bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adult Human Fibroblasts Are Potent Immunoregulatory Cells and Functionally Equivalent to Mesenchymal Stem Cells
Authors: Haniffa Muzlifah A. , Wang Xiao-Nong , Holtick Udo , Rae Michelle , Isaacs John D. , Dickinson Anne M. , Hilkens Catharien M. U. , Collin Matthew P. 
Published: April 2014

Abstract
Bone marrow mesenchymal stem cells (MSC) have potent immunosuppressive properties and have been advocated for therapeutic use in humans. The nature of their suppressive capacity is poorly understood but is said to be a primitive stem cell function. Demonstration that adult stromal cells such as fibroblasts (Fb) can modulate T cells would have important implications for immunoregulation and cellular therapy. In this report, we show that dermal Fb inhibit allogeneic T cell activation by autologously derived cutaneous APCs and other stimulators. Fb mediate suppression through soluble factors, but this is critically dependent on IFN-γ from activated T cells. IFN-γ induces IDO in Fb, and accelerated tryptophan metabolism is at least partly responsible for suppression of T cell proliferation. T cell suppression is reversible, and transient exposure to Fb during activation reprograms T cells, increasing IL-4 and IL-10 secretion upon restimulation. Increased Th2 polarization by stromal cells is associated with amelioration of pathological changes in a human model of graft-vs-host disease. Dermal Fb are highly clonogenic in vitro, suggesting that Fb-mediated immunosuppression is not due to outgrowth of rare MSC, although dermal Fb remain difficult to distinguish from MSC by phenotype or transdifferentiation capacity. These results suggest that immunosuppression is a general property of stromal cells and that dermal Fb may provide an alternative and accessible source of cellular therapy.
LFA-1-Mediated T Cell Costimulation through Increased Localization of TCR/Class II Complexes to the Central Supramolecular Activation Cluster and Exclusion of CD45 from the Immunological Synapse
Authors: Graf Beth , Bushnell Timothy , Miller Jim 
Published: April 2014

Abstract
T cell activation is associated with a dramatic reorganization of cell surface proteins and associated signaling components into discrete subdomains within the immunological synapse in T cell:APC conjugates. However, the signals that direct the localization of these proteins and the functional significance of this organization have not been established. In this study, we have used wild-type and LFA-1-deficient, DO11.10 TCR transgenic T cells to examine the role of LFA-1 in the formation of the immunological synapse. We found that coengagement of LFA-1 is not required for the formation of the central supramolecular activation cluster (cSMAC) region, but does increase the accumulation of TCR/class II complexes within the cSMAC. In addition, LFA-1 is required for the recruitment and localization of talin into the peripheral supramolecular activation cluster region and exclusion of CD45 from the synapse. The ability of LFA-1 to increase the amount of TCR engaged during synapse formation and segregate the phosphatase, CD45, from the synapse suggests that LFA-1 might enhance proximal TCR signaling. To test this, we combined flow cytometry-based cell adhesion and calcium-signaling assays and found that coengagement of LFA-1 significantly increased the magnitude of the intracellular calcium response following Ag presentation. These data support the idea that in addition to its important role on regulating T cell:APC adhesion, coengagement of LFA-1 can enhance T cell signaling, and suggest that this may be accomplished in part through the organization of proteins within the immunological synapse.
Detection of KIR3DS1 on the Cell Surface of Peripheral Blood NK Cells Facilitates Identification of a Novel Null Allele and Assessment of KIR3DS1 Expression during HIV-1 Infection
Authors: Pascal Véronique , Yamada Eriko , Martin Maureen P. , Alter Galit , Altfeld Marcus , Metcalf Julia A. , Baseler Michael W. , Adelsberger Joseph W. , Carrington Mary , Anderson Stephen K. , McVicar Daniel W. 
Published: April 2014

