bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional Activators of Helper T Cell Fate Are Required for Establishment but Not Maintenance of Signature Cytokine Expression
Authors: Martins Gislâine A. , Hutchins Anne S. , Reiner Steven L. 
Published: April 2014

Abstract
The stability of helper T cell fates is not well understood. Using conditional introduction of dominant-negative factors, we now show that T-bet and GATA-3 are far more critical in establishment than maintenance of IFN-γ and IL-4 activity during Th1 and Th2 maturation, respectively. We also show that a genetic interaction between T-bet and its target Hlx seems to be required for Th1 maturation, but that Hlx may also be dispensable for maintenance of a transcriptionally permissive ifng gene. In parallel to progressive activator independence in the permissive lineage, the ifng gene becomes more recalcitrant to switching as the forbidden lineage matures. T-bet plus Hlx can disrupt ifng silencing when introduced into developing Th2 cells, but they fail to perturb ifng silencing in mature Th2 cells. In contrast, a hypermorphic allele of T-bet can reverse silencing of the ifng gene in mature Th2 cells. These results suggest that signature gene activity of helper T cells is initially plastic but later becomes epigenetically fixed and offer an initial strategy for inducing mature cells to switch their fate.
Distinct Regulation of H2-M3-Restricted Memory T Cell Responses in Lymph Node and Spleen
Authors: Ploss Alexander , Leiner Ingrid , Pamer Eric G. 
Published: April 2014

Abstract
CD8 T cell populations restricted by H2-M3 MHC class Ib molecules expand rapidly during primary Listeria monocytogenes infection but only minimally upon reinfection. In contrast, CD8 T cells restricted by MHC class Ia molecules undergo more delayed expansion during primary infection but rapid and robust expansion following reinfection. In this study we demonstrate that primary H2-M3-restricted CD8 T cell responses are unaffected by the frequency of naive MHC class Ia-restricted T cells during L. monocytogenes infection. The magnitude of H2-M3-restricted memory responses, in contrast, is down-modulated by increasing frequencies of MHC class Ia-restricted effector T cells following secondary systemic infection. Suppression by MHC class Ia-restricted T cells, however, is not a universal feature of MHC class Ib-restricted memory responses. Primary systemic L. monocytogenes infection followed by secondary tissue infection, for example, results in robust expansion of H2-M3-restricted memory T cells in draining lymph nodes, despite the activation of MHC class Ia-restricted memory T cell responses. Thus, whereas MHC class Ia-restricted memory T cell populations predominate in spleens following systemic reinfection, H2-M3-restricted memory T cell responses remain prominent in lymph nodes draining localized infections. Our studies demonstrate that interactions between CD8 T cell populations can differ, depending on the status of the responding T cells (naive vs memory) and the route of reinfection. These results may have important implications for prime-boost vaccination strategies.
Osteopontin Is Not Required for the Development of Th1 Responses and Viral Immunity
Authors: Abel Brian , Freigang Stefan , Bachmann Martin F. , Boschert Ursula , Kopf Manfred 
Published: April 2014

Abstract
Osteopontin (OPN) has been defined as a key cytokine promoting the release of IL-12 and hence inducing the development of protective cell-mediated immunity to viruses and intracellular pathogens. To further characterize the role of OPN in antiviral immunity, OPN-deficient (OPN−/−) mice were analyzed after infection with influenza virus and vaccinia virus. Surprisingly, we found that viral clearance, lung inflammation, and recruitment of effector T cells to the lung were unaffected in OPN−/− mice after influenza infection. Furthermore, effector status of T cells was normal as demonstrated by normal IFN-γ production and CTL lytic activity. Moreover, activation and Th1 differentiation of naive TCR transgenic CD4+ T cells by dendritic cells and cognate Ag was normal in the absence of OPN in vitro. Contrary to a previous report, we found that OPN−/− mice mounted a normal immune response to Listeria monocytogenes. In conclusion, OPN is dispensable for antiviral immune responses against influenza virus and vaccinia virus.
Pattern Recognition Molecules Activated by Chlamydia muridarum Infection of Cloned Murine Oviduct Epithelial Cell Lines
Authors: Derbigny Wilbert A. , Kerr Micah S. , Johnson Raymond M. 
Published: April 2014

