bluuebunny/crossref_metadata_2025_split huggingface dataset:
IFN-αβ Secreted during Infection Is Necessary but Not Sufficient for Negative Feedback Regulation of IFN-αβ Signaling byMycobacterium tuberculosis
Authors: Prabhakar Savita , Qiao Yaming , Canova Antony , Tse Doris B. , Pine Richard 
Published: April 2014

AbstractIFN-αβ functions in the transition from innate to adaptive immunity and may impinge on the interaction of Mycobacterium tuberculosis with its host. Infection by M. tuberculosis causes IFN-αβ secretion and down-regulation of IFN-αβ signaling in human APC and the human monocytic cell line THP-1, which provides a model for these studies. Neutralization of secreted IFN-αβ prevents inhibition of IFN-α signaling during infection, but several lines of evidence distinguish inhibition due to infection from a negative feedback response to only IFN-αβ. First, greater inhibition of IFN-α-stimulated STAT-1 tyrosine phosphorylation occurs 3 days postinfection than 1 or 3 days after IFN-αβ pretreatment. Second, LPS also induces IFN-αβ secretion and causes IFN-αβ-dependent down-regulation of IFN-α signaling, yet the inhibition differs from that caused by infection. Third, IFN-α signaling is inhibited when cells are grown in conditioned medium collected from infected cells 1 day postinfection, but not if it is collected 3 days postinfection. Because IFN-αβ is stable, the results with conditioned medium suggest the involvement of an additional, labile substance during infection. Further characterizing signaling for effects of infection, we found that cell surface IFN-αβ receptor is not reduced by infection, but that infection increases association of protein tyrosine phosphatase 1c with the receptor and with tyrosine kinase 2. Concomitantly, IFN-α stimulation of tyrosine kinase 2 tyrosine phosphorylation and kinase activity decreases in infected cells. Moreover, infection reduces the abundance of JAK-1 and tyrosine-phosphorylated JAK-1. Thus, the distinctive down-regulation of IFN-α signaling by M. tuberculosis occurs together with a previously undescribed combination of inhibitory intracellular events.
Distinct Roles for IL-4 and IL-10 in Regulating T2 Immunity during Allergic Bronchopulmonary Mycosis
Authors: Hernandez Yadira , Arora Shikha , Erb-Downward John R. , McDonald Roderick A. , Toews Galen B. , Huffnagle Gary B. 
Published: April 2014

AbstractPulmonary Cryptococcus neoformans infection of C57BL/6 mice is an established model of an allergic bronchopulmonary mycosis that has also been used to test a number of immunomodulatory agents. Our objective was to determine the role of IL-4 and IL-10 in the development/manifestation of the T2 response to C. neoformans in the lungs and lung-associated lymph nodes. In contrast to wild-type (WT) mice, which develop a chronic infection, pulmonary clearance was significantly greater in IL-4 knockout (KO) and IL-10 KO mice but was not due to an up-regulation of a non-T cell effector mechanism. Pulmonary eosinophilia was absent in both IL-4 KO and IL-10 KO mice compared with WT mice. The production of IL-4, IL-5, and IL-13 by lung leukocytes from IL-4 KO and IL-10 KO mice was lower but IFN-γ levels remained the same. TNF-α and IL-12 production by lung leukocytes was up-regulated in IL-10 KO but not IL-4 KO mice. Overall, IL-4 KO mice did not develop the systemic (lung-associated lymph nodes and serum) or local (lungs) T2 responses characteristic of the allergic bronchopulmonary C. neoformans infection. In contrast, the systemic T2 elements of the response remained unaltered in IL-10 KO mice whereas the T2 response in the lungs failed to develop indicating that the action of IL-10 in T cell regulation was distinct from that of IL-4. Thus, although IL-10 has been reported to down-regulate pulmonary T2 responses to isolated fungal Ags, IL-10 can augment pulmonary T2 responses if they occur in the context of fungal infection.
CXC Chemokine Ligand 16 Promotes Integrin-Mediated Adhesion of Liver-Infiltrating Lymphocytes to Cholangiocytes and Hepatocytes within the Inflamed Human Liver
Authors: Heydtmann Mathis , Lalor Patricia F. , Eksteen J. Albertus , Hübscher Stefan G. , Briskin Mike , Adams David H. 
Published: April 2014

