bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Regulatory T Cells Prevent Efficient Clearance of Mycobacterium tuberculosis
Authors: Kursar Mischo , Koch Markus , Mittrücker Hans-Willi , Nouailles Geraldine , Bonhagen Kerstin , Kamradt Thomas , Kaufmann Stefan H. E. 
Published: April 2014

Abstract
Mycobacterium tuberculosis remains one of the top microbial killers of humans causing ∼2 million deaths annually. More than 90% of the 2 billion individuals infected never develop active disease, indicating that the immune system is able to generate mechanisms that control infection. However, the immune response generally fails to achieve sterile clearance of bacilli. Using adoptive cell transfer into C57BL/6J-Rag1tm1Mom mice (Rag1−/−), we show that regulatory T cells prevent eradication of tubercle bacilli by suppressing an otherwise efficient CD4+ T cell response. This protective CD4+ T cell response was not correlated with increased numbers of IFN-γ- or TNF-α-expressing cells or general expression levels of IFN-γ or inducible NO synthase in infected organs compared with wild-type C57BL/6 animals. Furthermore, suppression of protection by cotransferred regulatory T cells was neither accompanied by a general increase of IL-10 expression nor by higher numbers of IL-10-producing CD4+ T cells.
Murine Neonatal CD4+ Cells Are Poised for Rapid Th2 Effector-Like Function
Authors: Rose Shawn , Lichtenheld Mathias , Foote Monica R. , Adkins Becky 
Published: April 2014

Abstract
Murine neonates typically mount Th2-biased immune responses. This entails a cell-intrinsic component whose molecular basis is unknown. We found that neonatal CD4+ T cells are uniquely poised for rapid Th2 function. Within 24 h of activation, neonatal CD4+ cells made high levels of IL-4 and IL-13 mRNA and protein. The rapid high-level IL-4 production arose from a small subpopulation of cells, did not require cell cycle entry, and was unaffected by pharmacologic DNA demethylation. CpG methylation analyses in resting neonatal cells revealed pre-existing hypomethylation at a key Th2 cytokine regulatory region, termed conserved noncoding sequence 1 (CNS-1). Robust Th2 function and increased CNS-1 demethylation was a stable property that persisted in neonatal Th2 effectors. The transcription factor STAT6 was not required for CNS-1 demethylation and this state was already established in neonatal CD4 single-positive thymocytes. CNS-1 demethylation levels were much greater in IL-4-expressing CD4 single-positive thymocytes compared with unactivated cells. Together, these results indicate that neonatal CD4+ T cells possess distinct qualities that could predispose them toward rapid, effector-like Th2 function.
Invariant NKT Cells Amplify the Innate Immune Response to Lipopolysaccharide
Authors: Nagarajan Niranjana A. , Kronenberg Mitchell 
Published: April 2014

Abstract
NKT cells are thought of as a bridge between innate and adaptive immunity. In this study, we demonstrate that mouse NKT cells are activated in response to Escherichia coli LPS, and produce IFN-γ, but not IL-4, although activation through their TCR typically induces both IL-4 and IFN-γ production. IFN-γ production by NKT cells is dependent on LPS-induced IL-12 and IL-18 from APC. LPS induced IFN-γ production by NKT cells does not require CD1d-mediated presentation of an endogenous Ag and exposure to a combination of IL-12 and IL-18 is sufficient to activate them. In mice that are deficient for NKT cells, innate immune cells are activated less efficiently in response to LPS, resulting in the reduced production of TNF and IFN-γ. We propose that in addition to acting as a bridge to adaptive immunity, NKT cells act as an early amplification step in the innate immune response and that the rapid and complete initiation of this innate response depends on the early production of IFN-γ by NKT cells.
IL-2/Neuroantigen Fusion Proteins as Antigen-Specific Tolerogens in Experimental Autoimmune Encephalomyelitis (EAE): Correlation of T Cell-Mediated Antigen Presentation and Tolerance Induction
Authors: Mannie Mark D. , Clayson Barbara A. , Buskirk Elizabeth J. , DeVine Jarret L. , Hernandez Jose J. , Abbott Derek J. 
Published: April 2014

