bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Approach to the Blocking of Alloreactive T Cell-Mediated Graft-versus-Host Disease by In Vivo Administration of Anti-CXCR3 Neutralizing Antibody
Authors: He Shan , Cao Qi , Qiu Yuhua , Mi Jianqing , Zhang Jingwu Z. , Jin Min , Ge Hailiang , Emerson Stephen G. , Zhang Yi , Zhang Yanyun 
Published: April 2014

Abstract
Chemokines and chemokine receptors play critical roles in directing the migration of alloreactive donor T cells into graft-vs-host disease (GVHD) target organs. However, blockade of GVHD by antagonist Ab against chemokine receptors remains an elusive goal. Using a mouse model of human GVHD, we demonstrate that in vivo administration of anti-CXCR3 Ab for 21 days (long-term), but not for 7 days (short-term), inhibits alloreactive CD8+ T cell-mediated GVHD. During a graft-vs-host reaction, infused donor CD8+ T cells generate two subsets of potent inducers of GVHD: CXCR3+CD8+ and CXCR3−CD8+ T cells. Compared with CXCR3+CD8+ T cells, CXCR3−CD8+ T cells produce less granzyme B, Fas ligand, IFN-γ, and TNF-α. Interestingly, stimulation with either dendritic cells or IL-2 induces a dynamic conversion between CXCR3+CD8+ and CXCR3−CD8+ T cells. Short-term anti-CXCR3 Ab treatment inhibits only CXCR3+CD8+ T cell-mediated GVHD, but not the disease induced by CXCR3−CD8+ T cells. Prolonged in vivo administration of anti-CXCR3 Ab significantly reduces the infiltration of alloreactive CD8+ T cells into GVHD target organs and inhibits GVHD mediated by either CXCR3+CD8+ or CXCR3−CD8+ T cells. Thus, we have established a novel and effective approach with the potential to give rise to new clinical methods for preventing and treating GVHD after allogeneic hematopoietic stem cell transplantation.
The Immunosuppressor Mycophenolic Acid Kills Activated Lymphocytes by Inducing a Nonclassical Actin-Dependent Necrotic Signal
Authors: Chaigne-Delalande Benjamin , Guidicelli Gwendaline , Couzi Lionel , Merville Pierre , Mahfouf Walid , Bouchet Stéphane , Molimard Mathieu , Pinson Benoit , Moreau Jean-François , Legembre Patrick 
Published: April 2014

Abstract
Mycophenolate mofetil (MMF) is an immunosuppressive agent used in transplantation. Over the last decade, MMF has also emerged as an alternative therapeutic regimen for autoimmune diseases, mainly for patients refractory to other therapies. The active compound of MMF, mycophenolic acid (MPA), depletes the intracellular pool of guanosine tri-phosphate through inosine monophosphate dehydrogenase blockade. The molecular mechanism involved in the elimination of T and B lymphocytes upon inhibition of inosine monophosphate dehydrogenase remains elusive. In this study, we showed that in contrast to the immunosuppressors azathioprine, cyclosporin A, and tacrolimus, MPA killed lymphocytes through the activation of a caspase-independent necrotic signal. Furthermore, the MPA-mediated necrotic signal relied on the transmission of a novel intracellular signal involving Rho-GTPase Cdc42 activity and actin polymerization. In addition to its medical interest, this study sheds light on a novel and atypical molecular mechanism leading to necrotic cell death.
Signals and Sequences That Control CD28 Localization to the Central Region of the Immunological Synapse
Authors: Sanchez-Lockhart Mariano , Graf Beth , Miller Jim 
Published: April 2014

AbstractDuring T cell interaction with APC, CD28 is recruited to the central region (cSMAC) of the immunological synapse. CD28-mediated signaling through PI3K results in the recruitment of protein kinase C-θ (PKCθ) to the cSMAC, activation of NF-κB, and up-regulation of IL-2 transcription. However, the mechanism that mediates CD28 localization to the cSMAC and the functional consequences of CD28 localization to the cSMAC are not understood. In this report, we show that CD28 recruitment and persistence at the immunological synapse requires TCR signals and CD80 engagement. Addition of mAb to either MHC class II or CD80 results in the rapid displacement of CD28 from the immunological synapse. Ligand binding is not sufficient for CD28 localization to the immunological synapse, as truncation of the cytosolic tail of CD28 disrupts synapse localization without effecting the ability of CD28 to bind CD80. Furthermore, a single point mutation in the CD28 cytosolic tail (tyrosine 188) interferes with the ability of CD28 to preferentially accumulate at the cSMAC. PKCθ distribution at the immunological synapse mirrors the distribution of tyrosine 188-mutated CD28, indicating that CD28 drives the localization of PKCθ even when CD28 is not localized to the cSMAC. Mutation of tyrosine 188 also results in diminished activation of NF-κB, suggesting that CD28-mediated localization of PKCθ to the cSMAC is important for efficient signal transduction. These data reinforce the importance of the interplay of signals between TCR and CD28 and suggest that CD28 signaling through PCKθ may be mediated through localization to the cSMAC region of the immunological synapse.
Abnormal Regulatory and Effector T Cell Function Predispose to Autoimmunity following Xenogeneic Thymic Transplantation
Authors: Fudaba Yasuhiro , Onoe Takashi , Chittenden Meredith , Shimizu Akira , Shaffer Juanita M. , Bronson Roderick , Sykes Megan 
Published: April 2014

