bluuebunny/crossref_metadata_2025_split huggingface dataset:
Containment of Simian Immunodeficiency Virus Infection in Vaccinated Macaques: Correlation with the Magnitude of Virus-Specific Pre- and Postchallenge CD4+ and CD8+ T Cell Responses
Authors: Hel Zdenek , Nacsa Janos , Tryniszewska Elzbieta , Tsai Wen-Po , Parks Robyn Washington , Montefiori David C. , Felber Barbara K. , Tartaglia James , Pavlakis George N. , Franchini Genoveffa 
Published: April 2014

Abstract
Macaques infected with the SIV strain SIVmac251 develop a disease closely resembling human AIDS characterized by high viremia, progressive loss of CD4+ T cells, occurrence of opportunistic infection, cachexia, and lymphomas. We report in this study that vaccination with the genetically attenuated poxvirus vector expressing the structural Ags of SIVmac (NYVAC-SIV-gag, pol, env) in combination with priming with DNA-SIV-gag, env resulted in significant suppression of viremia within 2 mo after mucosal exposure to the highly pathogenic SIVmac251 in the majority of vaccinated macaques. The control of viremia in these macaques was long lasting and inversely correlated to the level of both pre- and postchallenge Gag-specific lymphoproliferative responses, as well as to the level of total SIV-specific CD4+ T lymphocyte responses at the peak of acute viremia as detected by intracellular cytokine-staining assay. Viremia containment also correlated with the frequency of the immunodominant Gag181–189CM9 epitope-specific CD8+ T cells present before the challenge or expanded during acute infection. These data indicate, for the first time, the importance of vaccine-induced CD4+ Th cell responses as an immune correlate of viremia containment. The results presented in this work also further demonstrate the potential of a DNA-prime/attenuated poxvirus-boost vaccine regimen in an animal model that well mirrors human AIDS.
Long-Lived Th2 Memory in Experimental Allergic Asthma
Authors: Mojtabavi Nazanin , Dekan Gerhard , Stingl Georg , Epstein Michelle M. 
Published: April 2014

Abstract
Although life-long immunity against pathogens is beneficial, immunological memory responses directed against allergens are potentially harmful. Because there is a paucity of information about Th2 memory cells in allergic disease, we established a model of allergic asthma in BALB/c mice to explore the generation and maintenance of Th2 memory. We induced disease without the use of adjuvants, thus avoiding Ag depots, and found that unlike allergic asthma in mice immunized with adjuvant, immunizing with soluble and aerosol OVA resulted in pathological lung lesions resembling human disease. To test memory responses we allowed mice with acute disease to recover and then re-exposed them to aerosol OVA a second time. Over 400 days later these mice developed OVA-dependent eosinophilic lung inflammation, airway hyperresponsiveness, mucus hypersecretion, and IgE. Over 1 year after recuperating from acute disease, mice had persistent lymphocytic lung infiltrates, Ag-specific production of IL-4 and IL-5 from spleen and lung cells in vitro, and elevated IgG1. Moreover, when recuperated mice were briefly aerosol challenged, we detected early expression of Th2 cytokine RNA in lungs. Taken together, these data demonstrate the presence of long-lived Th2 memory cells in spleen and lungs involved in the generation of allergic asthma upon Ag re-exposure.
T Cell Requirement for Development of Chronic Ulcerative Dermatitis in E- and P-Selectin-Deficient Mice
Authors: Forlow S. Bradley , White E. James , Thomas Kennard L. , Bagby Gregory J. , Foley Patricia L. , Ley Klaus 
Published: April 2014

Abstract
C57BL/6 mice deficient in E- and P-selectin (E−/−P−/−) kept under specific pathogen-free barrier conditions have high circulating neutrophil counts and develop hypercellular cervical lymph nodes with substantial plasma cell infiltrates, severe ulcerative dermatitis, conjunctivitis, and lung pathology, which eventually lead to premature death. To test the hypothesis that the pathology in E−/−P−/− mice may be caused by dysfunctional lymphocyte activity, we crossed E−/−P−/− mice with recombination activation gene (Rag)-1−/− mice to generate E−/−P−/−Rag-1−/− mice lacking mature T and B lymphocytes. E−/−P−/−Rag-1−/− mice had circulating neutrophil counts and plasma G-CSF levels similar to E−/−P−/− mice. Remarkably, none of the E−/−P−/−Rag-1−/− mice developed conjunctivitis or ulcerative dermatitis typical of E−/−P−/− mice. These mice were overall healthier in appearance than E−/−P−/− mice, and histopathologic changes in the lung were reduced. Cervical lymph nodes in E−/−P−/−Rag-1−/− mice were much smaller than those of E−/−P−/− mice, containing few mononuclear cells and no plasma cells. These data show that the severe disease phenotype of E−/−P−/− mice depends on lymphocyte function. We conclude that a dysregulated immune response in E−/−P−/− mice causes disease development, but is not necessary for elevated neutrophil counts.
Tumor-Induced L-Selectinhigh Suppressor T Cells Mediate Potent Effector T Cell Blockade and Cause Failure of Otherwise Curative Adoptive Immunotherapy
Authors: Peng Liaomin , Kjaergäard Jørgen , Plautz Gregory E. , Awad Mohamed , Drazba Judith A. , Shu Suyu , Cohen Peter A. 
Published: April 2014