Abstract
The purpose of this study was to assess whether the Ag-targeting activity of cytokine/neuroantigen (NAg) fusion proteins may be associated with mechanisms of tolerance induction. To assess this question, we expressed fusion proteins comprised of a N-terminal cytokine domain and a C-terminal NAg domain. The cytokine domain comprised either rat IL-2 or IL-4, and the NAg domain comprised the dominant encephalitogenic determinant of the guinea pig myelin basic protein. Subcutaneous administration of IL2NAg (IL-2/NAg fusion protein) into Lewis rats either before or after an encephalitogenic challenge resulted in an attenuated course of experimental autoimmune encephalomyelitis. In contrast, parallel treatment of rats with IL4NAg (IL-4/NAg fusion protein) or NAg lacked tolerogenic activity. In the presence of IL-2R+ MHC class II+ T cells, IL2NAg fusion proteins were at least 1,000 times more potent as an Ag than NAg alone. The tolerogenic activity of IL2NAg in vivo and the enhanced potency in vitro were both dependent upon covalent linkage of IL-2 and NAg. IL4NAg also exhibited enhanced antigenic potency. IL4NAg was ∼100-fold more active than NAg alone in the presence of splenic APC. The enhanced potency of IL4NAg also required covalent linkage of cytokine and NAg and was blocked by soluble IL-4 or by a mAb specific for IL-4. Other control cytokine/NAg fusion proteins did not exhibit a similar enhancement of Ag potency compared with NAg alone. Thus, the IL2NAg and IL4NAg fusion proteins targeted NAg for enhanced presentation by particular subsets of APC. The activities of IL2NAg revealed a potential relationship between NAg targeting to activated T cells, T cell-mediated Ag presentation, and tolerance induction.
Modulation of CD103 Expression on Human Colon Carcinoma-Specific CTL
Authors: Ling Khoon-Lin , Dulphy Nicolas , Bahl Pru , Salio Mariolina , Maskell Kevin , Piris Juan , Warren Bryan F. , George Bruce D. , Mortensen Neil J. , Cerundolo Vincenzo 
Published: April 2014

Abstract
Recent results have shown a correlation between survival and frequency of tumor-infiltrating T cells in colorectal cancer patients. However, the mechanisms controlling the ability of human T lymphocytes to infiltrate colon carcinoma remain unclear. Although, it is known that expression of the integrin CD103αE/β7 by intraepithelial lymphocytes controls the retention of lymphocytes in epithelial layers, very little is known about the expression of intestinal homing receptors in human T lymphocytes. In particular, it remains unknown whether expression of CD103/β7 by human colon cancer-specific T lymphocytes is controlled by recognition of tumor Ags and is imprinted during T cell priming, facilitating its expression during memory T cell activation. In this study, we demonstrate that expression of CD103/β7 in human colon carcinoma-specific CTL is synergistically enhanced by the simultaneous TGF-β1 stimulation and Ag recognition. These results were confirmed by using a panel of human CTL clones. Finally, we show that priming of naive CD8+ T cells in the presence of TGF-β1 ensures up-regulation of CD103/β7 in recall responses, at concentrations of TGF-β1 significantly lower than those required by memory T cells primed in the absence of TGF-β1. These results indicate a role of TGF-β1 during T cell priming in modulating expression of CD103/β7 and controlling retention of human memory CD8+ T cells into tumor epithelium.
Increased Positive Selection of B1 Cells and Reduced B Cell Tolerance to Intracellular Antigens in c1q-Deficient Mice
Authors: Ferry Helen , Potter Paul K. , Crockford Tanya L. , Nijnik Anastasia , Ehrenstein Michael R. , Walport Mark J. , Botto Marina , Cornall Richard J. 
Published: April 2014

Abstract
Inherited deficiency of early components of the classical complement pathway is strongly associated with the targeting of intracellular self Ags in systemic lupus erythematosus, but the reasons for this association are debated. In this study, we show that C1q deficiency increases the positive selection of B1b B cells and IgM autoantibodies by an intracellular self Ag, which is exposed on dying cells, and decreases the negative selection of autoreactive conventional B cells by the same Ag. These effects are specific to intracellular Ag because C1q deficiency does not affect negative selection by extracellular self Ag or increase the positive selection of naive B cells. The B1-derived IgM autoantibody binds to the intracellular Ag when it is expressed on dying cells, leading to fixation of C1q and clearance of cells by phagocytosis. These findings suggest that the positive selection of autoreactive B1 cells by self Ags may contribute to the IgM and C1q-dependent clearance of dying cells in a feedback loop that limits exposure of conventional B cells to immunogenic self Ags. We show that exposure of intracellular Ag leads to the activation of conventional B cells, when there is a source of T cell help in vivo.
CD4+ and CD8+ T Cell Survival Is Regulated Differentially by Protein Kinase Cθ, c-Rel, and Protein Kinase B
Authors: Saibil Samuel D. , Jones Russell G. , Deenick Elissa K. , Liadis Nicole , Elford Alisha R. , Vainberg Mitchell G. , Baerg Heather , Woodgett James R. , Gerondakis Steve , Ohashi Pamela S. 
Published: April 2014

