bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tc1 and Tc2 Effector Cell Therapy Elicit Long-Term Tumor Immunity by Contrasting Mechanisms That Result in Complementary Endogenous Type 1 Antitumor Responses
Authors: Dobrzanski Mark J. , Reome Joyce B. , Hollenbaugh Joseph A. , Dutton Richard W. 
Published: April 2014

AbstractCytolytic CD8+ effector cells fall into two subpopulations based on cytokine secretion. Type 1 CD8+ T cells (Tc1) secrete IFN-γ, whereas type 2 CD8+ T cells (Tc2) secrete IL-4 and IL-5. Both effector cell subpopulations display predominantly perforin-dependent cytolysis in vitro. Using an OVA-transfected B16 lung metastases model, we show that adoptively transferred OVA-specific Tc1 and Tc2 cells induce considerable suppression, but not cure, of pulmonary metastases. However, long-term tumor immunity prolonged survival times indefinitely and was evident by resistance to lethal tumor rechallenge. At early stages after therapy, protection by Tc2 and Tc1 effector cells were dependent in part on effector cell-derived IL-4, IL-5, and IFN-γ, respectively. Whereas effector cell-derived perforin was not necessary. Over time the numbers of both donor cells diminished to low, yet still detectable, levels. Concomitantly, Tc1 and Tc2 effector cell therapies potentiated endogenous recipient-derived antitumor responses by inducing 1) local T cell-derived chemokines associated with type 1-like immune responses; 2) elevated levels of recipient-derived OVA tetramer-positive CD8 memory T cells that were CD44high, CD122+, and Ly6Chigh that predominantly produced IFN-γ and TNF-α; and 3) heightened numbers of activated recipient-derived Th1 and Tc1 T cell subpopulations expressing CD25+, CD69+, and CD95+ cell surface activation markers. Moreover, both Tc2 and Tc1 effector cell therapies were dependent in part on recipient-derived IFN-γ and TNF-α for long-term survival and protection. Collectively, Tc1 and Tc2 effector cell immunotherapy mediate long-term tumor immunity by different mechanisms that subsequently potentiate endogenous recipient-derived type 1 antitumor responses.
Chimeric Donor Cells Play an Active Role in Both Induction and Maintenance Phases of Transplantation Tolerance Induced by Mixed Chimerism
Authors: Kanamoto Akira , Maki Takashi 
Published: April 2014

Abstract
Donor hemopoietic cell engraftment is considered to be an indicator of allograft tolerance. We depleted chimerism with cells specifically presensitized to the bone marrow donor to investigate its role in mixed chimera-induced tolerance. Three experimental models were used: model A, B10.A cells presensitized to B6 (a anti-b cells) were injected into (B6 × D2)F1 → B10.A mixed chimeras grafted with DBA/2 skin; model B, anti-B6 presensitized cells prepared in DBA/2 → B10.A mixed chimeras, thus unresponsive to DBA/2 (a anti-b/tol-d cells), were injected into (B6 × D2)F1 → B10.A mixed chimeras grafted with DBA/2 skin; and model C, (BALB/c × B6)F1 cells presensitized to CBA (d/b anti-k cells) were injected into (B6 × CBA)F1 → BALB/c mixed chimeras grafted with B6 skin. Skin was grafted on day 30. Injection of each cell type before skin grafting abolished hemopoietic cell engraftment and prevented allograft acceptance. Injection of presensitized cells after skin grafting resulted in different outcomes depending on the models. In model A, injection of a anti-b cells completely depleted chimerism and caused allograft rejection. In model B, injection of a anti-b/tol-d cells markedly reduced, but did not deplete, peripheral chimerism and maintained skin allograft survival. In model C, d/b anti-k cells reduced chimerism to the background levels but failed to cause graft rejection, probably due to persistence of injected cells which share MHC with skin grafts. Together, the results show that presence of chimeric donor cells is essential in both the induction and maintenance phases of tolerance induced by mixed chimerism.
Zwitterionic Polysaccharides Stimulate T Cells with No Preferential Vβ Usage and Promote Anergy, Resulting in Protection against Experimental Abscess Formation
Authors: Stingele Francesca , Corthésy Blaise , Kusy Nicole , Porcelli Steven A. , Kasper Dennis L. , Tzianabos Arthur O. 
Published: April 2014