Abstract
Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the United States and a major cause of female infertility due to infection-induced Fallopian tube scarring. Epithelial cells are likely central to host defense and pathophysiology as they are the principal cell type productively infected by C. trachomatis. We generated cloned murine oviduct epithelial cell lines without viral or chemical transformation to investigate the role of the TLRs and cytosolic nucleotide binding site/leucine-rich repeat proteins Nod1 and Nod2 in epithelial responses to Chlamydia muridarum infection. RT-PCR assays detected mRNA for TLR2 (TLRs 1 and 6), TLR3, and TLR5. No mRNA was detected for TLRs 4, 7, 8, and 9. Messenger RNAs for Nod1 and Nod2 were present in the epithelial cell lines. Oviduct epithelial cell lines infected with C. muridarum or exposed to the TLR2 agonist peptidoglycan secreted representative acute phase cytokines IL-6 and GM-CSF in a MyD88-dependent fashion. Infected epithelial cell lines secreted the immunomodulatory cytokine IFN-β, even though C. muridarum does not have a clear pathogen-associated molecular pattern (PAMP) for triggering IFN-β transcription. The oviduct epithelial lines did not secrete IFN-β in response to the TLR2 agonist peptidoglycan or to the TLR3 agonist poly(I:C). Our data identify TLR2 as the principal TLR responsible for secretion of acute phase cytokines by C. muridarum-infected oviduct epithelial cell lines. The pattern recognition molecule responsible for infection-induced IFN-β secretion by oviduct epithelial cells remains to be determined.
IL-4 Inhibits the Expression of Mouse Formyl Peptide Receptor 2, a Receptor for Amyloid β1–42, in TNF-α-Activated Microglia
Authors: Iribarren Pablo , Chen Keqiang , Hu Jinyue , Zhang Xia , Gong Wanghua , Wang Ji Ming 
Published: April 2014

Abstract
Microglia are phagocytic cells in the CNS and actively participate in proinflammatory responses in neurodegenerative diseases. We have previously shown that TNF-α up-regulated the expression of formyl peptide receptor 2 (mFPR2) in mouse microglial cells, resulting in increased chemotactic responses of such cells to mFPR2 agonists, including amyloid β1–42 (Aβ42), a critical pathogenic agent in Alzheimer’s disease. In the present study, we found that IL-4, a Th2-type cytokine, markedly inhibited TNF-α-induced expression of mFPR2 in microglial cells by attenuating activation of ERK and p38 MAPK as well as NF-κB. The effect of IL-4 was not dependent on Stat6 but rather required the protein phosphatase 2A (PP2A) as demonstrated by the capacity of PP2A small interfering RNA to reverse the effect of IL-4 in TNF-α-activated microglia. Since both IL-4 and TNF-α are produced in the CNS under pathophysiological conditions, our results suggest that IL-4 may play an important role in the maintenance of CNS homeostasis by limiting microglial activation by proinflammatory stimulants.
Effects of MHC and Gender on Lupus-Like Autoimmunity inNba2Congenic Mice
Authors: Gubbels Melanie R. , Jørgensen Trine N. , Metzger Troy E. , Menze Katherine , Steele Heather , Flannery Shannon A. , Rozzo Stephen J. , Kotzin Brian L. 
Published: April 2014

AbstractThe lupus-like disease that develops in hybrids of NZB and NZW mice is genetically complex, involving both MHC- and non-MHC-encoded genes. Studies in this model have indicated that the H2d/z MHC type, compared with H2d/d or H2z/z, is critical for disease development. C57BL/6 (B6) mice (H2b/b) congenic for NZB autoimmunity 2 (Nba2), a NZB-derived susceptibility locus on distal chromosome 1, produce autoantibodies to nuclear Ags, but do not develop kidney disease. Crossing B6.Nba2 to NZW results in H2b/z F1 offspring that develop severe lupus nephritis. Despite the importance of H2z in past studies, we found no enhancement of autoantibody production or nephritis in H2b/z vs H2b/b B6.Nba2 mice, and inheritance of H2z/z markedly suppressed autoantibody production. (B6.Nba2 × NZW)F1 mice, compared with MHC-matched B6.Nba2 mice, produced higher levels of IgG autoantibodies to chromatin, but not to dsDNA. Although progressive renal damage with proteinuria only occurred in F1 mice, kidneys of some B6.Nba2 mice showed similar extensive IgG and C3 deposition. We also studied male and female B6.Nba2 and F1 mice with different MHC combinations to determine whether increased susceptibility to lupus among females was also expressed within the context of the Nba2 locus. Regardless of MHC or the presence of NZW genes, females produced higher levels of antinuclear autoantibodies, and female F1 mice developed severe proteinuria with higher frequencies. Together, these studies help to clarify particular genetic and sex-specific influences on the pathogenesis of lupus nephritis.
Features of Medullary Thymic Epithelium Implicate Postnatal Development in Maintaining Epithelial Heterogeneity and Tissue-Restricted Antigen Expression
Authors: Gillard Geoffrey O. , Farr Andrew G. 
Published: April 2014

