IL-13Rα1, and IL-13Rα2. IL-4Rα and IL-13Rα1 form a high-affinity signaling heterodimer. IL-13Rα2 binds IL-13 with high affinity and has been found to exist in membrane and soluble forms. Soluble IL-13Rα2 has been postulated as a critical endogenous modulator of IL-13 responses. However, the mechanism of generation for the soluble form remains unclear. We present the initial study that a mechanism for generation of the soluble form is alternative splicing and that alternative splicing yields a distinct form of soluble IL-13Rα2. We found that several mouse organs expressed two IL-13Rα2 transcripts, the 1152-bp transcript encoding the full-length protein and the 1020-bp transcript lacking exon10, which encodes the transmembrane region. Deletion of exon 10 (ΔEx10) caused a frameshift resulting in a different amino acid sequence from position 327 to position 339 and early termination. Constructs encoding both splice variants were transfected into WEHI-274.1 cells. Transfectants expressing the full-length transcript had IL-13Rα2 on the cell surface but produced minimal soluble IL-13Rα2 in the supernatants. In contrast, transfectants expressing the ΔEx10 transcript displayed no membrane IL-13Rα2 but secreted high levels of soluble IL-13Rα2 capable of inhibiting IL-13 signaling. Both variants bound IL-13, but the ΔEx10 variant displayed ∼2-fold increase in IL-13 binding activity. Expression of the two IL-13Rα2 transcripts was differentially regulated in vivo in an experimental allergic asthma model. Thus, alternatively spliced variants of IL-13Rα2 may have a distinct biologic function in vivo.
Human Langerhans Cells Express a Specific TLR Profile and Differentially Respond to Viruses and Gram-Positive Bacteria
Authors: Flacher Vincent , Bouschbacher Marielle , Verronèse Estelle , Massacrier Catherine , Sisirak Vanja , Berthier-Vergnes Odile , de Saint-Vis Blandine , Caux Christophe , Dezutter-Dambuyant Colette , Lebecque Serge , Valladeau Jenny 
Published: April 2014

Abstract
Dendritic cells (DC) are APCs essential for the development of primary immune responses. In pluristratified epithelia, Langerhans cells (LC) are a critical subset of DC which take up Ags and migrate toward lymph nodes upon inflammatory stimuli. TLR allow detection of pathogen-associated molecular patterns (PAMP) by different DC subsets. The repertoire of TLR expressed by human LC is uncharacterized and their ability to directly respond to PAMP has not been systematically investigated. In this study, we show for the first time that freshly purified LC from human skin express mRNA encoding TLR1, TLR2, TLR3, TLR5, TLR6 and TLR10. In addition, keratinocytes ex vivo display TLR1–5, TLR7, and TLR10. Accordingly, highly enriched immature LC efficiently respond to TLR2 agonists peptidoglycan and lipoteichoic acid from Gram-positive bacteria, and to dsRNA which engages TLR3. In contrast, LC do not directly sense TLR7/8 ligands and LPS from Gram-negative bacteria, which signals through TLR4. TLR engagement also results in cytokine production, with marked differences depending on the PAMP detected. TLR2 and TLR3 ligands increase IL-6 and IL-8 production, while dsRNA alone stimulates TNF-α release. Strikingly, only peptidoglycan triggers IL-10 secretion, thereby suggesting a specific function in tolerance to commensal Gram-positive bacteria. However, LC do not produce IL-12p70 or type I IFNs. In conclusion, human LC are equipped with TLR that enable direct detection of PAMP from viruses and Gram-positive bacteria, subsequent phenotypic maturation, and differential cytokine production. This implies a significant role for LC in the control of skin immune responses.
The Role of TCR Engagement and Activation-Induced Cell Death in Sepsis-Induced T Cell Apoptosis
Authors: Unsinger Jacqueline , Herndon John M. , Davis Christopher G. , Muenzer Jared T. , Hotchkiss Richard S. , Ferguson Thomas A. 
Published: April 2014

