bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+CD25+ Foxp3+ Regulatory T Cells Protect against T Cell-Mediated Fulminant Hepatitis in a TGF-β-Dependent Manner in Mice
Authors: Wei Hua-Xing , Chuang Ya-Hui , Li Bofeng , Wei Haiming , Sun Rui , Moritoki Yuki , Gershwin M. Eric , Lian Zhe-Xiong , Tian Zhigang 
Published: April 2014

Abstract
Regulatory T cells (Tregs), which are characterized by expression of CD4, CD25, and Foxp3, play a crucial role in the control of immune responses to both self and non-self Ags. To date, there are only limited data on their role in physiological and pathological hepatic immune responses. In this study, we examined the role of hepatic Tregs in immune-mediated liver injury by using the murine Con A-induced hepatitis model. Con A treatment was associated with an increased number of Foxp3+ Tregs in liver but not in spleen. Moreover, the expression levels of Foxp3, CTLA-4, glucocorticoid-induced TNF receptor, as well as the frequency of CD103 of Tregs were increased after Con A injection, being significantly higher in liver than in spleen. Depleting CD25+ cells aggravated liver injury, whereas adoptively transferring CD25+ cells or Tregs reduced liver injury in Con A-treated recipients. Con A treatment induced elevated serum levels and hepatic mononuclear mRNA expressions of TGF-β, which were reduced by Tregs depletion. In addition, anti-TGF-β mAbs blocked the suppressive function of Tregs from Con A-treated mice in vitro. Finally, TGF-β receptor II dominant-negative mice, whose T cells express a dominant negative form of TGFβRII and therefore cannot respond to TGF-β, had a higher mortality rate and severer liver injury than normal mice injected with the same dose of Con A. These results indicate that CD4+CD25+ Tregs play an important role in limiting the liver injury in Con A-induced hepatitis via a TGF-β-dependent mechanism.
A New Mechanism for Inhalational Priming: IL-4 Bypasses Innate Immune Signals
Authors: Dittrich Anna M. , Chen Hui-Chen , Xu Lan , Ranney Patricia , Connolly Sean , Yarovinsky Timur O. , Bottomly H. Kim 
Published: April 2014

AbstractSignaling via innate immune mechanisms is considered pivotal for T cell-mediated responses to inhaled Ags. Furthermore, Th2 cells specific for one inhaled Ag can facilitate priming of naive T cells to unrelated new inhaled Ags, a process we call “Th2 collateral priming”. Interestingly, our previous studies showed that collateral priming is independent of signals via the innate immune system but depends on IL-4 secretion by CD4+ T cells. We thus hypothesized that IL-4 can bypass the need for signals via the innate immune system, considered essential for pulmonary priming. Indeed, we were able to show that IL-4 bypasses the requirement for TLR4- and MyD88-mediated signaling for responses to new allergens. Furthermore, we characterized the mechanisms by which IL-4 primes for new inhaled allergens: “IL-4-dependent pulmonary priming” relies on IL-4 receptor expression on hematopoietic cells and structural cells. Transfer experiments indicate that within the hematopoietic compartment both T cells and dendritic cells need to express the IL-4 receptor. Finally, we were able to show that IL-4 induces recruitment and maturation of myeloid dendritic cells in vivo and increases T cell recruitment to the draining lymph nodes. Our findings bring new mechanistic knowledge to the phenomenon of polysensitization and primary sensitization in asthma.
Dual Regulatory Roles of Phosphatidylinositol 3-Kinase in IFN Signaling
Authors: Kaur Surinder , Sassano Antonella , Joseph Ajith M. , Majchrzak-Kita Beata , Eklund Elizabeth A. , Verma Amit , Brachmann Saskia M. , Fish Eleanor N. , Platanias Leonidas C. 
Published: April 2014

Abstract
PI3K is activated by the type I and II IFN receptors, but its precise role in the generation of IFN responses is not well understood. In the present study we used embryonic fibroblasts from mice with targeted disruption of the genes encoding for both the p85α and p85β regulatory subunits of PI3′-kinase (p85α−/−β−/−) to precisely define the role of PI3K in the control of IFN-induced biological responses. Our data demonstrate that PI3K plays dual regulatory roles in the induction of IFN responses by controlling both IFN-α- and IFN-γ-dependent transcriptional regulation of IFN-sensitive genes and simultaneously regulating the subsequent initiation of mRNA translation for such genes. These processes include the Isg15, Cxcl10, and/or Irf7 genes, whose functions are important in the generation of the biological effects of IFNs. Consistent with this, the induction of IFN antiviral responses is defective in double p85α/p85β knockout cells. Thus, integration of signals via PI3K is a critical event during engagement of the IFN receptors that complements both the transcriptional activity of Jak-STAT pathways and controls initiation of mRNA translation.
Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells
Authors: Kimura Takao , Mogi Chihiro , Tomura Hideaki , Kuwabara Atsushi , Im Doon-Soon , Sato Koichi , Kurose Hitoshi , Murakami Masami , Okajima Fumikazu 
Published: April 2014