Abstract
Tumor-specific effector T cells (TE) are naturally sensitized within the L-selectinlow (CD62Llow) fraction of tumor-draining lymph nodes (TDLN). Whether isolated from day 9 (D9) or day 12 (D12) TDLN, 5 million L-selectinlow TE could be culture activated and adoptively transferred to achieve complete rejection of established intradermal, pulmonary, and brain tumors. Surprisingly, although 25 million unfractionated T cells from D9 TDLN were equally effective, even 100 million unfractionated T cells from D12 TDLN seldom prevented lethal intradermal tumor progression, despite a pronounced therapeutic excess of TE. This highly reproducible treatment failure was due to cotransfer of tumor-induced, L-selectinhigh suppressor T cells (TS) which were also present in D12 TDLN. In contrast, D9 TDLN and normal spleens lacked L-selectinhigh TS. Only those L-selectinhigh D12 TDLN T cells that down-regulated L-selectin during culture activation were suppressive in vivo and in vitro, and, like L-selectinlow TE, trafficked promptly into tumors following i.v. administration. This is the first demonstration that adoptive immunotherapy can fail as a direct result of passenger TS that share certain phenotypic and trafficking features of TE, even when otherwise curative doses of TE have been administered. Furthermore, in contrast to recently described CD4+CD25+ TS and plasmacytoid dendritic cell-activated TS, tumor-induced L-selectinhigh TS prevent tumor rejection via blockade of sensitized, activated TE rather than via afferent blockade.
Regulatory Effect of IFN-κ, A Novel Type I IFN, On Cytokine Production by Cells of the Innate Immune System
Authors: Nardelli Bernardetta , Zaritskaya Liubov , Semenuk Mark , Cho Yun Hee , LaFleur David W. , Shah Devanshi , Ullrich Stephen , Girolomoni Giampiero , Albanesi Cristina , Moore Paul A. 
Published: April 2014

AbstractIFN-κ is a recently identified type I IFN that exhibits both structural and functional homology with the other type I IFN subclasses. In this study, we have investigated the effect of IFN-κ on cells of the innate immune system by comparing cytokine release following treatment of human cells with either IFN-κ or two recombinant IFN subtypes, IFN-β and IFN-α2a. Although IFN-α2a failed to stimulate monocyte cytokine secretion, IFN-κ, like IFN-β, induced the release of several cytokines from both monocytes and dendritic cells, without the requirement of a costimulatory signal. IFN-κ was particularly effective in inhibiting inducible IL-12 release from monocytes. Unlike IFN-β, IFN-κ did not induce release of IFN-γ by PBL. Expression of the IFN-κ mRNA was observed in resting dendritic cells and monocytes, and it was up-regulated by IFN-γ stimulation in monocytes, while IFN-β mRNA was minimally detectable under the same conditions. Monocyte and dendritic cell expression of IFN-κ was also confirmed in vivo in chronic lesions of psoriasis vulgaris and atopic dermatitis. Finally, biosensor-based binding kinetic analysis revealed that IFN-κ, like IFN-β, binds strongly to heparin (Kd: 2.1 nM), suggesting that the cytokine can be retained close to the local site of production. The pattern of cytokines induced by IFN-κ in monocytes, coupled with the unique induction of IFN-κ mRNA by IFN-γ, indicates a potential role for IFN-κ in the regulation of immune cell functions.
CD4-Dependent Generation of Dominant Transplantation Tolerance Induced by Simultaneous Perturbation of CD154 and LFA-1 Pathways
Authors: Nicolls Mark R. , Coulombe Marilyne , Beilke Joshua , Gelhaus H. Carl , Gill Ronald G. 
Published: April 2014