Abstract
An effective immune response requires the expansion and survival of a large number of activated T cells. This study compared the role of protein kinase C (PKC)θ and associated signaling molecules in the survival of activated primary CD4+ vs CD8+ murine T cells. We demonstrate that the absence of PKCθ resulted in a moderate survival defect in CD4+ T cells and a striking survival defect of CD8+ T lymphocytes. CD8+ T cells lacking the c-Rel, but not the NF-κB1/p50, member of the NF-κB family of transcription factors displayed a similar impairment in cell survival as PKCθ−/− CD8+ T lymphocytes. This implicates c-Rel as a key target of PKCθ-mediated survival signals in CD8+ T cells. In addition, both c-Rel−/− and PKCθ−/− T cells also displayed impaired expression of the antiapoptotic Bcl-xL protein upon activation. Changes in Bcl-xL expression, however, did not correlate with the survival of CD4+ or CD8+ lymphocytes. The addition of protein kinase B-mediated survival signals could restore partially CD4+ T cell viability, but did not dramatically influence CD8+ survival. Active protein kinase B was also unable to restore proliferative responses in CD8+ PKCθ−/− T cells. The survival of CD4+ and CD8+ T cells deficient in either PKCθ or c-Rel, however, was promoted by the addition of IL-2. Collectively, these data demonstrate that CD4+ and CD8+ T cell survival signals are differentially programmed.
Regulatory T Cells Dynamically Control the Primary Immune Response to Foreign Antigen
Authors: Haribhai Dipica , Lin Wen , Relland Lance M. , Truong Nga , Williams Calvin B. , Chatila Talal A. 
Published: April 2014

Abstract
The population dynamics that enable a small number of regulatory T (TR) cells to control the immune responses to foreign Ags by the much larger conventional T cell subset were investigated. During the primary immune response, the expansion and contraction of conventional and TR cells occurred in synchrony. Importantly, the relative accumulation of TR cells at peak response significantly exceeded that of conventional T cells, reflecting extensive cell division within the TR cell pool. Transfer of a polyclonal TR cell population before immunization antagonized both polyclonal and TCR transgenic responses, whereas blocking TR cell function enhanced those responses. These results define an inverse quantitative relationship between TR and conventional T cells that controls the magnitude of the primary immune response. The high frequency of dividing TR cells suggests degenerate TCR specificity enabling activation by a broad spectrum of Ags.
Requirement for a Complex of Wiskott-Aldrich Syndrome Protein (WASP) with WASP Interacting Protein in Podosome Formation in Macrophages
Authors: Tsuboi Shigeru 
Published: April 2014

Abstract
Chemotactic migration of macrophages is critical for the recruitment of leukocytes to inflamed tissues. Macrophages use a specialized adhesive structure called a podosome to migrate. Podosome formation requires the Wiskott-Aldrich syndrome protein (WASP), which is a product of the gene defective in an X-linked inherited immunodeficiency disorder, the Wiskott-Aldrich syndrome. Macrophages from WASP-deficient Wiskott-Aldrich syndrome patients lack podosomes, resulting in defective chemotactic migration. However, the molecular basis for podosome formation is not fully understood. I have shown that the WASP interacting protein (WIP), a binding partner of WASP, plays an important role in podosome formation in macrophages. I showed that WASP bound WIP to form a complex at podosomes and that the knockdown of WIP impairs podosome formation. When WASP binding to WIP was blocked, podosome formation was also impaired. When WASP expression was reduced by small interfering RNA transfection, the amount of the complex of WASP with WIP decreased, resulting in reduced podosome formation. Podosomes were restored by reconstitution of the WASP-WIP complex in WASP knockdown cells. These results indicate that the WASP-WIP complex is required for podosome formation in macrophages. When podosome formation was reduced by blocking WASP binding to WIP, transendothelial migration of macrophages, the most crucial process in macrophage trafficking, was impaired. These results suggest that a complex of WASP with WIP plays a critical role in podosome formation, thereby mediating efficient transendothelial migration of macrophages.
Transmembrane Mutations to FcγRIIA Alter Its Association with Lipid Rafts: Implications for Receptor Signaling
Authors: García-García Erick , Brown Eric J. , Rosales Carlos 
Published: April 2014