Abstract
Changes in plasma lipoprotein profiles, especially low levels of high-density lipoprotein (HDL), are a common biomarker for several inflammatory and immune diseases, including atherosclerosis and rheumatoid arthritis. We examined the effect of simvastatin on HDL-induced anti-inflammatory actions. HDL and sphingosine 1-phosphate (S1P), a bioactive lipid component of the lipoprotein, inhibited TNF α-induced expression of VCAM-1, which was associated with NO synthase (NOS) activation, in human umbilical venous endothelial cells. The HDL- but not S1P-induced anti-inflammatory actions were enhanced by a prior treatment of the cells with simvastatin in a manner sensitive to mevalonic acid. Simvastatin stimulated the expression of scavenger receptor class B type I (SR-BI) and endothelial NOS. As for S1P receptors, however, the statin inhibited the expression of S1P3 receptor mRNA but caused no detectable change in S1P1 receptor expression. The reconstituted HDL, a stimulator of SR-BI, mimicked HDL actions in a simvastatin-sensitive manner. The HDL- and reconstituted HDL-induced actions were blocked by small interfering RNA specific to SR-BI regardless of simvastatin treatment. The statin-induced expression of SR-BI was attenuated by constitutively active RhoA and small interfering RNA specific to peroxisome proliferator-activated receptor-α. Administration of simvastatin in vivo stimulated endothelial SR-BI expression, which was accompanied by the inhibition of the ex vivo monocyte adhesion in aortas from TNF α-injected mice. In conclusion, simvastatin induces endothelial SR-BI expression through a RhoA- and peroxisome proliferator-activated receptor-α-dependent mechanism, thereby enhancing the HDL-induced activation of NOS and the inhibition of adhesion molecule expression.
Intestinal Macrophage/Epithelial Cell-Derived CCL11/Eotaxin-1 Mediates Eosinophil Recruitment and Function in Pediatric Ulcerative Colitis
Authors: Ahrens Richard , Waddell Amanda , Seidu Luqman , Blanchard Carine , Carey Rebecca , Forbes Elizabeth , Lampinen Maria , Wilson Tara , Cohen Elizabeth , Stringer Keith , Ballard Edgar , Munitz Ariel , Xu Huan , Lee Nancy , Lee James J. , Rothenberg Marc E. , Denson Lee , Hogan Simon P. 
Published: April 2014

AbstractClinical studies have demonstrated a link between the eosinophil-selective chemokines, eotaxins (eotaxin-1/CCL11 and eotaxin-2/CCL24), eosinophils, and the inflammatory bowel diseases, Crohn’s disease and ulcerative colitis (UC). However, the cellular source and individual contribution of the eotaxins to colonic eosinophilic accumulation in inflammatory bowel diseases remain unclear. In this study we demonstrate, by gene array and quantitative PCR, elevated levels of eotaxin-1 mRNA in the rectosigmoid colon of pediatric UC patients. We show that elevated levels of eotaxin-1 mRNA positively correlated with rectosigmoid eosinophil numbers. Further, colonic eosinophils appeared to be degranulating, and the levels positively correlated with disease severity. Using the dextran sodium sulfate (DSS)-induced intestinal epithelial injury model, we show that DSS treatment of mice strongly induced colonic eotaxin-1 and eotaxin-2 expression and eosinophil levels. Analysis of eosinophil-deficient mice defined an effector role for eosinophils in disease pathology. DSS treatment of eotaxin-2−/− and eotaxin-1/2−/− mice demonstrated that eosinophil recruitment was dependent on eotaxin-1. In situ and immunofluorescence analysis-identified eotaxin-1 expression was restricted to intestinal F4/80+CD11b+ macrophages in DSS-induced epithelial injury and to CD68+ intestinal macrophages and the basolateral compartment of intestinal epithelial cells in pediatric UC. These data demonstrate that intestinal macrophage and epithelial cell-derived eotaxin-1 plays a critical role in the regulation of eosinophil recruitment in colonic eosinophilic disease such as pediatric UC and provides a basis for targeting the eosinophil/eotaxin-1 axis in UC.
Multiple Glycines in TCR α-Chains Determine Clonally Diverse Nature of Human T Cell Memory to Influenza A Virus
Authors: Naumov Yuri N. , Naumova Elena N. , Yassai Maryam B. , Kota Kalyani , Welsh Raymond M. , Selin Liisa K. 
Published: April 2014

