bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recognition of Toxoplasma gondii by TLR11 Prevents Parasite-Induced Immunopathology
Authors: Yarovinsky Felix , Hieny Sara , Sher Alan 
Published: April 2014

Abstract
TLRs are thought to play a critical role in self/non-self discrimination by sensing microbial infections and initiating both innate and adaptive immunity. In this study, we demonstrate that in the absence of TLR11, a major TLR involved in recognition of Toxoplasma gondii, infection with this protozoan parasite induces an abnormal immunopathological response consisting of pancreatic tissue destruction, fat necrosis, and systemic elevations in inflammatory reactants. We further show that this immunopathology is the result of non-TLR dependent activation of IFN-γ secretion by NK cells in response to the infection. These findings reveal that in addition to triggering host resistance to infection, TLR recognition can be critical for the prevention of pathogen-induced immune destruction of self tissue.
Trehalose Dimycolate Elicits Eosinophilic Skin Hypersensitivity in Mycobacteria-Infected Guinea Pigs
Authors: Otsuka Atsushi , Matsunaga Isamu , Komori Takaya , Tomita Kadusa , Toda Yoshinobu , Manabe Toshiaki , Miyachi Yoshiki , Sugita Masahiko 
Published: April 2014

Abstract
Delayed-type hypersensitivity represents high levels of protein Ag-specific adaptive immunity induced by mycobacterial infection, and can be monitored in the Ag-challenged skin. Besides protein Ags, recent evidence has suggested that a substantial immunity directed against glycolipid Ags is also elicited in response to mycobacterial infection, but skin hypersensitivity to this class of Ags has not been fully assessed. To address this issue directly, glycolipid-specific skin reactions were evaluated in guinea pigs infected with Mycobacterium avium complex (MAC). Significant skin induration was observed in MAC-infected, but not mock-infected, guinea pigs, following intradermal administration of a mixture of MAC-derived glycolipids. Surprisingly, this glycolipid-specific skin response involved up-regulated expression of IL-5 mRNA in situ and marked local infiltration of eosinophils. Challenge experiments with individual glycolipid components detected an outstanding capability for trehalose dimycolate (TDM), but not a structurally related glycolipid, glucose monomycolate, to elicit the skin response. T lymphocytes derived from the spleen of MAC-infected, but not uninfected, guinea pigs specifically responded to TDM in vitro by up-regulating IL-5 transcription, and this response was not blocked by Abs that reacted to the known guinea pig group 1 CD1 proteins. Finally, the eosinophilic skin hypersensitivity to TDM was also elicited in guinea pigs vaccinated with bacillus Calmette-Guerin, which contrasted sharply with the classical delayed-type hypersensitivity response to the purified protein derivative. Therefore, the TDM-elicited eosinophilic response defines a new form of hypersensitivity in mycobacterial infection, which may account for local infiltration of eosinophils often observed at the site of infection.
A Role for Connexin43 in Macrophage Phagocytosis and Host Survival after Bacterial Peritoneal Infection
Authors: Anand Rahul J. , Dai Shipan , Gribar Steven C. , Richardson Ward , Kohler Jeff W. , Hoffman Rosemary A. , Branca Maria F. , Li Jun , Shi Xiao-Hua , Sodhi Chhinder P. , Hackam David J. 
Published: April 2014

Abstract
The pathways that lead to the internalization of pathogens via phagocytosis remain incompletely understood. We now demonstrate a previously unrecognized role for the gap junction protein connexin43 (Cx43) in the regulation of phagocytosis by macrophages and in the host response to bacterial infection of the peritoneal cavity. Primary and cultured macrophages were found to express Cx43, which localized to the phagosome upon the internalization of IgG-opsonized particles. The inhibition of Cx43 using small interfering RNA or by obtaining macrophages from Cx43 heterozygous or knockout mice resulted in significantly impaired phagocytosis, while transfection of Cx43 into Fc-receptor expressing HeLa cells, which do not express endogenous Cx43, conferred the ability of these cells to undergo phagocytosis. Infection of macrophages with adenoviruses expressing wild-type Cx43 restored phagocytic ability in macrophages from Cx43 heterozygous or deficient mice, while infection with viruses that expressed mutant Cx43 had no effect. In understanding the mechanisms involved, Cx43 was required for RhoA-dependent actin cup formation under adherent particles, and transfection with constitutively active RhoA restored a phagocytic phenotype after Cx43 inactivation. Remarkably, mortality was significantly increased in a mouse model of bacterial peritonitis after Cx43 inhibition and in Cx43 heterozygous mice compared with untreated and wild-type counterparts. These findings reveal a novel role for Cx43 in the regulation of phagocytosis and rearrangement of the F-actin cytoskeleton, and they implicate Cx43 in the regulation of the host response to microbial infection.
West Nile Virus-Specific CD4 T Cells Exhibit Direct Antiviral Cytokine Secretion and Cytotoxicity and Are Sufficient for Antiviral Protection
Authors: Brien James D. , Uhrlaub Jennifer L. , Nikolich-Žugich Janko 
Published: April 2014