Abstract
Lymphocyte recruitment to the liver is critical for viral clearance in acute hepatitis and in the pathogenesis of chronic inflammatory liver disease when persistent chronic inflammation leads to fibrosis and cirrhosis. Chemokines regulate leukocyte recruitment and positioning in tissues and are thus critical regulators of chronic inflammation. The chemokine CXCL16, which is found in liver tissue, exists in a transmembrane as well as soluble form, providing a potential mechanism for localization to particular structures. We studied the role of CXCL16 and its receptor CXCR6 in lymphocyte recruitment and retention in the liver. A higher proportion of CXCR6+ T cells was detected in blood of hepatitis C virus patients compared with healthy subjects, and in chronic inflammatory liver disease &gt;60% of intrahepatic T cells expressed CXCR6, including CD4, CD8, and CD56+ T cells compared with &lt;30% in matched blood samples. CXCR6+ lymphocytes were found in association with CXCL16+ bile ducts in portal tracts and with hepatocytes at sites of interface hepatitis. Analysis of CXCL16 expression and subcellular distribution in cultured human cholangiocytes, sinusoidal endothelial cells, and hepatocytes revealed that all three cell types expressed CXCL16, with the strongest staining seen on cholangiocytes. CXCL16 on the cholangiocyte membrane was able to support lymphocyte adhesion by triggering conformational activation of β1 integrins and binding to VCAM-1. Thus, CXCL16 can promote lymphocyte adhesion to epithelial cells and may function to attract and retain effector cells that promote biliary and hepatocyte destruction in inflammatory liver disease.
Phospholipids Inhibit Lipopolysaccharide (LPS)-Induced Cell Activation: A Role for LPS-Binding Protein
Authors: Mueller Mareile , Brandenburg Klaus , Dedrick Russ , Schromm Andra B. , Seydel Ulrich 
Published: April 2014

Abstract
The inhibition of LPS-induced cell activation by specific antagonists is a long-known phenomenon; however, the underlying mechanisms are still poorly understood. It is commonly accepted that the membrane-bound receptors mCD14 and TLR4 are involved in the activation of mononuclear cells by LPS and that activation may be enhanced by soluble LPS-binding protein (LBP). Hexaacylated Escherichia coli lipid A has the highest cytokine-inducing capacity, whereas lipid A with four fatty acids (precursor IVa, synthetic compound 406) is endotoxically inactive, but expresses antagonistic activity against active LPS. Seeking to unravel basic molecular principles underlying antagonism, we investigated phospholipids with structural similarity to compound 406 with respect to their antagonistic activity. The tetraacylated diphosphatidylglycerol (cardiolipin, CL) exhibits high structural similarity to 406, and our experiments showed that CL strongly inhibited LPS-induced TNF-α release when added to the cells before stimulation or as a CL/LPS mixture. Also negatively charged and to a lesser degree zwitterionic diacyl phospholipids inhibited LPS-induced cytokine production. Using Abs against LBP, we could show that the activation of cells by LPS was dependent on the presence of cell-associated LBP, thus making LBP a possible target for the antagonistic action of phospholipids. In experiments investigating the LBP-mediated intercalation of LPS and phospholipids into phospholipid liposomes mimicking the macrophage membrane, we could show that preincubation of soluble LBP with phospholipids leads to a significant reduction of LPS intercalation. In summary, we show that LBP is a target for the inhibitory function of phospholipids.
Cutting Edge: Species-Specific TLR9-Mediated Recognition of CpG and Non-CpG Phosphorothioate-Modified Oligonucleotides
Authors: Roberts Tara L. , Sweet Matthew J. , Hume David A. , Stacey Katryn J. 
Published: April 2014

Abstract
Different DNA motifs are required for optimal stimulation of mouse and human immune cells by CpG oligodeoxynucleotides (ODN). These species differences presumably reflect sequence differences in TLR9, the CpG DNA receptor. In this study, we show that this sequence specificity is restricted to phosphorothioate (PS)-modified ODN and is not observed when a natural phosphodiester backbone is used. Thus, human and mouse cells have not evolved to recognize different CpG motifs in natural DNA. Nonoptimal PS-ODN (i.e., mouse CpG motif on human cells and vice versa) gave delayed and less sustained phosphorylation of p38 MAPK than optimal motifs. When the CpG dinucleotide was inverted to GC in each ODN, some residual activity of the PS-ODN was retained in a species-specific, TLR-9-dependent manner. Thus, TLR9 may be responsible for mediating many published CpG-independent responses to PS-ODN.
Cutting Edge: Role of STAT1, STAT3, and STAT5 in IFN-αβ Responses in T Lymphocytes
Authors: Tanabe Yoshinari , Nishibori Takeaki , Su Leon , Arduini Robert M. , Baker Darren P. , David Michael 
Published: April 2014