AbstractZwitterionic polysaccharides (Zps) from pathogenic bacteria, such as Bacteroides fragilis, are virulence factors responsible for abscess formation associated with intra-abdominal sepsis. The underlying cellular mechanism for abscess formation requires T cell activation. Conversely, abscess formation can be prevented by prophylactic s.c. injection of purified Zps alone, a process also dependent on T cells. Hence, the modulatory role of T cells in abscess formation was investigated. We show that Zps interact directly with T cells with fast association/dissociation kinetics. Vβ repertoire analysis using RT-PCR demonstrates that Zps have broad Vβ usage. Zps-specific hybridomas responded to a variety of other Zps, but not to a nonzwitterionic polysaccharide, indicating cross-reactivity between different Zps. Furthermore, Zps-reactive T cell hybridomas could effectively transfer protection against abscess formation. Analysis of the proliferative capacity of T cells recovered from Zps-treated animals revealed that these T cells are anergic to subsequent stimulation by the different Zps or to alloantigens in an MLR. This anergic response was relieved by addition of IL-2. Taken together, the data show that this class of polysaccharides interacts directly with T cells in a nonbiased manner to elicit an IL-2-dependent anergic response that confers protection against abscess formation.
Effect of Chronic Viral Infection on Epitope Selection, Cytokine Production, and Surface Phenotype of CD8 T Cells and the Role of IFN-γ Receptor in Immune Regulation
Authors: Tewari Kavita , Sacha Jonah , Gao Xiaoyan , Suresh M. 
Published: April 2014

AbstractRegulation of CD8 T cell responses in chronic viral infections is not well understood. In this study, we have compared the CD8 T cell responses to immunodominant and subdominant epitopes during an acute and a chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. The epitope hierarchy of the primary CD8 T cell response was similar in acute and chronic LCMV infections. However, strikingly, the epitope hierarchy of the primary CD8 T cell response was conserved in the T cell memory only in an acute but not in a chronic LCMV infection. Interestingly, in an acute infection, increasing the viral dose caused significant changes in the epitope hierarchy of the LCMV-specific memory CD8 T cell pool, with no effect on the primary CD8 T cell response. Functional and phenotypic analyses revealed that exposure of CD8 T cells to extended periods of antigenic stimulation could lead to long-term defects in cytokine production and alteration in expression of cell surface L-selectin (CD62L). Whereas expression of CD44 was minimally altered, a greater proportion of LCMV-specific memory CD8 T cells were CD62Llow in mice that have recovered from a chronic LCMV infection, compared with acutely infected mice. Mechanistic studies showed that IFN-γR deficiency altered the epitope hierarchy of the pool of LCMV-specific memory CD8 T cells without significantly affecting the immunodominance of the primary CD8 T cell response in an acute infection. Taken together, these findings should further our understanding about the regulation of T cell responses in human chronic viral infections.
Expression of Dual TCR on DO11.10 T Cells Allows for Ovalbumin-Induced Oral Tolerance to Prevent T Cell-Mediated Colitis Directed against Unrelated Enteric Bacterial Antigens
Authors: Zhou Pengfei , Borojevic Rajka , Streutker Cathy , Snider Denis , Liang Hong , Croitoru Kenneth 
Published: April 2014

AbstractThe triggering Ag for inflammatory bowel disease and animal models of colitis is not known, but may include gut flora. Feeding OVA to DO11.10 mice with OVA-specific transgenic (Tg) TCR generates Ag-specific immunoregulatory CD4+ T cells (Treg) cells. We examined the ability of oral Ag-induced Treg cells to suppress T cell-mediated colitis in mice. SCID-bg mice given DO11.10 CD4+CD45RBhigh T cells developed colitis, and cotransferring DO11.10 CD45RBlowCD4+ T cells prevented CD4+CD45RBhigh T cell-induced colitis in the absence of OVA. The induction and prevention of disease by DO11.10 CD4+ T cell subsets were associated with an increase in endogenous TCRα chain expression on Tg T cells. Feeding OVA to SCID-bg mice reconstituted with DO11.10 CD4+CD45RBhigh attenuated the colitis in association with increased TGF-β and IL-10 secretion, and decreased proliferative responses to both OVA and cecal bacteria Ag. OVA feeding also attenuated colitis in SCID-bg mice reconstituted with a mix of BALB/c and DO11.10 CD45RBhigh T cells, suggesting that OVA-induced Treg cells suppressed BALB/c effector cells. The expression of endogenous non-Tg TCR allowed for DO11.10-derived T cells to respond to enteric flora Ag. Furthermore, feeding OVA-induced Treg cells prevented colitis by inducing tolerance in both OVA-reactive and non-OVA-reactive T cells and by inducing Ag-nonspecific Treg cells. Such a mechanism might allow for Ag-nonspecific modulation of intestinal inflammation in inflammatory bowel disease.
Deceptive Multilineage Reconstitution Analysis of Mice Transplanted with Hemopoietic Stem Cells, and Implications for Assessment of Stem Cell Numbers and Lineage Potentials
Authors: Bryder David , Sasaki Yutaka , Borge Ole Johan , Jacobsen Sten-Eirik W. 
Published: April 2014