Abstract
CD4 T cells have been shown to be necessary for the prevention of encephalitis during West Nile virus (WNV) infection. However, the mechanisms used by Ag-specific CD4 T cells to protect mice from WNV encephalitis remain incompletely understood. Contrary to the belief that CD4 T cells are protective because they merely maintain the CD8 T cell response and improve Ab production, in this study we provide evidence for the direct antiviral activity of CD4 T cells that functions to protect the host from WNV encephalitis. In adoptive transfers, naive CD4 T cells protected a significant number of lethally infected RAG−/− mice, demonstrating the protective effect of CD4 T cells independent of B cells and CD8 T cells. To shed light on the mechanism of this protection, we defined the peptide specificities of the CD4 T cells responding to WNV infection in C57BL/6 (H-2b) mice, and used these peptides to characterize the in vivo function of antiviral CD4 T cells. WNV-specific CD4 T cells produced IFN-γ and IL-2, but also showed potential for in vivo and ex vivo cytotoxicity. Furthermore, peptide vaccination using CD4 epitopes conferred protection against lethal WNV infection in immunocompetent mice. These results demonstrate the role of direct effector function of Ag-specific CD4 T cells in preventing severe WNV disease.
Sequence Variations in 185/333 Messages from the Purple Sea Urchin Suggest Posttranscriptional Modifications to Increase Immune Diversity
Authors: Buckley Katherine M. , Terwilliger David P. , Smith L. Courtney 
Published: April 2014

Abstract
The 185/333 gene family is highly expressed in two subsets of immune cells in the purple sea urchin in response to immune challenges. The genes encode a surprisingly diverse set of transcripts, which is a function of the variable presence or absence of blocks of shared sequences, known as elements that generate element patterns. Diversity is also the result of a significant level of point mutations. Together, variable element patterns and single nucleotide polymorphisms result in many unique transcripts. The 185/333 genes only have two exons, with the variable element patterns encoded entirely within the second exon. The diversity of the gene family may be the result of frequent recombination among the 185/333 genes that generates a mosaic distribution of element sequences among the genes. A comparative analysis of the sequences for the genes and messages from individual sea urchins indicates that these two sequence sets have largely different nucleotide sequences and appear to use different element patterns. Furthermore, the nucleotide substitution patterns between genes and messages reveal a strong bias toward transitions, particularly cytidine to uridine conversions. These data are consistent with cytidine deaminase activity and may represent a novel form of immunological diversification in an invertebrate immune response system.
Adenosine 5′-Monophosphate-Activated Protein Kinase Promotes Macrophage Polarization to an Anti-Inflammatory Functional Phenotype
Authors: Sag Duygu , Carling David , Stout Robert D. , Suttles Jill 
Published: April 2014

Abstract
Herein, we demonstrate a role of AMP-activated protein kinase (AMPK) as a potent counterregulator of inflammatory signaling pathways in macrophages. Stimulation of macrophages with anti-inflammatory cytokines (i.e., IL-10 and TGFβ) resulted in the rapid phosphorylation/activation of AMPK, whereas stimulation of macrophages with a proinflammatory stimulus (LPS) resulted in AMPK dephosphorylation/inactivation. Inhibition of AMPKα expression by RNA interference dramatically increased the mRNA levels of LPS-induced TNF-α, IL-6, and cyclooxygenase-2. Likewise, expression of a dominant negative AMPKα1 in macrophages enhanced TNF-α and IL-6 protein synthesis in response to LPS stimulation, while diminishing the production of IL-10. In contrast, transfection of macrophages with a constitutively active form of AMPKα1 resulted in decreased LPS-induced TNF-α and IL-6 production, and heightened production of IL-10. In addition, we found that AMPK negatively regulated LPS-induced IκB-α degradation and positively regulated Akt activation, accompanied by inhibition of glycogen synthase kinase β and activation of CREB. Thus, AMPK directs signaling pathways in macrophages in a manner that suppresses proinflammatory responses and promotes macrophage polarization to an anti-inflammatory functional phenotype.
CD40 Mediates Retinal Inflammation and Neurovascular Degeneration
Authors: Portillo Jose-Andres C. , Van Grol Jennifer , Zheng Ling , Okenka Genevieve , Gentil Katrin , Garland Alejandra , Carlson Eric C. , Kern Timothy S. , Subauste Carlos S. 
Published: April 2014