AbstractCD154 and LFA-1 (CD11a) represent conceptually distinct pathways of receptor/ligand interactions (costimulation and adhesion/homing, respectively) that have been effectively targeted to induce long-term allograft acceptance and tolerance. In the current study, we determined the relative efficacy and nature of tolerance induced by mAbs specific for these pathways. In vitro analysis indicated that simultaneous targeting of CD154 and LFA-1 resulted in profound inhibition of alloreactivity, suggesting that combined anti-CD154/anti-LFA-1 therapy could be highly effective in vivo. Thus, we evaluated combining mAb therapies targeting CD154 and LFA-1 for inducing transplantation tolerance to pancreatic islet allografts. Monotherapy with either anti-CD154 or anti-LFA-1 was partially effective for inducing long-term allograft survival, whereas the combination resulted in uniform allograft acceptance in high-responder C57BL/6 recipients. This combined therapy was not lymphocyte depleting and did not require the long-term deletion of donor-reactive T lymphocytes to maintain allograft survival. Importantly, combined anti-CD154/anti-LFA therapy uniquely resulted in “dominant” transplantation tolerance. Therefore, simultaneous perturbation of CD154 and LFA-1 molecules can result in profound tolerance induction not accomplished through individual monotherapy approaches. Furthermore, results show that such regulatory tolerance can coexist with the presence of robust anti-donor reactivity, suggesting that active tolerance does not require a corresponding deletion of donor-reactive T cells. Interestingly, although the induction of this regulatory state was highly CD4 dependent, the adoptive transfer of tolerance was less CD4 dependent in vivo.
Homeostasis of Peripheral CD4+ T Cells: IL-2Rα and IL-2 Shape a Population of Regulatory Cells That Controls CD4+ T Cell Numbers
Authors: Almeida Afonso R. M. , Legrand Nicolas , Papiernik Martine , Freitas António A. 
Published: April 2014

Abstract
We show that the lymphoid hyperplasia observed in IL-2Rα- and IL-2-deficient mice is due to the lack of a population of regulatory cells essential for CD4 T cell homeostasis. In chimeras reconstituted with bone marrow cells from IL-2Rα-deficient donors, restitution of a population of CD25+CD4+ T cells prevents the chaotic accumulation of lymphoid cells, and rescues the mice from autoimmune disease and death. The reintroduction of IL-2-producing cells in IL-2-deficient chimeras establishes a population of CD25+CD4+ T cells, and restores the peripheral lymphoid compartments to normal. The CD25+CD4+ T cells regulated selectively the number of naive CD4+ T cells transferred into T cell-deficient hosts. The CD25+CD4+/naive CD4 T cell ratio and the sequence of cell transfer determines the homeostatic plateau of CD4+ T cells. Overall, our findings demonstrate that IL-2Rα is an absolute requirement for the development of the regulatory CD25+CD4+ T cells that control peripheral CD4 T cell homeostasis, while IL-2 is required for establishing a sizeable population of these cells in the peripheral pools.
The Role of the Ets2 Transcription Factor in the Proliferation, Maturation, and Survival of Mouse Thymocytes
Authors: Zaldumbide Arnaud , Carlotti Françoise , Pognonec Philippe , Boulukos Kim E. 
Published: April 2014

Abstract
In this study, we investigated the effects of Ets2 expression on the proliferation, maturation, and survival of thymocytes by establishing transgenic mice that specifically express Ets2 or a dominant negative form of Ets2, Δets2, in the thymus. We show that, in young animals, there are fewer T cells in Δets2 transgenic thymi and that the maturation of these T cells is affected at the CD4−CD8− double-negative to CD4+CD8+ double-positive transition compared with wild-type littermate mice. Partial recovery in the number of thymocytes and full T cell maturation are restored with increasing age of Δets2 transgenic animals. However, thymocytes from adult Δets2 transgenic mice cultured ex vivo are more sensitive to cell death and to glucocorticoid-induced apoptosis than are T cells from control littermate mice. We also show that T cells from adult ets2 transgenic mice proliferate faster than their wild-type littermates. The proliferation and survival of these T cells are clearly affected upon apoptotic signals: glucocorticoid-induced apoptosis induces T cells from ets2 transgenic mice to continue to proliferate in vivo and to survive better ex vivo than T cells from control littermates. It has been shown that c-Myc expression is required for thymic proliferation and improves thymocyte survival of dexamethasone-treated animals. We show that the expression of c-Myc, an Ets2 target, is elevated in T cells freshly isolated from thymi of ets2 transgenic mice pretreated with dexamethasone. Together, these results show that Ets2 plays a role in the proliferation and survival of thymocytes, implicating a Myc-dependent pathway.
DNA Vaccination Breaks Tolerance for a Neo-Self Antigen in Liver: A Transgenic Murine Model of Autoimmune Hepatitis
Authors: Djilali-Saiah Idriss , Lapierre Pascal , Vittozi Susana , Alvarez Fernando 
Published: April 2014