Abstract
Hemopoietic stem cells (HSC) are identified through their unique ability, at the single cell level, to long-term reconstitute all blood cell lineages. Sustained myeloid reconstitution is considered the hallmark of HSC, because myeloid progenitors and their progeny have very short half-lives. Here we demonstrate that the established practice of relying on RB6-8C5 as a myeloid specific Ab can result in overestimation of HSC frequencies because the RB6-8C5 Ab also detects Ags expressed on a sizeable population of CD3+CD8+ T cells, constitutively as well as following transplantation. Likewise, a high fraction of mice transplanted with limiting numbers of ex vivo expanded Lin−Sca+kit+CD34− HSC show long-term RB6-8C5+CD3+ (lymphoid) but no RB6-8C5+CD3− (myeloid) reconstitution. Most noteworthy, the use of RB6-8C5 as a myeloid specific Ab can be deceptive by implicating the existence of lineage-restricted HSC capable of long-term reconstituting the myeloid and T, but not B, cell lineage. Because cross-lineage expression of “lineage-specific” markers is unlikely to be unique to the blood system, claims of unexpected cell fates should be substantiated not only by acquisition of lineage-specific markers, but also absence of markers of other lineages normally derived from the investigated stem cells.
Intravenous Injection of a Lentiviral Vector Encoding NY-ESO-1 Induces an Effective CTL Response
Authors: Palmowski Michael J. , Lopes Luciene , Ikeda Yasuhiro , Salio Mariolina , Cerundolo Vincenzo , Collins Mary K. 
Published: April 2014

Abstract
Lentiviral vectors can efficiently transduce a variety of nondividing cells, including APCs. We assessed the immunogenicity of a lentiviral vector encoding the melanoma Ag NY-ESO-1 in HLA-A2 transgenic mice. Direct i.v. injection of NY-ESO-1 lentivirus induced NY-ESO-1157–165-specific CD8+ cells, detected ex vivo with an A2/H-2Kb chimeric class I tetramer. These NY-ESO-1157–165-specific CD8+ cells could be expanded by boosting with an NY-ESO-1 vaccinia virus and could kill NY-ESO-1157–165 peptide-pulsed targets in vivo. Such direct lentiviral vector injection was similar in potency to the injection of in vitro-transduced dendritic cells (DC). In addition, human monocyte-derived DC transduced by the NY-ESO-1 lentivirus stimulated an NY-ESO-1157–165-specific specific CTL clone. These data suggest that direct lentiviral transduction of DC in vivo might provide a powerful immunotherapeutic strategy.
Ontogeny of γδ T Cells in Humans
Authors: De Rosa Stephen C. , Andrus James P. , Perfetto Stephen P. , Mantovani John J. , Herzenberg Leonard A. , Herzenberg Leonore A. , Roederer Mario 
Published: April 2014

Abstract
T cell receptors consist either of an α-chain combined with a β-chain or a γ-chain combined with a δ-chain. αβ T cells constitute the majority of T cells in human blood throughout life. Flow cytometric analyses presented in this study, which focus on the representation of the developmental (naive and memory) subsets of γδ T cells, show by function and phenotype that this lineage contains both naive and memory cells. In addition, we show that the representation of naive T cells is higher among αβ than γδ T cells in adults and that the low frequency of naive γδ T cells in adults reflects ontological differences between the two major γδ subsets, which are distinguished by expression of Vδ1 vs Vδ2 δ-chains. Vδ1 cells, which mirror αβ cells with respect to naive representation, predominate during fetal and early life, but represent the minority of γδ cells in healthy adults. In contrast, Vδ2 cells, which constitute the majority of adult γδ cells, show lower frequencies of naive cells than Vδ1 early in life and show vanishingly small naive frequencies in adults. In essence, nearly all naive Vδ2 cells disappear from blood by 1 year of life. Importantly, even in children less than 1 year old, most of the nonnaive Vδ2 cells stain for perforin and produce IFN-γ after short-term in vitro stimulation. This represents the earliest immunological maturation of any lymphocyte compartment in humans and most likely indicates the importance of these cells in controlling pathology due to common environmental challenges.
Critical Role of OX40 in CD28 and CD154-Independent Rejection
Authors: Demirci Gülçin , Amanullah Farhana , Kewalaramani Reshma , Yagita Hideo , Strom Terry B. , Sayegh Mohamed H. , Li Xian Chang 
Published: April 2014