Abstract
Retinopathies are major causes of visual impairment. We used a model of ischemic retinopathy to examine the role of CD40 in the pathogenesis of retinal injury. Retinal inflammation, loss of ganglion cells, and capillary degeneration were markedly attenuated in ischemic retinas of CD40−/− mice. Up-regulation of NOS2 and COX2 after retinal ischemia were blunted in CD40−/− mice. NOS2-COX-2 up-regulation in ischemic retinas from wild-type mice was at least in part explained by recruitment of NOS2+COX-2+ leukocytes. Up-regulation of KC/CXCL1 and ICAM-1 also required CD40. Retinal endothelial and Muller cells expressed CD40. Stimulation of these cells through CD40 caused ICAM-1 up-regulation and KC/CXCL1 production. Bone marrow transplant experiments revealed that leukocyte infiltration, ganglion cell loss, and up-regulation of proinflammatory molecules after retinal ischemia were dependent on CD40 expression in the retina and not peripheral blood leukocytes. These studies identified CD40 as a regulator of retinal inflammation and neurovascular degeneration. They support a model in which CD40 stimulation of endothelial and Muller cells triggers adhesion molecule up-regulation and chemokine production, promoting the recruitment of leukocytes that express NOS2/COX-2, molecules linked to neurovascular degeneration.
FOXP3 Induced by CD28/B7 Interaction Regulates CD25 and Anergic Phenotype in Human CD4+CD25− T Lymphocytes
Authors: Scottà Cristiano , Soligo Marzia , Camperio Cristina , Piccolella Enza 
Published: April 2014

AbstractAmong the signals necessary to generate CD4+CD25+FOXP3+ T cells from CD4+CD25−FOXP3− T cells, a pivotal role is played by CD28. However, in humans, it is not known whether CD28 signaling independently of TCR promotes forkhead box protein 3 (FOXP3) expression and regulates CD4+CD25+FOXP3+ T cell functions. To address this issue, starting from our previous experience, we analyzed the unique signals delivered by CD28 following stimulation by its natural ligand B7. Our results show that, in primary CD4+CD25− T cells, CD28 signals independent of TCR-mediated stimulatory pathways are sufficient to induce the transcription of FOXP3 in a small number of CD4+CD25− T cells committed to express FOXP3. These signals are dependent on CD28-derived PI3K/Akt pathways and resistant to cyclosporin A. In addition, we demonstrated that translated FOXP3 was recruited to CD25, Il-2, and Ctla4 target promoters. CD28-mediated FOXP3 expression was transient and correlated with CD25 expression. The presence of FOXP3 in CD28-activated CD4+CD25− T cells correlated with a transient unresponsiveness to antigenic stimuli. The addition of exogenous IL-2 did not influence either FOXP3 or CD25 expression but rescued CD28-activated T cells from apoptosis. Our results, demonstrating that FOXP3 expression driven solely by the CD28/B7 interaction inhibited T cell activation, support the role of CD28 in the regulation of peripheral tolerance and suggest a new mechanism through which it could occur.
Delayed Contraction of the CD8+ T Cell Response toward Lymphocytic Choriomeningitis Virus Infection in Mice Lacking Serglycin
Authors: Grujic Mirjana , Christensen Jan P. , Sørensen Maria R. , Abrink Magnus , Pejler Gunnar , Thomsen Allan R. 
Published: April 2014