Abstract
KIR3DL1 is a highly polymorphic killer cell Ig-like receptor gene with at least 23 alleles described, including its activating counterpart, KIR3DS1. Recently, the KIR3DS1 allele has been shown to slow progression to AIDS in individuals expressing HLA-Bw4 with isoleucine at position 80. However, due to the lack of a specific Ab, KIR3DS1 expression and function is not well characterized. In this study, we demonstrate KIR3DS1 expression on a substantial subset of peripheral natural killer cells through its recognition by the mAb Z27. The fidelity of this detection method was confirmed by analysis of KIR3DS1 transfectants and the identification of a novel KIR3DS1 null allele. Interestingly, KIR3DS1 is also expressed by a small proportion of CD56+ T cells. We show that ligation of KIR3DS1 by Z27 leads to NK cell IFN-γ production and degranulation as assessed by expression of CD107a. Furthermore, we document the persistence of KIR3DS1+ NK cells in HIV-1 viremic patients. The high frequency of KIR3DS1 expression, along with its ability to activate NK cells, and its maintenance during HIV-1 viremia are consistent with the epidemiological data suggesting a critical role for this receptor in controlling HIV-1 pathogenesis.
Modulatory Effects of 1,25-Dihydroxyvitamin D3 on Human B Cell Differentiation
Authors: Chen Sheng , Sims Gary P. , Chen Xiao Xiang , Gu Yue Ying , Chen Shunle , Lipsky Peter E. 
Published: April 2014

Abstract1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) can modulate immune responses, but whether it directly affects B cell function is unknown. Patients with systemic lupus erythematosus, especially those with antinuclear Abs and increased disease activity, had decreased 1,25(OH)2D3 levels, suggesting that vitamin D might play a role in regulating autoantibody production. To address this, we examined the effects of 1,25(OH)2D3 on B cell responses and found that it inhibited the ongoing proliferation of activated B cells and induced their apoptosis, whereas initial cell division was unimpeded. The generation of plasma cells and postswitch memory B cells was significantly inhibited by 1,25(OH)2D3, although the up-regulation of genetic programs involved in B cell differentiation was only modestly affected. B cells expressed mRNAs for proteins involved in vitamin D activity, including 1α-hydroxylase, 24-hydroxylase, and the vitamin D receptor, each of which was regulated by 1,25(OH)2D3 and/or activation. Importantly, 1,25(OH)2D3 up-regulated the expression of p27, but not of p18 and p21, which may be important in regulating the proliferation of activated B cells and their subsequent differentiation. These results indicate that 1,25(OH)2D3 may play an important role in the maintenance of B cell homeostasis and that the correction of vitamin D deficiency may be useful in the treatment of B cell-mediated autoimmune disorders.
Functional Role for IκBNS in T Cell Cytokine Regulation As Revealed by Targeted Gene Disruption
Authors: Touma Maki , Antonini Valeria , Kumar Manoj , Osborn Stephanie L. , Bobenchik April M. , Keskin Derin B. , Connolly John E. , Grusby Michael J. , Reinherz Ellis L. , Clayton Linda K. 
Published: April 2014

Abstract
Triggering of the TCR by cognate peptide/MHC ligands induces expression of IκBNS, a member of the IκB family of NF-κB inhibitors whose expression is associated with apoptosis of immature thymocytes. To understand the role of IκBNS in TCR triggering, we created a targeted disruption of the IκBNS gene. Surprisingly, mice lacking IκBNS show normal thymic progression but both thymocytes and T cells manifest reduced TCR-stimulated proliferation. Moreover, IκBNS knockout thymocytes and T cells produce significantly less IL-2 and IFN-γ than wild-type cells. Transfection analysis demonstrates that IκBNS and c-Rel individually increase IL-2 promoter activity. The effect of IκBNS on the IL-2 promoter, unlike c-Rel, is dependent on the NF-κB rather than the CD28RE site; mutation of the NF-κB site extinguishes the induction of transcription by IκBNS in transfectants and prevents association of IκBNS with IL-2 promoter DNA. Microarray analyses confirm the reduction in IL-2 production and some IFN-γ-linked transcripts in IκBNS knockout T cells. Collectively, our findings demonstrate that IκBNS regulates production of IL-2 and other cytokines induced via “strong” TCR ligation.
Neonatal B Cells Suppress Innate Toll-Like Receptor Immune Responses and Modulate Alloimmunity
Authors: Walker Wendy E. , Goldstein Daniel R. 
Published: April 2014