AbstractPorcine thymus grafts support robust murine and human thymopoiesis, generating a diverse T cell repertoire that is deleted of donor and host-reactive cells, achieving specific xenograft tolerance. Positive selection is mediated exclusively by the xenogeneic thymic MHC. Although thymectomized, T cell-depleted normal mice usually remain healthy following xenogeneic thymic transplantation, thymus-grafted congenitally athymic mice frequently develop multiorgan autoimmunity. We investigated the etiology of this syndrome by adoptively transferring lymphocyte populations from fetal pig thymus-grafted BALB/c nude mice to secondary BALB/c nude recipients. Fetal pig thymus-grafted nude mice generated normal numbers of CD25+Foxp3+CD4 T cells, but these cells lacked the capacity to block autoimmunity. Moreover, thymocytes and peripheral CD4+CD25− cells from fetal pig thymus-grafted nude mice, but not those from normal mice, induced autoimmunity in nude recipients. Injection of thymic epithelial cells from normal BALB/c mice into fetal pig thymus grafts reduced autoimmunity and enhanced regulatory function of splenocytes. Our data implicate abnormalities in postthymic maturation, expansion, and/or survival of T cells positively selected by a xenogeneic MHC, as well as incomplete intrathymic deletion of thymocytes recognizing host tissue-specific Ags, in autoimmune pathogenesis. Regulatory cell function is enhanced and negative selection of host-specific thymocytes may potentially also be improved by coimplantation of recipient thymic epithelial cells in the thymus xenograft.
Galectin-9 Increases Tim-3+ Dendritic Cells and CD8+ T Cells and Enhances Antitumor Immunity via Galectin-9-Tim-3 Interactions
Authors: Nagahara Keiko , Arikawa Tomohiro , Oomizu Souichi , Kontani Keiichi , Nobumoto Atsuya , Tateno Hiroaki , Watanabe Kota , Niki Toshiro , Katoh Shigeki , Miyake Minoru , Nagahata Syun-Ichiro , Hirabayashi Jun , Kuchroo Vijay K. , Yamauchi Akira , Hirashima Mitsuomi 
Published: April 2014

Abstract
A Tim-3 ligand, galectin-9 (Gal-9), modulates various functions of innate and adaptive immune responses. In this study, we demonstrate that Gal-9 prolongs the survival of Meth-A tumor-bearing mice in a dose- and time-dependent manner. Although Gal-9 did not prolong the survival of tumor-bearing nude mice, transfer of naive spleen cells restored a prolonged Gal-9-induced survival in nude mice, indicating possible involvement of T cell-mediated immune responses in Gal-9-mediated antitumor activity. Gal-9 administration increased the number of IFN-γ-producing Tim-3+ CD8+ T cells with enhanced granzyme B and perforin expression, although it induced CD4+ T cell apoptosis. It simultaneously increased the number of Tim-3+CD86+ mature dendritic cells (DCs) in vivo and in vitro. Coculture of CD8+ T cells with DCs from Gal-9-treated mice increased the number of IFN-γ producing cells and IFN-γ production. Depletion of Tim-3+ DCs from DCs of Gal-9-treated tumor-bearing mice decreased the number of IFN-γ-producing CD8+ T cells. Such DC activity was significantly abrogated by Tim-3-Ig, suggesting that Gal-9 potentiates CD8+ T cell-mediated antitumor immunity via Gal-9-Tim-3 interactions between DCs and CD8+ T cells.
An In Vitro System to Model the Establishment and Reactivation of HIV-1 Latency
Authors: Marini Alessandra , Harper Jill M. , Romerio Fabio 
Published: April 2014