Abstract
We previously reported that the lack of serglycin proteoglycan affects secretory granule morphology and granzyme B (GrB) storage in in vitro generated CTLs. In this study, the role of serglycin during viral infection was studied by infecting wild-type (wt) mice and serglycin-deficient (SG−/−) mice with lymphocytic choriomeningitis virus (LCMV). Wt and SG−/− mice cleared 103 PFU of highly invasive LCMV with the same kinetics, and the CD8+ T lymphocytes from wt and SG−/− animals did not differ in GrB, perforin, IFN-γ, or TNF-α content. However, when a less invasive LCMV strain was used, SG−/− GrB+ CD8+ T cells contained ∼30% less GrB than wt GrB+ CD8+ T cells. Interestingly, the contraction of the antiviral CD8+ T cell response to highly invasive LCMV was markedly delayed in SG−/− mice, and a delayed contraction of the virus-specific CD8+ T cell response was also seen after infection with vesicular stomatitis virus. BrdU labeling of cells in vivo revealed that the delayed contraction was associated with sustained proliferation of Ag-specific CD8+ T cells in SG−/− mice. Moreover, wt LCMV-specific CD8+ T cells from TCR318 transgenic mice expanded much more extensively in virus-infected SG−/− mice than in matched wt mice, indicating that the delayed contraction represents a T cell extrinsic phenomenon. In summary, the present report points to a novel, previously unrecognized role for serglycin proteoglycan in regulating the kinetics of antiviral CD8+ T cell responses.
CD4+CD25− T Cells Transduced to Express MHC Class I-Restricted Epitope-Specific TCR Synthesize Th1 Cytokines and Exhibit MHC Class I-Restricted Cytolytic Effector Function in a Human Melanoma Model
Authors: Chhabra Arvind , Yang Lili , Wang Pin , Comin-Anduix Begoña , Das Raja , Chakraborty Nitya G. , Ray Swagatam , Mehrotra Shikhar , Yang Haiguang , Hardee Cinnamon L. , Hollis Roger , Dorsky David I. , Koya Richard , Kohn Donald B. , Ribas Antoni , Economou James S. , Baltimore David , Mukherji Bijay 
Published: April 2014

Abstract
Cytolytic T cell-centric active specific and adoptive immunotherapeutic approaches might benefit from the simultaneous engagement of CD4+ T cells. Considering the difficulties in simultaneously engaging CD4+ and CD8+ T cells in tumor immunotherapy, especially in an Ag-specific manner, redirecting CD4+ T cells to MHC class I-restricted epitopes through engineered expression of MHC class I-restricted epitope-specific TCRs in CD4+ T cells has emerged as a strategic consideration. Such TCR-engineered CD4+ T cells have been shown to be capable of synthesizing cytokines as well as lysing target cells. We have conducted a critical examination of functional characteristics of CD4+ T cells engineered to express the α- and β-chains of a high functional avidity TCR specific for the melanoma epitope, MART-127–35, as a prototypic human tumor Ag system. We found that unpolarized CD4+CD25− T cells engineered to express the MART-127–35 TCR selectively synthesize Th1 cytokines and exhibit a potent Ag-specific lytic granule exocytosis-mediated cytolytic effector function of comparable efficacy to that of CD8+ CTL. Such TCR engineered CD4+ T cells, therefore, might be useful in clinical immunotherapy.
IL-15 Serves as a Costimulator in Determining the Activity of Autoreactive CD8 T Cells in an Experimental Mouse Model of Graft-versus-Host-Like Disease
Authors: Miyagawa Fumi , Tagaya Yutaka , Kim Brian S. , Patel Hiral J. , Ishida Kazuto , Ohteki Toshiaki , Waldmann Thomas A. , Katz Stephen I. 
Published: April 2014

Abstract
To elucidate the mechanisms controlling peripheral tolerance, we established two transgenic (Tg) mouse strains expressing different levels of membrane-bound OVA (mOVA) as a skin-associated self-Ag. When we transferred autoreactive TCR-Tg CD8 T cells (OT-I cells), keratin 14 (K14)-mOVAhigh Tg mice developed autoreactive skin disease (graft-vs-host disease (GVHD)-like skin lesions) while K14-mOVAlow Tg mice did not. OT-I cells in K14-mOVAhigh Tg mice were fully activated with full development of effector function. In contrast, OT-I cells in K14-mOVAlow Tg mice proliferated but did not gain effector function. Exogenous IL-15 altered the functional status of OT-I cells and concomitantly induced disease in K14-mOVAlow Tg mice. Conversely, neutralization of endogenous IL-15 activity in K14-mOVAhigh Tg mice attenuated GVHD-like skin lesions induced by OT-I cell transfer. Futhermore, K14-mOVAhigh Tg mice on IL-15 knockout or IL-15Rα knockout backgrounds did not develop skin lesions after adoptive transfer of OT-I cells. These results identify IL-15 as an indispensable costimulator that can determine the functional fate of autoreactive CD8 T cells and whether immunity or tolerance ensues, and they suggest that inhibition of IL-15 function may be efficacious in blocking expression of autoimmunity where a breach in peripheral tolerance is suspected.
SOCS1 Regulates CCR7 Expression and Migration of CD4+ T Cells into Peripheral Tissues
Authors: Yu Cheng-Rong , Mahdi Rashid M. , Liu Xuebin , Zhang Allen , Naka Tetsuji , Kishimoto Tadamitsu , Egwuagu Charles E. 
Published: April 2014