Abstract
It has been known for decades that neonates are susceptible to transplant tolerance, but the immunological mechanisms involved remain to be fully elucidated. Recent evidence indicates that the maturation state of DCs responding to an allograft may have a profound impact on whether immunity or tolerance ensues. Given that TLR activation is a key process leading to DC maturation, we hypothesized that DCs from neonates have defective TLR immune responses. Contrary to our hypothesis, we found that murine neonatal DCs demonstrated enhanced TLR responses in comparison to adult counterparts in vitro. However, we found that neonatal B cells possess unique immunoregulatory functions as they impaired DC responses to TLR activation in an IL-10-dependent fashion. Functionally, we demonstrated that TLR-activated neonatal, but not adult, B cells impaired Th1, but not Th2, T cell alloimmune responses in vitro and in vivo, in models of alloimmune priming and allotransplantation. We conclude that neonatal B cells possess unique immunoregulatory properties that inhibit DC function and modulate alloimmunity in our murine experimental systems.
Coordinated Involvement of Mast Cells and T Cells in Allergic Mucosal Inflammation: Critical Role of the CC Chemokine Ligand 1:CCR8 Axis
Authors: Gonzalo Jose-Angel , Qiu Yubin , Lora Jose M. , Al-Garawi Amal , Villeval Jean-Luc , Boyce Joshua A. , Martinez-A Carlos , Marquez Gabriel , Goya Iñigo , Hamid Qutayba , Fraser Christopher C. , Picarella Dominic , Cote-Sierra Javier , Hodge Martin R. , Gutierrez-Ramos Jose-Carlos , Kolbeck Roland , Coyle Anthony J. 
Published: April 2014

Abstract
CCL1 is the predominant chemokine secreted from IgE-activated human and mouse mast cells in vitro, colocalizes to mast cells in lung biopsies, and is elevated in asthmatic airways. CCR8, the receptor for CCL1, is expressed by ∼70% of CD4+ T lymphocytes recruited to the asthmatic airways, and the number of CCR8-expressing cells is increased 3-fold in the airways of asthmatic subjects compared with normal volunteers. In vivo, CCL1 expression in the lung is reduced in mast cell-deficient mice after aeroallergen provocation. Neutralization of CCL1 or CCR8 deficiency results in reduced mucosal lung inflammation, airway hyperresponsiveness, and mucus hypersecretion to a similar degree as detected in mast cell-deficient mice. Adenoviral delivery of CCL1 to the lungs of mast cell-deficient mice restores airway hyperresponsiveness, lung inflammation, and mucus hypersecretion to the degree observed in wild-type mice. The consequences of CCR8 deficiency, including a marked reduction in Th2 cytokine levels, are comparable with those observed by depletion of CD4+ T lymphocytes. Thus, mast cell-derived CCL1- and CCR8-expressing CD4+ effector T lymphocytes play an essential role in orchestrating lung mucosal inflammatory responses.
NF-κB p50/p65 Affects the Frequency of Ly49 Gene Expression by NK Cells
Authors: Pascal Véronique , Nathan Neera R. , Claudio Estefania , Siebenlist Ulrich , Anderson Stephen K. 
Published: April 2014

Abstract
In mice, acquisition of Ly49 receptors characterizes one of the developmental stages of NK cells. We previously described a novel Ly49 promoter, Pro1, involved in Ly49 gene regulation in immature NK cells. Pro1 transcriptional activity requires a NF-κB binding site; however, only NF-κB/p50 binding to this element was observed. Cotransfection of NF-κB/p65 with Ly49g Pro1 in LNK cells induced a decrease in the transcriptional activity of the core promoter. Moreover, decreasing NF-κB/p65 protein expression by RNA interference increases Pro1 transcriptional activity. A high rate of NF-κB/p65 degradation in LNK cells correlates with Pro1 activity, since treatment with the proteasome inhibitor MG132 increased levels of NF-κB/p65 protein and decreased Pro1 activity. In addition, analysis of the Ly49 repertoire in NF-κB/p50 null mice reveals a decrease in the proportion of NK cells expressing a given Ly49 molecule. The defect in Ly49 expression is observed in the bone marrow and the spleen with a similar altered pattern of developmental stages in each tissue. The frequency of Ly49 expression in NF-κB/p52 null mice is slightly increased, indicating the specific role of NF-κB/p50 in Ly49 gene activation. These results suggest that NF-κB p50/p65 plays a major role in the initiation of Ly49 gene expression in NK cells.
The Related Adaptors, Adaptor in Lymphocytes of Unknown Function X and Rlk/Itk-Binding Protein, Have Nonredundant Functions in Lymphocytes
Authors: Perchonock Claire E. , Pajerowski Anthony G. , Nguyen Chau , Shapiro Michael J. , Shapiro Virginia Smith 
Published: April 2014