Abstract
HIV-1 establishes latency primarily by infecting activated CD4+ T cells that later return to quiescence as memory cells. Latency allows HIV-1 to evade immune responses and to persist during antiretroviral therapy, which represents an important problem in clinical practice. The lack of a valid cellular model to study HIV-1 latency has hindered advances in the understanding of its biology. In this study, we attempted to model HIV-1 latency using human primary CD4+ T cells infected in vitro with HIV-1 after activation with Ag-loaded dendritic cells and then brought back to quiescence through a resting phase in the presence of IL-7. During the resting phase, expression of cellular activation markers disappeared and cell proliferation and viral replication ceased, but resumed following restimulation of rested cells with Ag or mAbs directed to CD3/CD28. In addition, higher cell death rates were observed in HIV-1-infected than uninfected cultures during secondary but not primary stimulation. Thus, this system may allow us to study the biology of HIV-1 latency, as well as the mechanisms of CD4+ T cell death following HIV-1 reactivation.
The Magnitude of Thymic Output Is Genetically Determined through Controlled Intrathymic Precursor T Cell Proliferation
Authors: Dulude Gaël , Cheynier Remi , Gauchat Dominique , Abdallah Ali , Kettaf Nadia , Sékaly Rafick-Pierre , Gratton Sophie 
Published: April 2014

Abstract
The thymus plays a crucial role in providing the immune system with naive T cells showing a diverse TCR repertoire. Whereas the diversity of thymic production is mainly ensured by TCR rearrangement at both the TRA and TRB loci, the number of cells reaching the double-positive differentiation stage defines the extent of thymic output. A quantitative analysis of TCR excision circles (TREC; signal-joint TRECs and DJβTRECs) produced at different stages of thymopoiesis was performed in nine laboratory mouse strains. The results clearly demonstrate that the magnitude of thymic output is directly proportional to the extent of proliferation in the double-negative 4 thymocyte subset. Strikingly, intrathymic precursor T cell proliferation was found to be strain dependent, thus suggesting a genetic regulation of thymic output. The inherited character of thymic output was further confirmed by the transmission of the phenotype in a recessive fashion in F1 progeny of the different parental strains. Our results provide the first demonstration of the genetic regulation of thymic output.
TCR β-Chain Sharing in Human CD8+ T Cell Responses to Cytomegalovirus and EBV
Authors: Venturi Vanessa , Chin Hui Yee , Asher Tedi E. , Ladell Kristin , Scheinberg Phillip , Bornstein Ethan , van Bockel David , Kelleher Anthony D. , Douek Daniel C. , Price David A. , Davenport Miles P. 
Published: April 2014

Abstract
The CD8+ TCR repertoires specific for many immunogenic epitopes of CMV and EBV are dominated by a few TCR clonotypes and involve public TCRs that are shared between many MHC-matched individuals. In previous studies, we demonstrated that the observed sharing of epitope-specific TCRβ chains between individuals is strongly associated with TCRβ production frequency, and that a process of convergent recombination facilitates the more efficient production of some TCRβ sequences. In this study, we analyzed a total of 2836 TCRβ sequences from 23 CMV-infected and 10 EBV-infected individuals to investigate the factors that influence the sharing of TCRβ sequences in the CD8+ T cell responses to two immunodominant HLA-A*0201-restricted epitopes from these viruses. The most shared TCRβ amino acid sequences were found to have two features that indicate efficient TCRβ production, as follows: 1) they required fewer nucleotide additions, and 2) they were encoded by a greater variety of nucleotide sequences. We used simulations of random V(D)J recombination to demonstrate that the in silico TCRβ production frequency was predictive of the extent to which both TCRβ nucleotide and amino acid sequences were shared in vivo. These results suggest that TCRβ production frequency plays an important role in the interindividual sharing of TCRβ sequences within CD8+ T cell responses specific for CMV and EBV.
Mucosal Clearance of Capsule-Expressing Bacteria Requires Both TLR and Nucleotide-Binding Oligomerization Domain 1 Signaling
Authors: Zola Tracey A. , Lysenko Elena S. , Weiser Jeffrey N. 
Published: April 2014