AbstractBlocking both CD28 and CD154 costimulatory pathways can induce transplant tolerance in some, but not all, transplant models. Under stringent conditions, however, this protocol often completely fails to block allograft rejection. The precise nature of such CD28/CD154 blockade-resistant rejection is largely unknown. In the present study we developed a new model in which both CD28 and CD154, two conventional T cell costimulatory molecules, are genetically knocked out (i.e., CD28/CD154 double-knockout (DKO) mice) and used this model to examine the role of novel costimulatory molecule-inducible costimulator (ICOS), OX40, 4-1BB, and CD27 in mediating CD28/CD154-independent rejection. We found that CD28/CD154 DKO mice vigorously rejected fully MHC-mismatched DBA/2 skin allografts (mean survival time, 12 days; n = 6) compared with the wild-type controls (mean survival time, 8 days; n = 7). OX40 costimulation is critically important in skin allograft rejection in this model, as blocking the OX40/OX40 ligand pathway, but not the ICOS/ICOS ligand, 4-1BB/4-1BBL, or CD27/CD70 pathway, markedly prolonged skin allograft survival in CD28/CD154 DKO mice. The critical role of OX40 costimulation in CD28/CD154-independent rejection is further confirmed in wild-type C57BL/6 mice, as blocking the OX40/OX40 ligand pathway in combination with CD28/CD154 blockade induced long term skin allograft survival (&gt;100 days; n = 5). Our study revealed a key cellular mechanism of rejection and identified OX40 as a critical alternative costimulatory molecule in CD28/CD154-independent rejection.
IFN-α Sensitizes Human Umbilical Vein Endothelial Cells to Apoptosis Induced by Double-Stranded RNA
Authors: Kaiser William J. , Kaufman Jonathan L. , Offermann Margaret K. 
Published: April 2014

Abstract
The ability of endothelial cells to mount an efficient antiviral response is important in restricting viral dissemination and eliminating viral infection from the endothelium and surrounding tissues. We demonstrate that dsRNA, a molecular signature of viral infection, induced apoptosis in HUVEC, and priming with IFN-α shortened the time between when dsRNA was encountered and when apoptosis was initiated. IFN-α priming induced higher levels of mRNA for dsRNA-activated protein kinase, 2′5′-oligoadenylate synthetase, and Toll-like receptor 3, transcripts that encode dsRNA-responsive proteins. dsRNA induced activation of dsRNA-activated protein kinase and nuclear translocation of transcription factors RelA and IFN regulatory factor-3 in IFN-α-primed HUVECs before the activation of intrinsic and extrinsic apoptotic pathways. These changes did not occur in the absence of dsRNA, and apoptosis resulting from incubation with dsRNA occurred much later when cells were not primed with IFN-α. The entire population of IFN-α-primed HUVECs underwent nuclear translocation of RelA and IFN regulatory factor-3 in response to dsRNA, whereas less than one-half of the population responded with apoptosis. When IFN-α-primed HUVECs were coincubated with dsRNA and proteasome inhibitors, all HUVECs were rendered susceptible to dsRNA-induced apoptosis. These studies provide evidence that many endothelial cells that are alerted to the risk of infection by IFN-α would undergo apoptosis sooner in response to dsRNA than non-IFN-α-primed cells, and this would enhance the likelihood of eliminating infected cells prior to the production of progeny virions.
Impaired Production of Proinflammatory Cytokines and Host Resistance to Acute Infection withTrypanosoma cruziin Mice Lacking Functional Myeloid Differentiation Factor 88
Authors: Campos Marco A. , Closel Meire , Valente Eneida P. , Cardoso Jarbas E. , Akira Shizuo , Alvarez-Leite Jacqueline I. , Ropert Catherine , Gazzinelli Ricardo T. 
Published: April 2014