Abstract
Many immunoreceptors have been reported to associate with lipid rafts upon ligand binding. The way in which this association is regulated is still obscure. We investigated the roles for various domains of the human immunoreceptor FcγRIIA in regulating its association with lipid rafts by determining the resistance of unligated, or ligated and cross-linked, receptors to solubilization by the nonionic detergent Triton X-100, when expressed in RBL-2H3 cells. Deletion of the cytoplasmic domain, or destruction of the cytoplasmic palmitoylation site, had no effect on the association of the receptor with lipid rafts. A transmembrane mutant, A224S, lost the ability to associate with lipid rafts upon receptor cross-linking, whereas transmembrane mutants VA231-2MM and VVAL234-7GISF showed constitutive lipid raft association. Wild-type (WT) FcγRIIA and all transmembrane mutants activated Syk, regardless of their association with lipid rafts. WT FcγRIIA and mutants that associated with lipid rafts efficiently activated NF-κB, in an ERK-dependent manner. In contrast, WT FcγRIIA and the A224S mutant both presented efficient phagocytosis, while VA231-2MM and VVAL234-7GISF mutants presented lower phagocytosis, suggesting that phagocytosis may proceed independently of lipid raft association. These data identify the transmembrane domain of FcγRIIA as responsible for regulating its inducible association with lipid rafts and suggest that FcγRIIA-mediated responses, like NF-κB activation or phagocytosis, can be modulated by lipid raft association of the ligated receptor.
Hidden Epitopes Emerge in Secondary Influenza Virus-Specific CD8+ T Cell Reponses
Authors: Thomas Paul G. , Brown Scott A. , Keating Rachael , Yue Wen , Morris Melissa Y. , So Jenny , Webby Richard J. , Doherty Peter C. 
Published: April 2014

Abstract
Influenza A virus-specific CD8+ T cell responses in H2b mice are characterized by reproducible hierarchies. Compensation by the DbPB1-F262 epitope is apparent following infection with a variant H3N2 virus engineered to disrupt the prominent DbNP366 and DbPA224 epitopes (a double knockout or DKO). Analysis with a “triple” knockout (TKO) virus, which also compromises DbPB1-F262, did not reveal further compensation to the known residual, minor, and predicted epitopes. However, infection with this deletion mutant apparently switched protective immunity to an alternative Ab-mediated pathway. As expected, TKO virus clearance was significantly delayed in Ab-deficient MHC class II−/− and Ig−/− mice, which were much more susceptible following primary, intranasal infection with the TKO, but not DKO, virus. CD8+ T cell compensation was detected in DKO, but not TKO, infection of Ig-deficient mice, suggestive of cooperation among CD8+ T cell responses. However, after priming with a TKO H1N1 mutant, MHC II−/− mice survived secondary intranasal exposure to the comparable H3N2 TKO virus. Such prime/challenge experiments with the DKO and TKO viruses allowed the emergence of two previously unknown epitopes. The contrast between the absence of compensatory effect following primary exposure and the substantial clonal expansion after secondary challenge suggests that the key factor limiting the visibility of these “hidden” epitopes may be very low naive T cell precursor frequencies. Overall, these findings suggest that vaccine approaches using virus vectors to deliver an Ag may be optimized by disrupting key peptides in the normal CD8+ T cell response associated with common HLA types.
Human Peptidoglycan Recognition Proteins Require Zinc to Kill Both Gram-Positive and Gram-Negative Bacteria and Are Synergistic with Antibacterial Peptides
Authors: Wang Minhui , Liu Li-Hui , Wang Shiyong , Li Xinna , Lu Xiaofeng , Gupta Dipika , Dziarski Roman 
Published: April 2014