Abstract
Expression of capsular polysaccharide by bacterial pathogens is associated with increased resistance to host clearance mechanisms, in particular by evading opsonization and uptake by professional phagocytes. The potential for rapid progression of disease caused by encapsulated bacteria points to the importance of innate immunity at the mucosal surface where infection is initiated. Using a murine model of nasopharyngeal colonization, host immune components that contribute to the mucosal clearance of capsule-expressing bacteria were investigated. Clearance of encapsulated Haemophilus influenzae (Hi) required both TLR and nucleotide-binding oligomerization domain (NOD) signaling pathways, whereas individual deficiencies in each of these signaling cascades did not affect clearance of nonencapsulated strains. Moreover, clearance of Hi-expressing capsular polysaccharide required the recruitment of neutrophils to the site of infection, and ex vivo phagocytic bacterial killing required expression of the NOD1 signaling pathway. Conversely, redundancies within these innate immune pathways of non-neutrophil cells were sufficient to promote mucosal clearance of nonencapsulated Hi. Our findings reveal a role for NOD1 in protection from encapsulated pathogens. In addition, this study provides an example of a microbial virulence determinant that alters the requirements for host signaling to provide effective protection.
Interaction between RANTES Promoter Variant and CCR5Δ32 Favors Recovery from Hepatitis B
Authors: Thio Chloe L. , Astemborski Jacquie , Thomas Rasmi , Mosbruger Timothy , Witt Mallory D. , Goedert James J. , Hoots Keith , Winkler Cherie , Thomas David L. , Carrington Mary 
Published: April 2014

Abstract
Recovery from acute hepatitis B virus (HBV) infection occurs in 95% of adult-acquired infections. A 32-bp deletion in CCR5 (CCR5Δ32), which encodes for a nonfunctional receptor, increases the likelihood of recovery. Using 181 subjects with persistent HBV infection and 316 who had recovered, we tested the hypothesis that an epistatic interaction between functional polymorphisms in RANTES (a CCR5 ligand) and CCR5 impacts recovery. Specific models designed to assess individual contributions of compound genotypes demonstrated that the only combination associated with recovery from an HBV infection was RANTES −403A with CCR5Δ32 (odds ratio 0.36, p = 0.02). Because the phenotypic consequence of −403A is reported to be higher levels of RANTES, we propose a model in which excess RANTES in combination with low CCR5 favors recovery from an HBV infection, which will require validation through functional testing.
Aging Mice Exhibit a Functional Defect in Mucosal Dendritic Cell Response against an Intracellular Pathogen
Authors: Moretto Magali M. , Lawlor Elizabeth M. , Khan Imtiaz A. 
Published: April 2014

AbstractDown-regulation of the immune response in aging individuals puts this population at a potential risk against infectious agents. In-depth studies conducted in humans and mouse models have demonstrated that with increasing age, the T cell immune response against pathogens is compromised and response to vaccinations is subdued. In the present study, using a mouse model, we demonstrate that older animals exhibit greater susceptibility to Encephalitozoon cuniculi infection, and their ability to evoke an Ag-specific T cell response at the gut mucosal site is reduced. The dampening of T cell immunity was due to the defective priming by the dendritic cells (DC) isolated from the mucosal tissues of aging animals. When primed with DC from younger mice, T cells from older animals were able to exhibit an optimal Ag-specific response. The functional defect in DC from older mice can be attributed to a large extent to reduced IL-15 message in these cells, which can be reversed by addition of exogenous IL-15 to the cultures. IL-15 treatment led to optimal expression of costimulatory molecules (CD80 and CD86) on the surface of older DC and restored their ability to prime a T cell response against the pathogen. To our knowledge, this is the first report which demonstrates the inability of the DC population from aging animals to prime a robust T cell response against an infectious agent. Moreover, the observation that IL-15 treatment can reverse this defect has far-reaching implications in developing strategies to increase vaccination protocols for aging populations.
Dysregulation of CXCR3 Signaling due to CXCL10 Deficiency Impairs the Antiviral Response to Herpes Simplex Virus 1 Infection
Authors: Wuest Todd R. , Carr Daniel J. J. 
Published: April 2014

Abstract
The chemokine, CXCL10, chemotactic for NK cells, activated T cells, and dendritic cells is highly expressed during viral infections, including HSV-1. The importance of this chemokine to the control of HSV-1 infection was tested using mice deficient in CXCL10 (CXCL10−/−). Following corneal infection, HSV-1 viral titers were elevated in the nervous system of CXCL10−/− mice, which correlated with defects in leukocyte recruitment including dendritic cells, NK cells, and HSV-1-specific CD8+ T cells to the brain stem. In the absence of NK cells and HSV-1-specific CD8+ T cells in wild-type (WT) or CXCL10−/− mice, similar levels of virus were recovered in the nervous system, suggesting these cells are responsible for the observed defects in the control of viral replication in CXCL10−/− mice. Leukocyte mobilization was also compared between WT, CXCL10−/−, and mice deficient in the only known receptor for CXCL10, CXCR3 (CXCR3 −/−). NK cell mobilization was comparably reduced in both CXCL10−/− and CXCR3−/− mice relative to WT animals. However, the reduction in mobilization of HSV-1-specific CD8+ T cells in CXCL10−/− was not observed in CXCR3−/− mice following HSV-1 infection. The defect was not the result of an alternative receptor for CXCL10, as Ag-specific CD8+ T cell recruitment was not reduced in mice which were deficient in both CXCL10 and CXCR3. Thus, CXCL10 deficiency results in reduced mobilization of HSV-1-specific CD8+ T cells as a result of dysregulation of CXCR3 signaling.
Anti-Inflammatory Effects of Sphingosine Kinase Modulation in Inflammatory Arthritis
Authors: Lai Wen-Qi , Irwan Anastasia Windy , Goh Hong Heng , Howe Hwee Siew , Yu David T. , Valle-Oñate Rafael , McInnes Iain B. , Melendez Alirio J. , Leung Bernard P. 
Published: April 2014