AbstractStudies performed in vitro suggest that activation of Toll-like receptors (TLRs) by parasite-derived molecules may initiate inflammatory responses and host innate defense mechanisms against Trypanosoma cruzi. Here, we evaluated the impact of TLR2 and myeloid differentiation factor 88 (MyD88) deficiencies in host resistance to infection with T. cruzi. Our results show that macrophages derived from TLR2 −/− and MyD88−/− mice are less responsive to GPI-mucin derived from T. cruzi trypomastigotes and parasites. In contrast, the same cells from TLR2−/− still produce TNF-α, IL-12, and reactive nitrogen intermediates (RNI) upon exposure to live T. cruzi trypomastigotes. Consistently, we show that TLR2−/− mice mount a robust proinflammatory cytokine response as well as RNI production during the acute phase of infection with T. cruzi parasites. Further, deletion of the functional TLR2 gene had no major impact on parasitemia nor on mortality. In contrast, the MyD88−/− mice had a diminished cytokine response and RNI production upon acute infection with T. cruzi. More importantly, we show that MyD88−/− mice are more susceptible to infection with T. cruzi as indicated by the higher parasitemia and accelerated mortality, as compared with the wild-type mice. Together, our results indicate that T. cruzi parasites elicit an alternative inflammatory pathway independent of TLR2. This pathway is partially dependent on MyD88 and necessary for mounting optimal inflammatory and RNI responses that control T. cruzi replication during the early stages of infection.
Dendritic Cells Pulsed with Live and DeadLegionella pneumophilaElicit Distinct Immune Responses
Authors: Kikuchi Toshiaki , Kobayashi Takao , Gomi Kazunori , Suzuki Takuji , Tokue Yutaka , Watanabe Akira , Nukiwa Toshihiro 
Published: April 2014

AbstractLegionella pneumophila is the causative pathogen of Legionnaires’ disease, which is characterized by severe pneumonia. In regard to the pathophysiology of Legionella infection, the role of inflammatory phagocytes such as macrophages has been well documented, but the involvement of dendritic cells (DCs) has not been clarified. In this study, we have investigated the immune responses that DCs generate in vitro and in vivo after contact with L. pneumophila. Heat- and formalin-killed L. pneumophila, but not live L. pneumophila, induced immature DCs to undergo similar phenotypic maturation, but the secreted proinflammatory cytokines showed different patterns. The mechanisms of the DC maturation by heat- or formalin-killed L. pneumophila depended, at least in part, on Toll-like receptor 4 signaling or on Legionella LPS, respectively. After transfer to naive mice, DCs pulsed with dead Legionella produced serum Ig isotype responses specific for Legionella, leading to protective immunity against an otherwise lethal respiratory challenge with L. pneumophila. The in vivo immune responses required the Ag presentation of DCs, especially that on MHC class II molecules, and the immunity yielded cross-protection between clinical and environmental strains of L. pneumophila. Although the DC maturation was impaired by live Legionella, macrophages were activated by live as well as dead L. pneumophila, as evidenced by the up-regulation of MHC class II. Finally, DCs, but not macrophages, exhibited a proliferative response to live L. pneumophila that was consistent with their cell cycle progression. These findings provide a better understanding of the role of DCs in adaptive immunity to Legionella infection.
Human T Cell Lymphotropic Virus Type I (HTLV-I)-Specific CD4+ T Cells: Immunodominance Hierarchy and Preferential Infection with HTLV-I
Authors: Goon Peter K. C. , Igakura Tadahiko , Hanon Emmanuel , Mosley Angelina J. , Barfield Anna , Barnard Amanda L. , Kaftantzi Lambrini , Tanaka Yuetsu , Taylor Graham P. , Weber Jonathan N. , Bangham Charles R. M. 
Published: April 2014

Abstract
CD4+ T cells predominate in early lesions in the CNS in the inflammatory disease human lymphotropic T cell virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but the pathogenesis of the disease remains unclear and the HTLV-I-specific CD4+ T cell response has been little studied. We quantified the IFN-γ-producing HTLV-I-specific CD4+ T cells, in patients with HAM/TSP and in asymptomatic carriers with high proviral load, to test two hypotheses: that HAM/TSP patients and asymptomatic HTLV-I carriers with a similar proviral load differ in the immunodominance hierarchy or the total frequency of specific CD4+ T cells, and that HTLV-I-specific CD4+ T cells are preferentially infected with HTLV-I. The strongest CD4+ T cell response in both HAM/TSP patients and asymptomatic carriers was specific to Env. This contrasts with the immunodominance of Tax in the HTLV-I-specific CD8+ T cell response. The median frequency of HTLV-I-specific IFN-γ+ CD4+ T cells was 25-fold greater in patients with HAM/TSP (p = 0.0023, Mann-Whitney) than in asymptomatic HTLV-I carriers with a similar proviral load. Furthermore, the frequency of CD4+ T cells infected with HTLV-I (expressing Tax protein) was significantly greater (p = 0.0152, Mann-Whitney) among HTLV-I-specific cells than CMV-specific cells. These data were confirmed by quantitative PCR for HTLV-I DNA. We conclude that the high frequency of specific CD4+ T cells was associated with the disease HAM/TSP, and did not simply reflect the higher proviral load that is usually found in HAM/TSP patients. Finally, we conclude that HTLV-I-specific CD4+ T cells are preferentially infected with HTLV-I.