Abstract
Engagement of the IFN-αβ receptor initiates multiple signaling cascades, including activation of the STAT. In this study, we demonstrate that IFN-αβ, although antiproliferative in wild-type CD4+ or CD8+ T cells, act as strong mitogens on their STAT1−/− counterparts. Furthermore, IFN-αβ exert little effect on apoptosis in wild-type cells, but are potent survival factors in the absence of STAT1. The antiapoptotic response in the absence of STAT1 is predominantly mediated by STAT3, and to a lesser extent by STAT5A/B. In contrast, the mitogenic IFN-αβ response gained through the absence of STAT1 is only marginally affected when STAT5A/B expression is also abrogated, but is completely dependent on STAT3 activation. These findings provide the first evidence for a function of STAT3 and STAT5A/B in the IFN-αβ response, and support a model in which the IFN-αβ receptor initiates both pro- and antiapoptotic responses through STAT1, and STAT3 and STAT5A/B, respectively.
Cutting Edge: MHC Class II-Restricted Killing In Vivo during Viral Infection
Authors: Jellison Evan R. , Kim Sung-Kwon , Welsh Raymond M. 
Published: April 2014

Abstract
Class II-restricted CD4 T cell-mediated killing of target cells has previously been documented in vitro but not in vivo. In this study, we demonstrate CD4-dependent MHC class II-restricted killing in lymphocytic choriomeningitis virus-infected mice in vivo using an in vivo cytotoxicity assay that features class II-expressing B cells as targets.
Peripheral “CD8 Tuning” Dynamically Modulates the Size and Responsiveness of an Antigen-Specific T Cell Pool In Vivo
Authors: Maile Robert , Siler Catherine A. , Kerry Samantha E. , Midkiff Katherine E. , Collins Edward J. , Frelinger Jeffrey A. 
Published: April 2014

Abstract
In this study, we suggest that CD8 levels on T cells are not static, but can change and, as a result, modulate CD8+ T cell responses. We describe three models of CD8 modulation using novel weak-agonist (K1A) and super-agonist (C2A) altered peptide ligands of the HY smcy peptide. First, we used peripheral nonresponsive CD8low T cells produced after peripheral HY-Db MHC class I tetramer stimulation of female HY TCR transgenic and wild-type mice. Second, we used genetically lowered CD8int T cells from heterozygote CD8+/0 mice. Finally, we used pre-existing nonresponsive CD8low T cells from male HY TCR transgenic mice. In CD8low and CD8high mice, presence of a lower level of CD8 greatly decreased the avidity of the peptide-MHC for HY TCR as reflected by avidity (KD) and dissociation constant (T1/2) measurements. All three models demonstrated that lowering CD8 levels resulted in the requirement for a higher avidity peptide-MHC interaction with the TCR to respond equivalently to unmanipulated CD8high T cells of the same specificity. Additionally, direct injections of wild-type HY-Db and C2A-Db tetramers into female HY TCR or female B6 mice induced a high frequency of peripheral nonresponsive CD8low T cells, yet C2A-Db was superior in inducing a primed CD8+CD44+ memory population. The ability to dynamically modulate the size and responsiveness of an Ag-specific T cell pool by “CD8 tuning” of the T cell during the early phases of an immune response has important implications for the balance of responsiveness, memory, and tolerance.
Heterogeneity of Expression of IgA Receptors by Human, Mouse, and Rat Eosinophils
Authors: Decot Véronique , Woerly Gaëtane , Loyens Marc , Loiseau Sylvie , Quatannens Brigitte , Capron Monique , Dombrowicz David 
Published: April 2014

Abstract
IgA is the most abundant class of Abs at mucosal surfaces where eosinophils carry out many of their effector functions. Most of the known IgA-mediated functions require interactions with IgA receptors, six of which have been identified in humans. These include the IgA FcR FcαRI/CD89 and the receptor for the secretory component, already identified on human eosinophils, the polymeric IgR, the Fcα/μR, asialoglycoprotein (ASGP)-R, and transferrin (Tf)R/CD71. In rodents, the existence of IgA receptors on mouse and rat eosinophils remains unclear. We have compared the expression and function of IgA receptors by human, rat, and mouse eosinophils. Our results show that human eosinophils express functional polymeric IgR, ASGP-R, and TfR, in addition to CD89 and the receptor for the secretory component, and that IgA receptors are expressed by rodent eosinophils. Indeed, mouse eosinophils expressed only TfR, whereas rat eosinophils expressed ASGP-R and CD89 mRNA. These results provide a molecular basis for the differences observed between human, rat, and mouse regarding IgA-mediated immunity.
Differential Activation of Anti-Erythrocyte and Anti-DNA Autoreactive B Lymphocytes by the Yaa Mutation
Authors: Moll Thomas , Martinez-Soria Eduardo , Santiago-Raber Marie-Laure , Amano Hirofumi , Pihlgren-Bosch Maria , Marinkovic Dragan , Izui Shozo 
Published: April 2014