Abstract
Sphingosine kinase (SphK) is a key enzyme in the sphingolipid metabolic pathway responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P). SphK/S1P play a critical role in angiogenesis, inflammation, and various pathologic conditions. Recently, S1P1 receptor was found to be expressed in rheumatoid arthritis (RA) synovium, and S1P signaling via S1P1 enhances synoviocyte proliferation, COX-2 expression, and prostaglandin E2 production. Here, we examined the role of SphK/S1P in RA using a potent SphK inhibitor, N,N-dimethylsphingosine (DMS), and a molecular approach against one of its isoenzymes, SphK1. We observed that levels of S1P in the synovial fluid of RA patients were significantly higher than those of osteoarthritis patients. Additionally, DMS significantly reduced the levels of TNF-α, IL-6, IL-1β, MCP-1, and MMP-9 in cell-contact assays using both Jurkat-U937 cells and RA PBMCs. In a murine collagen-induced arthritis model, i.p. administration of DMS significantly inhibited disease severity and reduced articular inflammation and joint destruction. Treatment of DMS also down-regulated serum levels IL-6, TNF-α, IFN-γ, S1P, and IgG1 and IgG2a anti-collagen Ab. Furthermore, DMS-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Moreover, similar reduction in incidence and disease activity was observed in mice treated with SphK1 knock-down via small interfering RNA approach. Together, these results demonstrate SphK modulation may provide a novel approach in treating chronic autoimmune conditions such as RA by inhibiting the release of pro-inflammatory cytokines.
Infiltrated Neutrophils Acquire Novel Chemokine Receptor Expression and Chemokine Responsiveness in Chronic Inflammatory Lung Diseases
Authors: Hartl Dominik , Krauss-Etschmann Susanne , Koller Barbara , Hordijk Peter L. , Kuijpers Taco W. , Hoffmann Florian , Hector Andreas , Eber Ernst , Marcos Veronica , Bittmann Iris , Eickelberg Oliver , Griese Matthias , Roos Dirk 
Published: April 2014

AbstractVarious inflammatory diseases are characterized by tissue infiltration of neutrophils. Chemokines recruit and activate leukocytes, but neutrophils are traditionally known to be restricted in their chemokine receptor (CR) expression repertoire. Neutrophils undergo phenotypic and functional changes under inflammatory conditions, but the mechanisms regulating CR expression of infiltrated neutrophils at sites of chronic inflammation are poorly defined. Here we show that infiltrated neutrophils from patients with chronic inflammatory lung diseases and rheumatoid arthritis highly express CR on their surface that are absent or only marginally expressed on circulating neutrophils, i.e., CCR1, CCR2, CCR3, CCR5, CXCR3, and CXCR4, as measured by flow cytometry, immunohistochemistry, and confocal microscopy. The induction of CR surface expression on infiltrated neutrophils was functionally relevant, because receptor activation by chemokine ligands ex vivo modulated neutrophil effector functions such as respiratory burst activity and bacterial killing. In vitro studies with isolated neutrophils demonstrated that the surface expression of CR was differentially induced in a cytokine-mediated, protein synthesis-dependent manner (CCR1, CCR3), through Toll-like (CXCR3) or NOD2 (CCR5) receptor engagement, through neutrophil apoptosis (CCR5, CXCR4), and/or via mobilization of intracellular CD63+ granules (CXCR3). CR activation on infiltrated neutrophils may represent a key mechanism by which the local inflammatory microenvironment fine-tunes neutrophil effector functions in situ. Since the up-regulation of CR was exclusively found on infiltrated neutrophils at inflammatory sites in situ, the targeting of these G protein-coupled receptors may have the potential to site-specifically target neutrophilic inflammation.