Abstract
Suppressors of cytokine signaling (SOCS) proteins control many aspects of lymphocyte function through regulation of STAT pathways. SOCS1-deficient mice develop severe skin and eye diseases that result from massive infiltration of inflammatory cells into these tissues. In this study, we have used SOCS1-, STAT1-, or STAT6-deficient mice, as well as, T cells with stable overexpression or deletion of SOCS1, to examine whether SOCS1 is involved in regulating lymphocyte trafficking to peripheral tissues. We show that SOCS1-deficient mice have increased numbers of T cells with characteristics of effector memory cells and expression of CCR7, a protein that promotes retention of T cells in lymphoid tissues, is markedly reduced in these cells. The decrease in CCR7 expression correlates with hyperactivation of STAT6, suggesting that aberrant recruitment of T cells into SOCS1-deficient mouse skin or eye results from abrogation of negative feedback regulation of STAT6 activation and CCR7 expression. Consistent with in vivo regulation of CCR7 expression and lymphocyte migration by SOCS1, forced overexpression of SOCS1 in T cells up-regulates CCR7 expression and enhances chemotaxis toward CCL19 or CCL21. CCR6 and CXCR3 are also up-regulated on SOCS1-deficient T cells and in situ analysis of the cornea or retina further reveal that these cells may mediate the chronic skin and eye inflammation through recruitment of Th1 and Th17 cells into these tissues. Collectively, these results suggest that SOCS1 regulates steady-state levels of chemokine receptors through its inhibitory effects on STAT pathways and this may underscore its role in regulating recruitment and retention of effector cells into nonlymphoid tissues.
The Potency of Erythropoietin-Mimic Antibodies Correlates Inversely with Affinity
Authors: Lacy Susan E. , DeVries Peter J. , Xie Nancy , Fung Emma , Lesniewski Richard R. , Reilly Edward B. 
Published: April 2014

Abstract
Preclinical animal studies have shown that Ab12.6, an agonistic human Ab targeting the erythropoietin receptor (EPOR), exhibits several potential dosing and safety features that make it an attractive clinical candidate for the treatment of anemia. Ab12.6 was derived by yeast display affinity maturation of parental Ab12, a strategy initially intended to improve off-rate and affinity for EPOR, thereby enhancing erythropoietic activity. Analysis of full-length IgGs derived from yeast clones identified sequences within Ab12 CDRH2 that independently influenced both affinity and potency. The Ab12.6 derivative displayed improved in vitro potency and in vivo efficacy, although its binding affinity to the EPOR was lower than that of the parent Ab12. Additional Ab12 derivatives also exhibited an inverse correlation between affinity and potency. These results suggest that for this class of agonistic Abs, faster off-rates may permit continuous receptor stimulation and more efficient erythropoiesis.
IL-17A Inhibits the Expansion of IL-17A-Producing T Cells in Mice through “Short-Loop” Inhibition via IL-17 Receptor
Authors: Smith Emily , Stark Matthew A. , Zarbock Alexander , Burcin Tracy L. , Bruce Anthony C. , Vaswani Devin , Foley Patricia , Ley Klaus 
Published: April 2014

Abstract
IL-23 and IL-17A regulate granulopoiesis through G-CSF, the main granulopoietic cytokine. IL-23 is secreted by activated macrophages and dendritic cells and promotes the expansion of three subsets of IL-17A-expressing neutrophil-regulatory T (Tn) cells; CD4−CD8−αβlow, CD4+CD8−αβ+ (Th17), and γδ+ T cells. In this study, we investigate the effects of IL-17A on circulating neutrophil levels using IL-17R-deficient (Il17ra−/−) mice and Il17ra−/−Itgb2−/− mice that lack both IL-17R and all four β2 integrins. IL-17R deficiency conferred a reduction in neutrophil numbers and G-CSF levels, as did Ab blockade against IL-17A in wild-type mice. Bone marrow transplantation revealed that IL-17R expression on nonhemopoietic cells had the greatest effects on regulating blood neutrophil counts. Although circulating neutrophil numbers were reduced, IL-17A expression, secretion, and the number of IL-17A-producing Tn cells were elevated in Il17ra−/− and Il17ra−/−Itgb2−/− mice, suggesting a negative feedback effect through IL-17R. The negative regulation of IL-17A-producing T cells and IL-17A and IL-17F gene expression through the interactions of IL-17A or IL-17F with IL-17R was confirmed in splenocyte cultures in vitro. We conclude that IL-17A regulates blood neutrophil counts by inducing G-CSF production mainly in nonhemopoietic cells. IL-17A controls the expansion of IL-17A-producing Tn cell populations through IL-17R.