Abstract
Although putative thymic epithelial progenitor cells have been identified, the developmental potential of these cells, the extent of medullary thymic epithelium (mTEC) heterogeneity, and the mechanisms that mediate the expression of a wide range of peripheral tissue-restricted Ags (TRAs) by mTECs remain poorly defined. Here we have defined several basic properties of the mTEC population that refine our understanding of these cells and impose important constraints for any model of mTEC differentiation and function. We report here that mTECs from adult mice are mitotically active, implying continual turnover, differentiation, and replacement of mTEC populations in the adult thymus. The mTEC population in adult thymus expresses transcription factors implicated in the maintenance of multipotential progenitor cell populations, suggesting that epithelial progenitors in the adult thymus may not be restricted to a thymic fate. mTECs also express multiple transcription factors required for the specification of multiple epithelial lineages in peripheral tissues. Thus, expression of some TRAs by mTECs may represent coordinated gene expression that reflects alternate programs of epithelial differentiation among mTECs. Analysis of TRA expression in individual and small pools of sorted mTECs show that mTECs are highly heterogeneous; each individual mTEC expresses a limited spectrum of TRAs, and the frequency of mTECs that express any individual TRA is quite low (&gt;0.4–2%). Collectively, these findings suggest that the differentiation of mTECs can involve some of the developmental programs used by other epithelial lineages and that expression of some TRAs by mTECs may reflect this activity.
Regulatory T Cell Responses Develop in Parallel to Th Responses and Control the Magnitude and Phenotype of the Th Effector Populatio
Authors: Taylor Justin J. , Mohrs Markus , Pearce Edward J. 
Published: April 2014

AbstractHost survival during schistosomiasis requires the development of a tightly regulated and Th2-polarized immune response against parasite egg Ags. In this system, Th1 response suppression has been thought to be enforced through the production of IL-10 by Th2 cells and natural T regulatory (Treg) cells. By comparing Th responses in schistosome egg-injected mice that lack IL-10, IL-4, and/or Treg cells, we have been able to build a detailed picture of the relative contributions of Treg cells, Th2 cells, and IL-10 to regulation of the egg-induced response. Our data indicate that eggs induce a marked Treg cell response, evident as the extensive proliferation of Foxp3+ cells that is proportionally as great as the response occurring within the Th compartment. Furthermore, we show that Treg cells prevent Th1 response development and limit the magnitude of the Th2 response. Although Treg cells are able to produce IL-10 after egg injection, we found no evidence for a role for IL-10 in Treg-mediated suppression of Th cell responses, nor did we find evidence for an inhibitory effect of Th2 cells on Th1 response development. Thus, the magnitude and phenotype of the egg-induced effector Th response are controlled by a parallel response within the Treg population.
Human Metapneumovirus Elicits Weak IFN-γ Memory Responses Compared with Respiratory Syncytial Virus
Authors: Douville Renée N. , Bastien Nathalie , Li Yan , Pochard Pierre , Simons F. Estelle R. , HayGlass Kent T. 
Published: April 2014