Abstract
An as-yet-unidentified mutation, Y-linked autoimmune acceleration (Yaa), is responsible for the accelerated development of lupus-like autoimmune syndrome in mice. In view of a possible role for Yaa as a positive regulator of BCR signaling, we have explored whether the expression of the Yaa mutation affects the development and activation of transgenic autoreactive B cells expressing either 4C8 IgM anti-RBC or Sp6 IgM anti-DNA. In this study, we show that the expression of the Yaa mutation induced a lethal form of autoimmune hemolytic anemia in 4C8 transgenic C57BL/6 mice, likely as a result of activation of 4C8 anti-RBC autoreactive B cells early in life. This was further supported, although indirectly, by increased T cell-independent IgM production in spleens of nontransgenic C57BL/6 mice bearing the Yaa mutation. In contrast, Yaa failed to induce activation of Sp6 anti-DNA autoreactive B cells, consistent with a lack of increased IgM anti-DNA production in nontransgenic C57BL/6 Yaa mice. Our results suggest that Yaa can activate autoreactive B cells in a BCR-dependent manner, related to differences in the form and nature of autoantigens.
T Cells Undergo Rapid ON/OFF but Not ON/OFF/ON Cycling of Cytokine Production in Response to Antigen
Authors: Corbin Gail A. , Harty John T. 
Published: April 2014

Abstract
Inflammatory cytokines such as IFN-γ and TNF produced by Ag-stimulated CD4+ and CD8+ T cells are important in defense against microbial infection. However, production of these cytokines must be tightly regulated to prevent immunopathology. Previous studies, conducted with BALB/c mice, have suggested that 1) CD8+ T cells maintain IFN-γ production but transiently produce TNF in the continued presence of Ag and 2) lymphocytic choriomeningitis virus-specific and in vitro-propagated effector CD8+ T cells could rapidly cycle IFN-γ production ON/OFF/ON in response to Ag exposure, removal, and re-exposure. In contrast with CD8+ T cells, our results show that Listeria monocytogenes-specific CD4+ T cells from C57BL/6 mice rapidly initiate (ON cycling) and maintain production of both IFN-γ and TNF in the continued presence of Ag. Upon Ag removal, production of both cytokines rapidly ceases (OFF cycling). However, if the initial stimulation was maximal, Ag-specific CD4+ T cells were unable to reinitiate cytokine production after a second Ag exposure. Furthermore, L. monocytogenes-specific CD8+ T cells in the same mice and lymphocytic choriomeningitis virus-specific CD8+ T cells in BALB/c mice also underwent ON/OFF cycling, but if the initial Ag stimulus was maximal, they could not produce IFN-γ after Ag re-exposure. As the initial Ag dose was reduced, the number of cells producing cytokine in response to the second Ag exposure exhibited a corresponding increase. However, T cells that were marked for IFN-γ secretion during the first stimulation did not contribute cytokine production during the second stimulation. Thus, T cells are not able to undergo rapid ON/OFF/ON cytokine cycling in vitro in response to Ag.
TLR Ligands Can Activate Dendritic Cells to Provide a MyD88-Dependent Negative Signal for Th2 Cell Development
Authors: Sun Jie , Walsh Matthew , Villarino Alejandro V. , Cervi Laura , Hunter Christopher A. , Choi Yongwon , Pearce Edward J. 
Published: April 2014