Abstract
Understanding the pathogenesis of autoimmune hepatitis requires an animal model in which chronic progressive immune injury develops spontaneously or with minimal manipulations. The new transgenic mouse model proposed in this study is based on the hypothesis that infectious agents have the potential to initiate autoreactivity through molecular mimicry. A transgenic mouse expressing lymphocytic choriomeningitis virus nucleoprotein (NP) in a H-2b background developed liver injury when vaccinated with plasmids expressing NP as an intracellular or a secretory protein. Coinjection of plasmids coding for NP and IL-12 facilitated the induction of a Th1 phenotype as detected by a specific B lymphocyte response characterized by a predominance of IgG2 subclass anti-NP Abs. CTLs activated in peripheral lymphoid organs by DNA vaccination migrated to the periportal and lobular areas of the liver. Their presence was associated with a significant degree of cytolysis, as evidenced by elevated transaminases several weeks after immunization. As activated specific T lymphocytes proliferated in the periphery and caused cytolysis of target cells, this study suggests that autoimmune hepatitis can be triggered by molecular mimicry, and that local injury may not be essential to initiate autoreactivity in the liver.
Highly Immunogenic and Totally Synthetic Lipopeptides as Self-Adjuvanting Immunocontraceptive Vaccines
Authors: Zeng Weiguang , Ghosh Souravi , Lau Yuk Fai , Brown Lorena E. , Jackson David C. 
Published: April 2014

Abstract
In this study, we describe the synthesis of various lipopeptides based on the sequence of luteinizing hormone-releasing hormone (LHRH) and report on their abilities to induce Abs against this “self” hormone when inoculated into mice in the absence of additional adjuvant. The peptides consisted of a colinear CD4+ T helper cell epitope from the L chain of influenza virus hemagglutinin and LHRH, which has B cell epitopes but no T cell epitopes present in its sequence. Lipids were attached either at the N terminus or between the T cell epitope and LHRH, in the approximate center of the peptide. The lipopeptide constructs displayed different solubilities and immunological properties that depended not only on the lipid content but also on the position of attachment of the lipids. Some of these constructs were highly immunogenic, inducing high titers of Ab, which were capable of efficiently sterilizing female mice when administered in saline by s.c. or intranasal routes. The most effective vaccines were highly soluble, contained the dipalmitoyl-S-glyceryl cysteine moiety, and had this lipid attached at the center of the molecule. The relative ability of the lipopeptides to induce an Ab response in the absence of external adjuvant was reflected by their ability to up-regulate the surface expression of MHC class II molecules on immature dendritic cells. These results demonstrate that the composition and position within peptide vaccines of self-adjuvanting lipid groups can influence the ability to induce the maturation of dendritic cells and, in turn, the magnitude of the resulting Ab response.
Repertoire of Antibody Response in Bone Marrow and the Memory Response Are Differentially Affected in Aging Mice
Authors: Lu Yi-Feng , Cerny Jan 
Published: April 2014

Abstract
The primary burst of Ab and germinal center (GC) formation in response to T-dependent Ag is compromised in aging mice. Here we examine the effects of aging on the post-GC phase of memory B cell differentiation and the late Ab repertoire maturation in bone marrow (BM) in mice immunized with a hapten nitrophenyl coupled to chicken γ-globulin. Specific Ab-forming cells (AFC) with mutated VH genes accumulated preferentially in the BM of aged mice, although the AFC numbers and average number of mutations per VH were lower, and the D gene usage was less restricted compared with those in the young animals. However, the repertoire of AFC after an Ag boost demonstrated the hallmarks of Ag selection, including the recurrent mutations and canonical VD rearrangements, similar to the late primary response in young animals. It is postulated that the Ab repertoire maturation in aged mice is delayed and may be notably improved by repeated immunizations.
Efficient Priming of CD4+ and CD8+ T Cells by DNA Vaccination Depends on Appropriate Targeting of Sufficient Levels of Immunologically Relevant Antigen to Appropriate Processing Pathways
Authors: Rush Catherine , Mitchell Tim , Garside Paul 
Published: April 2014