Abstract
Adaptors play a critical role in regulating signaling pathways that control lymphocyte development and activation. Adaptor in lymphocytes of unknown function X (ALX) and Rlk/Itk-binding protein (RIBP) are adaptors related by structure and sequence, coexpressed in T cells. Mice deficient for each adaptor demonstrated that ALX and RIBP, respectively, negatively and positively regulate T cell activation in response to TCR/CD28 stimulation. However, these results did not preclude that they may function redundantly in other cell populations, or in response to other stimuli. Therefore, to understand the relationship between these related adaptors, ALX/RIBP-deficient mice were generated. We demonstrate that although ALX and RIBP are expressed throughout T cell development, T cell development occurs normally in these mice. Using the H-Y TCR transgenic model, positive and negative selection were found to proceed unimpeded in the absence of ALX and RIBP. We demonstrate that RIBP is also expressed in B cells; however, RIBP- and ALX/RIBP-deficient mice had normal B cell development, and responded equivalently to wild type in response to IgM, CD40, B cell-activating factor/B lymphocyte stimulator, CpG, and LPS. Interestingly, T cells deficient in both ALX and RIBP behaved similarly to those deficient in ALX alone during T cell activation in response to TCR/CD28, exhibiting increased IL-2 production, CD25 expression, and proliferation, thus showing that ALX deficiency masked the effect of RIBP deficiency. ALX/RIBP-deficient T cells did not have any alterations in either activation-induced cell death or Th1/2 polarization. Therefore, we did not find any functional redundancy or synergy during lymphocyte development, selection, activation, or survival in ALX/RIBP-deficient mice, demonstrating that these molecules function independently.
Despite Inhibition of Nuclear Localization of NF-κB p65, c-Rel, and RelB, 17-β Estradiol Up-Regulates NF-κB Signaling in Mouse Splenocytes: The Potential Role of Bcl-3
Authors: Dai Rujuan , Phillips Rebecca A. , Ahmed S. Ansar 
Published: April 2014

Abstract
NF-κB plays a major role in regulating the immune system. Therefore, alterations in NF-κB activity have profound effects on many immunopathologies, including inflammation, autoimmunity, and lymphoid neoplasia. We investigated the effects of estrogen (17β-estradiol) on NF-κB in C57BL/6 mice since estrogen is a natural immunomodulator and we have recently reported that estrogen up-regulates several NF-κB-regulated proteins (inducible NO synthase, IFN-γ, and MCP-1). We found that in vivo estrogen treatment had differential effects on NF-κB family members. Estrogen profoundly blocked the nuclear translocation of p65, c-Rel, and Rel-B, partially blocked p52, but permitted translocation of p50. Despite blockade of both the classical (p65/p50) and alternative (RelB/p52) NF-κB activation pathways, estrogen induced constitutive NF-κB activity and increased the levels of cytokines regulated by NF-κB (IL-1α, IL-1β, IL-10, and IFN-γ). Studies involving a NF-κB inhibitor confirmed a positive regulatory role of NF-κB on these cytokines. Remarkably, estrogen selectively induced B cell lymphoma 3 (Bcl-3), which is known to associate with p50 to confer transactivation capabilities, thereby providing a potential link between observed p50 DNA-binding activity and estrogen up-regulation of NF-κB transcriptional activity. Chromatin immunoprecipitation assays confirmed that Bcl-3 bound to the promoter of the NF-κB-regulated inducible NO synthase gene in cells from estrogen-treated mice. Estrogen appeared to act at the posttranscriptional level to up-regulate Bcl-3 because mRNA levels in splenocytes from placebo- and estrogen-treated mice were comparable. The novel findings of differential regulation of NF-κB proteins by estrogen provide fresh insight into potential mechanisms by which estrogen can regulate NF-κB-dependent immunological events.
The p47 GTPases Iigp2 and Irgb10 Regulate Innate Immunity and Inflammation to Murine Chlamydia psittaci Infection
Authors: Miyairi Isao , Tatireddigari Venkat R. R. Arva , Mahdi Olaimatu S. , Rose Lorne A. , Belland Robert J. , Lu Lu , Williams Robert W. , Byrne Gerald I. 
Published: April 2014