AbstractDetailed assessment of how the structural properties of T cell receptors affect clonal repertoires of Ag-specific cells is a prerequisite for a better understanding of human antiviral immunity. Herein we examine the α TCR repertoires of CD8 T cells reactive against the influenza A viral epitope M158–66, restricted by HLA-A2.1. Using molecular cloning, we systematically studied the impact of α-chain usage in the formation of T cell memory and revealed that M158–66-specific, clonally diverse VB19 T cells express α-chains encoded by multiple AV genes with different CDR3 sizes. A unique feature of these α TCRs was the presence of CDR3 fitting to an AGA(Gn)GG-like amino acid motif. This pattern was consistent over time and among different individuals. Further molecular assessment of human CD4+CD8− and CD4−CD8+ thymocytes led to the conclusion that the poly-Gly/Ala runs in CDR3α were a property of immune, but not naive, repertoires and could be attributed to influenza exposure. Repertoires of T cell memory are discussed in the context of clonal diversity, where poly-Gly/Ala runs in the CDR3 of α- and β-chains might provide high levels of TCR flexibility during Ag recognition while gene-encoded CDR1 and CDR2 contribute to the fine specificity of the TCR-peptide MHC interaction.
Low Expression of the IL-23/Th17 Pathway in Atopic Dermatitis Compared to Psoriasis
Authors: Guttman-Yassky Emma , Lowes Michelle A. , Fuentes-Duculan Judilyn , Zaba Lisa C. , Cardinale Irma , Nograles Kristine E. , Khatcherian Artemis , Novitskaya Inna , Carucci John A. , Bergman Reuven , Krueger James G. 
Published: April 2014

Abstract
The classical Th1/Th2 paradigm previously defining atopic dermatitis (AD) and psoriasis has recently been challenged with the discovery of Th17 T cells that synthesize IL-17 and IL-22. Although it is becoming evident that many Th1 diseases including psoriasis have a strong IL-17 signal, the importance of Th17 T cells in AD is still unclear. We examined and compared skin biopsies from AD and psoriasis patients by gene microarray, RT-PCR, immunohistochemistry, and immunofluorescence. We found a reduced genomic expression of IL-23, IL-17, and IFN-γ in AD compared with psoriasis. To define the effects of IL-17 and IL-22 on keratinocytes, we performed gene array studies with cytokine-treated keratinocytes. We found lipocalin 2 and numerous other innate defense genes to be selectively induced in keratinocytes by IL-17. IFN-γ had no effect on antimicrobial gene-expression in keratinocytes. In AD skin lesions, protein and mRNA expression of lipocalin 2 and other innate defense genes (hBD2, elafin, LL37) were reduced compared with psoriasis. Although AD has been framed by the Th1/Th2 paradigm as a Th2 polar disease, we present evidence that the IL-23/Th17 axis is largely absent, perhaps accounting for recurrent skin infections in this disease.
Cutting Edge: TheIdd3Genetic Interval Determines Regulatory T Cell Function through CD11b+CD11c− APC
Authors: Anderson Ana C. , Chandwaskar Rucha , Lee David H. , Kuchroo Vijay K. 
Published: April 2014

AbstractThe Idd3 genetic interval confers protection against multiple autoimmune diseases, including type 1 diabetes and experimental autoimmune encephalomyelitis. The favored candidate gene in this interval is Il2, which is polymorphic between susceptible and resistant strains of mice. IL-2 regulates the growth/death of effector T cells as well as the generation/maintenance of regulatory T cells (Tregs), and recent studies have shown that NOD.Idd3 Tregs are more suppressive than their NOD counterparts. We have further dissected the mechanisms underlying the differential suppression by NOD and NOD.Idd3 Tregs and find that it is determined by CD11b+CD11c− APCs. Thus, contrary to what might be expected, our data suggest that the differential suppressive activity of NOD and NOD.Idd3 Tregs is not due to an effect of the Idd3 genetic interval on T cells but rather is due to differences in the APC compartment.
Increased Osteopontin Expression in Dendritic Cells Amplifies IL-17 Production by CD4+ T Cells in Experimental Autoimmune Encephalomyelitis and in Multiple Sclerosis
Authors: Murugaiyan Gopal , Mittal Akanksha , Weiner Howard L. 
Published: April 2014