Abstract
Human metapneumovirus (MPV) is a recently discovered pathogen that causes repeated lower respiratory tract infections beginning in infancy. The prevalence, nature and control of human regulatory responses to MPV are unknown. In this study, we develop and optimize systems to evaluate MPV-driven cytokine responses. Using primary culture of human PBMC from previously exposed adults, MPV-stimulated responses were directly compared with those elicited by genetically and clinically similar respiratory syncytial virus (RSV). Intense IL-6 production was evident following culture with infectious or inactivated RSV. MPV elicited IL-6 responses averaging 3.5-fold more intense (p &lt; 0.001). Virus-dependent expression of IL-11, IL-12, IFN-α, and other innate immunity cytokines differed little between MPV and RSV. When examining adaptive immunity, RSV infection elicited strong IFN-γ responses by all 60 adults. In marked contrast, MPV elicited IFN-γ in a lower frequency of adults (p &lt; 0.002) and at levels averaging 6-fold weaker (p &lt; 0.001). These Th1-dominated responses were CD4, CD8, CD86 dependent, and were closely paralleled by strong virus-driven IL-10 and CCL5 production. For MPV and RSV, Th2 (IL-5, IL-13) responses were sporadic, occurring in 10–40% of the population. Thus, MPV and RSV, although both ubiquitous and leading to very high levels of infection, seroconversion, and clinically similar presentation in the population, evoke distinct innate and adaptive T cell-dependent cytokine responses. Although both viruses yield Th1-dominated responses with strong IL-10 and CCL5 production, MPV restimulation results in markedly more robust IL-6 and significantly weaker adaptive cytokine responses, in both prevalence and intensity, than does RSV.
Differential Effects of IL-27 on Human B Cell Subsets
Authors: Larousserie Frédérique , Charlot Pascaline , Bardel Emilie , Froger Josy , Kastelein Robert A. , Devergne Odile 
Published: April 2014

Abstract
IL-27 is a novel heterodimeric cytokine of the IL-12 family that plays an important role in the regulation of T cell responses. Its role on human B cells has not been previously studied. In this study, we show that both chains of the IL-27 receptor complex, IL-27R and gp130, are constitutively expressed at the surface of naive and memory human tonsillar B cells, and are induced on germinal center B cells following CD40 stimulation. In naive B cells, IL-27 induced strong STAT1 and STAT3 phosphorylation, whereas it induced moderate STAT1 and low STAT3 activation in memory B cells. IL-27 induced T-bet expression in naive and memory B cells stimulated by CD40 or surface Ig engagement, but induced significant IL-12Rβ2 surface expression in anti-Ig-stimulated naive B cells only. In anti-Ig-stimulated naive or memory B cells, IL-27 also induced CD54, CD86, and CD95 surface expression. In addition, IL-27 increased proliferation of anti-Ig-activated naive B cells and of anti-CD40-activated naive and germinal center B cells, but not of CD40-activated memory B cells. These data indicate that the B cell response to IL-27 is modulated during B cell differentiation and varies depending on the mode of B cell activation.
CD2BP1 Modulates CD2-Dependent T Cell Activation via Linkage to Protein Tyrosine Phosphatase (PTP)-PEST
Authors: Yang Hailin , Reinherz Ellis L. 
Published: April 2014

Abstract
Human CD2 regulates T cell activation and adhesion via mechanisms yet to be fully understood. This study focuses on CD2BP1, a CD2 cytoplasmic tail-binding protein preferentially expressed in hematopoetic cells. Structural and functional analyses suggest that CD2BP1 acts as a scaffold protein, participating in regulation of the actin cytoskeleton. In this study, using a murine Ag-specific primary T cell transduction system to assess CD69, IL-2, and IFN-γ expression, we provide evidence that CD2BP1 directly and negatively impacts T cell activation via isolated CD2 triggering or TCR stimulation dependent on coordinate CD2 engagement. Disruption of protein tyrosine phosphatase-PEST and/or CD2BP1 association with the CD2 signalsome rescues T cells from the inhibitory effect of CD2 crosslinking. The overexpression of CD2BP1 selectively attenuates phospholipase Cγ1, ERK1/2, and p38 phosphorylation without abrogating CD2-independent TCR stimulation. This study provides new insight on the regulation of T cell activation and may have implications for autoimmune processes known to be associated with CD2BP1 mutations.
Further Differentiation of Murine Double-Positive Thymocytes Is Inhibited in Adenosine Deaminase-Deficient Murine Fetal Thymic Organ Culture
Authors: Van De Wiele C. Justin , Joachims Michelle L. , Fesler Amy M. , Vaughn James G. , Blackburn Michael R. , McGee Stephanie T. , Thompson Linda F. 
Published: April 2014