Abstract
C57BL/6J mice were 105-fold more resistant to Chlamydia psittaci infection than DBA/2J mice by LD100 determinations. Linkage analysis using BXD recombinant inbred strains revealed a single effector locus at a 1.5-Mbp region on chromosome 11 encoding a cluster of three p47 GTPases (Irgb10, Igtp, and Iigp2). Western blots of infected tissue showed that Irgb10 was elevated in resistant mice and one of the two possible Iigp2 protein isoforms was preferentially expressed in susceptible mice. The BXD39 strain, susceptible at Irgb10 and resistant at Iigp2, had an intermediate phenotype implicating the nonredundant role of these p47 GTPases. C57BL/6J and DBA/2J exhibited a difference in IFN-γ-dependent chlamydial control, which was reversible by Iigp2 small interfering RNA knockdown. Microarrays of infected peritoneal lavage revealed &gt;10-fold up-regulation of neutrophil-recruiting chemokines in susceptible mice and &gt;100-fold increase in macrophage differentiation genes in resistant mice, indicating that the susceptibility pattern involves the stimulation of different inflammatory cell-recruiting pathways. Massive neutrophil recruitment was seen in susceptible mice by histology and flow cytometry, and neutrophil chemokine receptor (CXCR2) knockout mice on a susceptible background survived a lethal challenge, confirming that neutrophil recruitment was required for susceptibility. Congenic Igtp knockout mice also susceptible at Irgb10 and Iigp2 on a resistant background recruited neutrophils and succumbed to infection. We conclude that Irgb10 and Iigp2 act together to confer differential susceptibility against murine chlamydial infection. Data indicate that these p47 GTPases have cell-autonomous effects that result in vastly different inflammatory stimulations, leading to either recovery or death.
The Intrinsic Apoptotic Pathway Is Required for Lipopolysaccharide-Induced Lung Endothelial Cell Death
Authors: Wang Helena L. , Akinci I. Ozkan , Baker Christina M. , Urich Daniela , Bellmeyer Amy , Jain Manu , Chandel Navdeep S. , Mutlu Gökhan M. , Budinger G. R. Scott 
Published: April 2014

Abstract
LPS has been implicated in the pathogenesis of endothelial cell death associated with Gram-negative bacterial sepsis. The binding of LPS to the TLR-4 on the surface of endothelial cells initiates the formation of a death-inducing signaling complex at the cell surface. The subsequent signaling pathways that result in apoptotic cell death remain unclear and may differ among endothelial cells in different organs. We sought to determine whether LPS and cycloheximide-induced cell death in human lung microvascular endothelial cells (HmVECs) was dependent upon activation of the intrinsic apoptotic pathway and the generation of reactive oxygen species. We found that cells overexpressing the anti-apoptotic protein Bcl-XL were resistant to LPS and cycloheximide-induced death and that the proapoptotic Bcl-2 protein Bid was cleaved following treatment with LPS. The importance of Bid was confirmed by protection of Bid-deficient (bid−/−) mice from LPS-induced lung injury. Neither HmVECs treated with the combined superoxide dismutase/catalase mimetic EUK-134 nor HmVECs depleted of mitochondrial DNA (ρ0 cells) were protected against LPS and cycloheximide-induced death. We conclude that LPS and cycloheximide-induced death in HmVECs requires the intrinsic cell death pathway, but not the generation of reactive oxygen species.
Streptococcus suis Serotype 2, an Important Swine and Human Pathogen, Induces Strong Systemic and Cerebral Inflammatory Responses in a Mouse Model of Infection
Authors: Domínguez-Punaro María C. , Segura Mariela , Plante Marie-Michèle , Lacouture Sonia , Rivest Serge , Gottschalk Marcelo 
Published: April 2014

Abstract
Streptococcus suis, an important swine and human pathogen, causes septic shock and meningitis. The pathogenesis of both systemic and CNS infections caused by S. suis is poorly understood. A hematogenous model of infection in CD1 mice was developed to study the systemic release of cytokines during the septic shock phase and the proinflammatory events in the CNS associated with this pathogen. Using a liquid array system, high levels of systemic TNF-α, IL-6, IL-12, IFN-γ, CCL2, CXCL1, and CCL5 were observed 24 h after infection and might be responsible for the sudden death of 20% of animals. Infected mice that survived the early sepsis later developed clinical signs of meningitis and exhibited lesions in the meninges and in numerous regions of the brain, such as the cortex, hippocampus, thalamus, hypothalamus, and corpus callosum. Bacterial Ags were found in association with microglia residing only in the affected zones. In situ hybridization combined with immunocytochemistry showed transcriptional activation of TLR2 and TLR3 as well as CD14, NF-κB, IL-1β, CCL2, and TNF-α, mainly in myeloid cells located in affected cerebral structures. Early transcriptional activation of TLR2, CD14, and inflammatory cytokines in the choroid plexus and cells lining the brain endothelium suggests that these structures are potential entry sites for the bacteria into the CNS. Our data indicate an important role of the inflammatory response in the pathogenesis of S. suis infection in mice. This experimental model may be useful for studying the mechanisms underlying sepsis and meningitis during bacterial infection.