Abstract
Osteopontin (Opn) is a broadly expressed pleiotropic cytokine, and has been shown to play an important role in various autoimmune diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). It is reported that Opn exacerbates EAE by skewing T cell differentiation toward IFN-γ-producing Th1 cells. Opn expression in dendritic cells (DCs) and its role in IL-17 induction from T cells during EAE or MS are unknown. We found that during EAE, Opn expression is elevated in DCs both in the periphery and in the CNS. There was increased expression of Opn receptor on T cells, and Opn induced IL-17 production by CD4+ T cells via the β3 integrin receptor and Opn inhibited IL-10 production via the CD44 receptor. Furthermore, anti-Opn treatment reduced clinical severity of EAE by reducing IL-17 production. Anti-Opn was also effective in reducing clinical severity of EAE when given after the appearance of clinical symptoms. Analogous to EAE, in subjects with MS, we found increased expression of Opn in DCs and increased expression of the Opn receptors CD44, β3, and αv on T cells. Furthermore, Opn-stimulated CD4+ T cells from MS patients produced significantly higher amounts of IL-17. Our results demonstrate a role for DC-produced Opn both in EAE and MS that is linked to the production of IL-17.
NK Cells Induce Apoptosis in Tubular Epithelial Cells and Contribute to Renal Ischemia-Reperfusion Injury
Authors: Zhang Zhu-Xu , Wang Shuang , Huang Xuyan , Min Wei-Ping , Sun Hongtao , Liu Weihua , Garcia Bertha , Jevnikar Anthony M. 
Published: April 2014

Abstract
Renal ischemia-reperfusion injury (IRI) can result in acute renal failure with mortality rates of 50% in severe cases. NK cells are important participants in early-stage innate immune responses. However, their role in renal tubular epithelial cell (TEC) injury in IRI is currently unknown. Our data indicate that NK cells can kill syngeneic TEC in vitro. Apoptotic death of TEC in vitro is associated with TEC expression of the NK cell ligand Rae-1, as well as NKG2D on NK cells. In vivo following IRI, there was increased expression of Rae-1 on TEC. FACS analyses of kidney cell preparations indicated a quantitative increase in NKG2D-bearing NK cells within the kidney following IRI. NK cell depletion in wild-type C57BL/6 mice was protective, while adoptive transfer of NK cells worsened injury in NK, T, and B cell-null Rag2−/−γc−/− mice with IRI. NK cell-mediated kidney injury was perforin (PFN)-dependent as PFN−/− NK cells had minimal capacity to kill TEC in vitro compared with NK cells from wild-type, FasL-deficient (gld), or IFN-γ−/− mice. Taken together, these results demonstrate for the first time that NK cells can directly kill TEC and that NK cells contribute substantially to kidney IRI. NK cell killing may represent an important underrecognized mechanism of kidney injury in diverse forms of inflammation, including transplantation.
Inhibition of the Alloimmune Response through the Generation of Regulatory T Cells by a MHC Class II-Derived Peptide
Authors: Zang Weiping , Lin Marvin , Kalache Safa , Zhang Nan , Krüger Bernd , Waaga-Gasser Ana Maria , Grimm Martin , Hancock Wayne , Heeger Peter , Schröppel Bernd , Murphy Barbara 
Published: April 2014

AbstractWe have previously shown that HLA-DQA1, a peptide derived from a highly conserved region of MHC class II, prevents alloreactive T cell priming and effector function in vivo, although underlying mechanisms are obscure. In this study, we demonstrate that 28% of mice treated with HLA-DQA1 combined with low-dose rapamycin achieved permanent engraftment of fully MHC-disparate islet allografts and significantly prolonged survival in the remaining animals (log rank, p &lt; 0.001). Immunohistologic examination of the grafts from HLA-DQA1/rapamycin-treated animals revealed up-regulated expression of TGF-ß and FoxP3. In vivo administration of blocking anti-TGF-ß or depleting anti-CD25 mAb augmented T cell alloimmunity and prevented the long-term engraft induced by HLA-DQA1. In vitro experiments further showed that HLA-DQA1 induced differentiation of CD4+ T cells into CD4+CD25+FoxP3+ regulatory T cells. Together, these data provide the first demonstration that HLA-DQA1, a MHC class II-derived peptide, can prolong allograft survival via a TGF-β and regulatory T cell-dependent mechanisms.
Resolution of Unique Sca-1highc-Kit− Lymphoid-Biased Progenitors in Adult Bone Marrow
Authors: Harman Benjamin C. , Northrup Daniel L. , Allman David 
Published: April 2014