Abstract
Mammals have four peptidoglycan recognition proteins (PGRPs or PGLYRPs), which are secreted innate immunity pattern recognition molecules with effector functions. In this study, we demonstrate that human PGLYRP-1, PGLYRP-3, PGLYRP-4, and PGLYRP-3:4 have Zn2+-dependent bactericidal activity against both Gram-positive and Gram-negative bacteria at physiologic Zn2+ concentrations found in serum, sweat, saliva, and other body fluids. The requirement for Zn2+ can only be partially replaced by Ca2+ for killing of Gram-positive bacteria but not for killing of Gram-negative bacteria. The bactericidal activity of PGLYRPs is salt insensitive and requires N-glycosylation of PGLYRPs. The LD99 of PGLYRPs for Gram-positive and Gram-negative bacteria is 0.3–1.7 μM, and killing of bacteria by PGLYRPs, in contrast to killing by antibacterial peptides, does not involve permeabilization of cytoplasmic membrane. PGLYRPs and antibacterial peptides (phospholipase A2, α- and β-defensins, and bactericidal permeability-increasing protein), at subbactericidal concentrations, synergistically kill Gram-positive and Gram-negative bacteria. These results demonstrate that PGLYRPs are a novel class of recognition and effector molecules with broad Zn2+-dependent bactericidal activity against both Gram-positive and Gram-negative bacteria that are synergistic with antibacterial peptides.
Differential Recognition of TLR-Dependent Microbial Ligands in Human Bronchial Epithelial Cells
Authors: Mayer Anja K. , Muehmer Mario , Mages Jörg , Gueinzius Katja , Hess Christian , Heeg Klaus , Bals Robert , Lang Roland , Dalpke Alexander H. 
Published: April 2014

Abstract
Bronchial epithelial cells represent the first line of defense against invading airborne pathogens. They are important contributors to innate mucosal immunity and provide a variety of antimicrobial effectors. However, mucosal surfaces are prone to contact with pathogenic, as well as nonpathogenic microbes, and therefore, immune recognition principles have to be tightly controlled to avoid uncontrolled permanent activation. TLRs have been shown to recognize conserved microbial patterns and to mediate inducible activation of innate immunity. Our experiments demonstrate that bronchial epithelial cells express functional TLR1–6 and TLR9 and thus make use of a common principle of professional innate immune cells. Although it was observed that TLR2 ligands dependent on heterodimeric signaling either with TLR1 or TLR6 were functional, other ligands like lipoteichoic acid were not. Additionally, it was found that bronchial epithelial cells could be stimulated only marginally by Gram-positive bacteria bearing known TLR2 ligands while Gram-negative bacteria were easily recognized. This correlated with low expression of TLR2 and the missing expression of the coreceptor CD36. Transgenic expression of both receptors restored responsiveness to the complete set of TLR2 ligands and Staphylococcus aureus. Additional gene-array experiments confirmed hyporesponsiveness to this bacterium while Pseudomonas aeruginosa and respiratory syncytial virus induced common, as well as pathogen-specific, sets of genes. The findings indicate that bronchial epithelium regulates its sensitivity to recognize microbes by managing receptor expression levels. This could serve the special needs of controlled microbial recognition in mucosal compartments.
The Type I IFN Response to Infection withMycobacterium tuberculosisRequires ESX-1-Mediated Secretion and Contributes to Pathogenesis
Authors: Stanley Sarah A. , Johndrow James E. , Manzanillo Paolo , Cox Jeffery S. 
Published: April 2014

AbstractThe ESX-1 secretion system is a major determinant of Mycobacterium tuberculosis virulence, although the pathogenic mechanisms resulting from ESX-1-mediated transport remain unclear. By global transcriptional profiling of tissues from mice infected with either wild-type or ESX-1 mutant bacilli, we found that host genes controlled by ESX-1 in vivo are predominantly IFN regulated. ESX-1-mediated secretion is required for the production of host type I IFNs during infection in vivo and in macrophages in vitro. The macrophage signaling pathway leading to the production of type I IFN required the host kinase TANK-binding kinase 1 and occurs independently of TLR signaling. Importantly, the induction of type I IFNs during M. tuberculosis infection is a pathogenic mechanism as mice lacking the type I IFNR were more restrictive for bacterial growth in the spleen than wild-type mice, although growth in the lung was unaffected. We propose that the ESX-1 secretion system secretes effectors into the cytosol of infected macrophages, thereby triggering the type I IFN response for the manipulation of host immunity.