Abstract
The initial cellular events and interactions that occur following DNA immunization are likely to be key to determining the character and magnitude of the resulting immune response, and as such, a better understanding of these events could ultimately lead to the design of more effective pathogen-appropriate DNA vaccines. Therefore, we have used a variety of sensitive cell-based techniques to study the induction of adaptive immunity in vivo. We examined the efficacy of induction of Ag-specific CD4+ and CD8+ T cell responses in vivo by the adoptive transfer of fluorescently labeled Ag-specific TCR transgenic T cells and have demonstrated how such approaches can be used to study the effect of simple DNA construct manipulations on immunological priming. OVA-specific CD8+ and CD4+ T cells were activated and divided in vivo following immunization with DNA constructs that targeted OVA expression to different subcellular locations; however, the kinetics and degree of cell proliferation were dependent on the cellular location of the expressed protein. DNA vectors encoding cell-associated OVA resulted in greater CD8+ T cell division compared with other forms of OVA. In contrast, soluble secreted OVA targeted to the classical secretory pathway enhanced division of CD4+ T cells. Furthermore, the inclusion of mammalian introns to enhance protein expression increased the ability of poorly immunogenic forms of Ag to activate naive T cells, indicating that not only the location, but also the amount of Ag expression, is important for efficient T cell priming following DNA injection.
Single T Cell Receptor-Mediated Recognition of an Identical HIV-Derived Peptide Presented by Multiple HLA Class I Molecules
Authors: Ueno Takamasa , Tomiyama Hiroko , Takiguchi Masafumi 
Published: April 2014

Abstract
A dual specific human CTL clone harboring one β and two inframe α transcripts of TCR was previously reported to recognize an HIV Pol-derived nonapeptide (IPLTEEAEL) endogenously presented by both syngeneic HLA-B*3501 and HLA-B*5101. In the current study, a retrovirus-mediated TCR transfer of individual α- and β-chains to TCR-negative hybridoma showed that Vα12.1 TCR in complex with Vβ5.6 were responsible for the peptide-specific response in the context of both HLA-B*3501 and HLA-B*5101, confirming single TCR-mediated dual specificity. The second TCR-α chain was not somehow expressed on the cell surface. Remarkably, the Vα12.1/Vβ5.6 TCR also recognized the same peptide presented by allogeneic HLA class I molecules that share the similar peptide-binding motifs, such as HLA-B*5301 and HLA-B*0702. The sensitivity of peptide recognition by the Vα12/Vβ5.6 TCR appeared to be comparable when the peptide was presented by syngeneic and allogeneic HLA class I molecules, with changes in T cell responsiveness caused largely by peptide-binding capacity. Moreover, the CTL clone bearing Vα12.1/Vβ5.6 TCR showed substantial cytolytic activity against the peptide-loaded cells expressing HLA-B*3501, HLA-B*5101, HLA-B*5301, or HLA-B*0702, providing further evidence that a single TCR complex can recognize the same peptide presented by a broad range of HLA class I molecules. A TCR with fine specificity for an HIV Ag but broad specificity to multiple HLA molecules may provide an advantage to the generation of allorestricted, peptide-specific T cells, and thus could be a potent candidate for immunotherapy against HIV infection.
Bovine γδ T Cell Subsets Express Distinct Patterns of Chemokine Responsiveness and Adhesion Molecules: A Mechanism for Tissue-Specific γδ T Cell Subset Accumulation
Authors: Wilson Eric , Hedges Jodi F. , Butcher Eugene C. , Briskin Michael , Jutila Mark A. 
Published: April 2014

Abstract
Subsets of γδ T cells localize to distinct tissue sites in the absence of exogenous Ag stimulation or development of effector/memory cells. Selective lymphocyte homing from the blood into tissues is controlled by a multistep process involving vascular and lymphocyte adhesion molecules, and G protein-linked chemokine receptors. The role of these mechanisms in the tissue tropism of γδ T cells is still poorly understood. In this study, we demonstrate that a subset of γδ T cells, most of which express an antigenically distinct TCR and are characterized by coexpression of CD8, selectively accumulated in tissues that expressed high levels of the mucosal vascular addressin, mucosal addressin cell adhesion molecule 1. These cells expressed higher levels of α4β7 integrins than other γδ T cell subsets and selectively migrated to the CCR7 ligand secondary lymphoid-tissue chemokine (CCL21). Integrin activation by CCL21 selectively increased CD8+γδ T cell binding to recombinant mucosal addressin cell adhesion molecule 1. These results suggest that the tropism of circulating CD8+γδ T cells for mucosal tissues is due, at least in part, to selective developmental expression of adhesion molecules and chemokine receptors.