Abstract
We have identified a distinctive lymphoid-restricted progenitor population in adult mouse bone marrow based on a unique c-Kit−Sca-1highFlt3+ AA4+ surface phenotype. These cells are highly lymphoid biased and rapidly generate B and T cells after adoptive transfer. However, whereas previously described lymphoid progenitors such as common lymphoid progenitors express TdT and relatively high levels of RAG2, and are enriched for cells with an active V(D)J recombinase, Flt3+ AA4+ cells within the c-Kit−Sca-1high bone marrow fraction are TdT−, are RAG2low, and do not display evidence for ongoing or past recombinase activity. Furthermore, unlike common lymphoid progenitors that readily generate B cells upon stimulation with IL-7, c-Kit−Sca-1highFlt3+ precursors do not express abundant levels of the IL-7R, and require costimulation with Flt3 ligand and IL-7 to generate B cells in vitro. Moreover, these findings suggest that hematopoietic stem cells in adults generate an array of lymphoid-biased progenitor populations characterized by distinct gene expression and cytokine response profiles.
Retinal Pigment Epithelium-Derived CTLA-2α Induces TGFβ-Producing T Regulatory Cells
Authors: Sugita Sunao , Horie Shintaro , Nakamura Orie , Futagami Yuri , Takase Hiroshi , Keino Hiroshi , Aburatani Hiroyuki , Katunuma Nobuhiko , Ishidoh Kazumi , Yamamoto Yoshimi , Mochizuki Manabu 
Published: April 2014

Abstract
T cells that encounter ocular pigment epithelium in vitro are inhibited from undergoing TCR-triggered activation, and instead acquire the capacity to suppress the activation of bystander T cells. Because retinal pigment epithelial (RPE) cells suppress T cell activation by releasing soluble inhibitory factors, we studied whether soluble factors also promote the generation of T regulatory (Treg) cells. We found that RPE converted CD4+ T cells into Treg cells by producing and secreting CTLA-2α, a cathepsin L (CathL) inhibitor. Mouse rCTLA-2α converted CD4+ T cells into Treg cells in vitro, and CTLA-2α small interfering RNA-transfected RPE cells failed to induce the Treg generation. RPE CTLA-2α induced CD4+CD25+Foxp3+ Treg cells that produced TGFβ in vitro. Moreover, CTLA-2α produced by RPE cells inhibited CathL activity in the T cells, and losing CathL activity led to differentiation to Treg cells in some populations of CD4+ T cells. In addition, T cells in the presence of CathL inhibitor increased the expression of Foxp3. The CTLA-2α effect on Treg cell induction occurred through TGFβ signaling, because CTLA-2α promoted activation of TGFβ in the eye. These results show that immunosuppressive factors derived from RPE cells participate in T cell suppression. The results are compatible with the hypothesis that the eye-derived Treg cells acquire functions that participate in the establishment of immune tolerance in the posterior segment of the eye.
Targeting the Neonatal Fc Receptor for Antigen Delivery Using Engineered Fc Fragments
Authors: Mi Wentao , Wanjie Sylvia , Lo Su-Tang , Gan Zhuo , Pickl-Herk Beatrix , Ober Raimund J. , Ward E. Sally 
Published: April 2014

AbstractThe development of approaches for Ag delivery to the appropriate subcellular compartments of APCs and the optimization of Ag persistence are both of central relevance for the induction of protective immunity or tolerance. The expression of the neonatal Fc receptor, FcRn, in APCs and its localization to the endosomal system suggest that it might serve as a target for Ag delivery using engineered Fc fragment-epitope fusions. The impact of FcRn binding characteristics of an Fc fragment on in vivo persistence allows this property to also be modulated. We have therefore generated recombinant Fc (mouse IgG1-derived) fusions containing the N-terminal epitope of myelin basic protein that is associated with experimental autoimmune encephalomyelitis in H-2u mice. The Fc fragments have distinct binding properties for FcRn that result in differences in intracellular trafficking and in vivo half-lives, allowing the impact of these characteristics on CD4+ T cell responses to be evaluated. To dissect the relative roles of FcRn and the “classical” FcγRs in Ag delivery, analogous aglycosylated Fc-MBP fusions have been generated. We show that engineered Fc fragments with increased affinities for FcRn at pH 6.0–7.4 are more effective in delivering Ag to FcRn-expressing APCs in vitro relative to their lower affinity counterparts. However, higher affinity of the FcRn-Fc interaction at near neutral pH results in decreased in vivo persistence. The trade-off between improved FcRn targeting efficiency and lower half-life becomes apparent during analyses of T cell proliferative responses in mice, particularly when Fc-MBP fusions with both FcRn and FcγR binding activity are used.