Abstract
Murine fetal thymic organ culture (FTOC) was used to investigate the mechanism by which a lack of adenosine deaminase (ADA) leads to a failure of T cell production in the thymus. We previously showed that T cell development was inhibited beginning at the CD4−CD8−CD25+CD44low stage in ADA-deficient FTOC initiated at day 15 of gestation when essentially all thymocytes are CD4−CD8−. In the present study, we asked whether thymocytes at later stages of differentiation would also be sensitive to ADA inhibition by initiating FTOC when substantial numbers of CD4+CD8+ thymocytes were already present. dATP was highly elevated in ADA-deficient cultures, and the recovery of αβ TCR+ thymocytes was inhibited by 94%, indicating that the later stages of thymocyte differentiation are also dependent upon ADA. ADA-deficient cultures were partially rescued by the pan-caspase inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone or by the use of apoptotic protease-activating factor-1-deficient mice. Rescue was even more dramatic, with 60- to &gt;200-fold increases in the numbers of CD4+CD8+ cells, when FTOC were performed with an inhibitor of adenosine kinase, the major thymic deoxyadenosine phosphorylating enzyme, or with bcl-2 transgenic mice. dATP levels were normalized by treatment with either carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone or an adenosine kinase inhibitor, but not in cultures with fetal thymuses from bcl-2 transgenic mice. These data suggest that ADA deficiency leads to the induction of mitochondria-dependent apoptosis as a consequence of the accumulation of dATP derived from thymocytes failing the positive/negative selection checkpoint.
Class I and III Phosphatidylinositol 3′-Kinase Play Distinct Roles in TLR Signaling Pathway
Authors: Kuo Cheng-Chin , Lin Wen-Ting , Liang Chi-Ming , Liang Shu-Mei 
Published: April 2014

Abstract
PI3K involvement has been implicated in the TLR signal pathway. However, the precise roles of the different classes of PI3K in the pathway remain elusive. In this study, we have explored the functions of class I and class III PI3K in the TLR signal pathway using specific kinase mutants and PI3K lipid products. Our results reveal that class III PI3K specifically regulates CpG oligodeoxynucleotide (ODN)-induced cytokine and NO production as well as NF-κB activation, whereas class I PI3K regulates both CpG ODN- and LPS-induced IL-12 production and NF-κB activation. Additional studies of CpG ODN uptake with flow cytometric analysis show that class III PI3K, but not class I, regulates cellular CpG ODN uptake. Furthermore, experiments with MyD88-overexpressing fibroblast cells transfected with dominant-negative mutants of PI3K demonstrate that class III PI3K regulates CpG ODN-mediated signaling upstream of MyD88, while class I PI3K regulation is downstream of MyD88. These results suggest that class I and class III PI3K play distinct roles in not only the uptake of CpG ODN, but also responses elicited by CpG ODN and LPS.
CD4+ T Regulatory Cell Induction and Function in Transplant Recipients after CD154 Blockade Is TLR4 Independent
Authors: Zhai Yuan , Meng Lingzhong , Gao Feng , Wang Yue , Busuttil Ronald W. , Kupiec-Weglinski Jerzy W. 
Published: April 2014

Abstract
Although the role of CD4+ T regulatory cells (Treg) in transplantation tolerance has been established, putative mechanisms of Treg induction and function in vivo remain unclear. TLR4 signaling has been implicated in the regulation of CD4+CD25+ Treg functions recently. In this study, we first examined the role of recipient TLR4 in the acquisition of operational CD4+ Treg following CD154 blockade in a murine cardiac transplant model. Then, we determined whether TLR4 activation in allograft tolerant recipients would reverse alloimmune suppression mediated by CD4+ Treg. We document that donor-specific immune tolerance was readily induced in TLR4-deficient recipients by a single dose of anti-CD154 mAb, similar to wild-type counterparts. The function and phenotype of CD4+ Treg in both wild-type and TLR4 knockout long-term hosts was demonstrated by a series of depletion experiments examining their ability to suppress the rejection of secondary donor-type test skin grafts and to inhibit alloreactive CD8+ T cell activation in vivo. Furthermore, TLR4 activation in tolerant recipients following exogenous LPS infusion in conjunction with donor-type skin graft challenge, failed to break Treg-mediated immune suppression. In conclusion, our data reveals a distinctive property of CD4+ Treg in tolerant allograft recipients, whose induction and function are independent of TLR4 signaling.