Abstract
Sepsis induces extensive apoptosis in T and B cells suggesting that the loss of immune effector cells could be one explanation for the profound immunosuppression observed in this disorder. Unfortunately, the mechanisms responsible for lymphocyte apoptosis in sepsis remain unknown. In T cells, apoptosis can occur through activation-induced cell death (AICD) in which engagement of the Ag receptors by cognate Ag or polyclonal activators such as bacteria-derived superantigens induces activation, proliferation, and apoptosis. We examined whether proliferation and AICD are necessary for apoptotic cell death in sepsis using normal and TCR transgenic mice. Results show that although sepsis resulted in activation of a small percentage of T cells, no proliferation was detected during the first 48 h following onset, a time when extensive apoptosis is observed. We also observed that T cells do not enter the cell cycle, and stimulation via the TCR in TCR transgenic animals does not enhance or decrease cell death in sepsis. Interestingly, T cells recovered from septic mice retained their ability to proliferate and synthesize cytokines albeit at reduced levels. With the exception of IL-10, which was increased in lymphocytes from mice with sepsis, sepsis caused a decrease in the production of both proinflammatory and anti-inflammatory cytokines. We conclude that lymphocyte apoptosis in sepsis does not require proliferation, TCR engagement, or AICD. Thus the immunosuppression observed in sepsis cannot be the result of T cell deletion via the TCR.
Antigen-Specific CD8+ T Cells Respond to Chlamydia trachomatis in the Genital Mucosa
Authors: Roan Nadia R. , Starnbach Michael N. 
Published: April 2014

Abstract
Following sexual transmission, Chlamydia trachomatis specifically targets genital tract epithelial cells. Because epithelial cells are readily recognized by CD8+ T cells, the response of CD8+ T cells to Chlamydia infection has been explored in a number of studies. It has been shown that CD8+ T cells are present in the genital tracts of mice following C. trachomatis infection, but the specificity of these T cells has remained undefined. To determine whether Chlamydia-specific CD8+ T cells migrate to the genital tract in response to Chlamydia infection, we generated retrogenic mice that express a TCR specific for a Chlamydia-specific T cell Ag CrpA. T cells from the retrogenic mice were transferred into naive recipient animals to increase the frequency of Chlamydia-specific T cells to a level at which they could be tracked during primary infection. We observed that the Chlamydia-specific retrogenic T cells proliferated in lymph nodes draining the genital tract in response to genital infection with C. trachomatis. Furthermore, we found that these cells acquired the ability to produce IFN-γ and migrated into the genital mucosa of the infected mice.
TLR4 Mediates Vaccine-Induced Protective Cellular Immunity to Bordetella pertussis: Role of IL-17-Producing T Cells
Authors: Higgins Sarah C. , Jarnicki Andrew G. , Lavelle Ed C. , Mills Kingston H. G. 
Published: April 2014

Abstract
Whole cell pertussis vaccines (Pw) induce Th1 responses and protect against Bordetella pertussis infection, whereas pertussis acellular vaccines (Pa) induce Ab and Th2-biased responses and also protect against severe disease. In this study, we show that Pw failed to generate protective immunity in TLR4-defective C3H/HeJ mice. In contrast, protection induced with Pa was compromised, but not completely abrogated, in C3H/HeJ mice. Immunization with Pw, but not Pa, induced a population of IL-17-producing T cells (Th-17), as well as Th1 cells. Ag-specific IL-17 and IFN-γ production was significantly lower in Pw-immunized TLR4-defective mice. Furthermore, treatment with neutralizing anti-IL-17 Ab immediately before and after B. pertussis challenge significantly reduced the protective efficacy of Pw. Stimulation of dendritic cells (DC) with Pw promoted IL-23, IL-12, IL-1β, and TNF-α production, which was impaired in DC from TLR4-defective mice. B. pertussis LPS, which is present in high concentrations in Pw, induced IL-23 production by DC, which enhanced IL-17 secretion by T cells, but the induction of Th-17 cells was also dependent on IL-1. In addition, we identified a new effector function for IL-17, activating macrophage killing of B. pertussis, and this bactericidal activity was less efficient in macrophages from TLR4-defective mice. These data provide the first definitive evidence of a role for TLRs in protective immunity induced by a human vaccine. Our findings also demonstrate that activation of innate immune cells through TLR4 helps to direct the induction of Th1 and Th-17 cells, which mediate protective cellular immunity to B. pertussis.