Abstract
During infection, CD4+ Th cell responses polarize to become primarily Th1 or Th2. Th1 cells, which make IFN-γ, are crucial for immunity to many bacterial and protozoal infections, whereas Th2 cells, which make IL-4, IL-5, and IL-13, are important for resistance to helminth infections. Polarized Th1 responses are induced by dendritic cells (DCs), which respond to pathogen-derived TLR ligands to produce IL-12 and related cytokines that are instrumental in Th1 cell outgrowth, and coordinately process and present Ag in the context of MHC class II to activate naive Th cells. In this study we show that in addition to providing positive signals for Th1 cell development, mouse DCs activated by TLR engagement can also provide a potent negative signal that prevents the development of Th2 cells. Production of this signal, which is not IL-12, IL-18, IL-23, IL-27, or IFN-γ and is not provided via Th1 cells, is dependent upon a MyD88-dependent, TNF receptor-associated factor-6-independent signaling pathway in DCs. The signal is released from DCs in response to activation via TLR ligands and exerts an effect directly on Th cells rather than through a third-party cell. Our findings indicate that DCs can provide potent negative as well as positive instruction for Th response polarization, and that these instructional signals are distinct and independent.
IFN-γ Negatively Modulates Self-Renewal of Repopulating Human Hemopoietic Stem Cells
Authors: Yang Liping , Dybedal Ingunn , Bryder David , Nilsson Lars , Sitnicka Ewa , Sasaki Yutaka , Jacobsen Sten Eirik W. 
Published: April 2014

Abstract
Whereas multiple growth-promoting cytokines have been demonstrated to be involved in regulation of the hemopoietic stem cell (HSC) pool, the potential role of negative regulators is less clear. However, IFN-γ, if overexpressed, can mediate bone marrow suppression and has been directly implicated in a number of bone marrow failure syndromes, including graft-vs-host disease. Whether IFN-γ might directly affect the function of repopulating HSCs has, however, not been investigated. In the present study, we used in vitro conditions promoting self-renewing divisions of human HSCs to investigate the effect of IFN-γ on HSC maintenance and function. Although purified cord blood CD34+CD38− cells underwent cell divisions in the presence of IFN-γ, cycling HSCs exposed to IFN-γ in vitro were severely compromised in their ability to reconstitute long-term cultures in vitro and multilineage engraft NOD-SCID mice in vivo (&gt;90% reduced activity in both HSC assays). In vitro studies suggested that IFN-γ accelerated differentiation of targeted human stem and progenitor cells. These results demonstrate that IFN-γ can negatively affect human HSC self-renewal.
Pharmacological Targeting of Anaphylatoxin Receptors during the Effector Phase of Allergic Asthma Suppresses Airway Hyperresponsiveness and Airway Inflammation
Authors: Baelder Ralf , Fuchs Barbara , Bautsch Wilfried , Zwirner Joerg , Köhl Jörg , Hoymann Heinz G , Glaab Thomas , Erpenbeck Veit , Krug Norbert , Braun Armin 
Published: April 2014

Abstract
Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested, as deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresponsiveness, airway inflammation, and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.
Role of CD28 in Polyclonal and Specific T and B Cell Responses Required for Protection against Blood Stage Malaria
Authors: Elias Rosa M. , Sardinha Luiz R. , Bastos Karina R. B. , Zago Cláudia A. , da Silva Ana Paula Freitas , Alvarez José M. , Lima Maria Regina D’Império 
Published: April 2014

Abstract
The role of B7/CD28 costimulatory pathway in the polyclonal and specific lymphocyte activation induced by blood stages of Plasmodium chabaudi AS was investigated in CD28 gene knockout (CD28−/−) and C57BL/6 (CD28+/+) mice. Analysis of the spleen during the acute infection revealed a similar increase in T and B cell populations in both groups of mice. Moreover, CD28−/− mice were able to develop a polyclonal IgM response to P. chabaudi. On the contrary, the polyclonal IgG2a response was markedly reduced in the absence of CD28. Production of IFN-γ; up-regulation of CD69, CD40L, CD95 (Fas), and CD95L (Fas ligand); and induction of apoptosis were also affected by the lack of CD28. Interestingly, the ability to control the first parasitemia peak was not compromised in acutely infected CD28−/− mice, but CD28−/− mice failed to eradicate the parasites that persisted in the blood for &gt;3 mo after infection. In addition, drug-cured CD28−/− mice were unable to generate memory T cells, develop an anamnesic IgG response, or eliminate the parasites from a secondary challenge. The incapacity of CD28−/− mice to acquire a full protective immunity to P. chabaudi correlated with an impaired production of specific IgG2a. Moreover, reinfected CD28−/− mice were protected by the adoptive transfer of serum from reinfected CD28+/+ mice containing specific IgG2a. Our results demonstrate that the polyclonal lymphocyte response is only partially affected by the absence of CD28, but this coreceptor is essential to generate specific T and B cell responses required for complete protection against P. chabaudi malaria.