bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Induction of IFN-γ Production but Not Cytotoxicity by the Killer Cell Ig-Like Receptor KIR2DL4 (CD158d) in Resting NK Cells
Authors: Rajagopalan Sumati , Fu Jacqueline , Long Eric O. 
Published: April 2014

Abstract
Activated NK cells lyse tumor cells and virus-infected cells and produce IFN-γ upon contact with sensitive target cells. The regulation of these effector responses in resting NK cells is not well understood. We now describe a receptor, KIR2DL4, that has the unique property of inducing IFN-γ production, but not cytotoxicity, by resting NK cells in the absence of cytokines. In contrast, the NK cell-activation receptors CD16 and 2B4 induced cytotoxicity but not IFN-γ production. The induction by KIR2DL4 of IFN-γ production by resting NK cells was blocked by an inhibitor of the p38 mitogen-activated protein kinase signaling pathway, in contrast to the IL-2-induced IFN-γ secretion that was sensitive to inhibition of the extracellular signal-regulated kinase mitogen-activated protein kinase pathway. These results reveal a functional dichotomy (cytokine production vs cytotoxicity) in the response of resting NK cells, as dictated by the signals of individual receptors.
Cutting Edge: Expansion and Activation of A Population of Autoreactive Marginal Zone B Cells in a Model of Estrogen-Induced Lupus
Authors: Grimaldi Christine M. , Michael Daniel J. , Diamond Betty 
Published: April 2014

Abstract
We have demonstrated previously that 17 β-estradiol (E2) treatment of BALB/c mice transgenic for the heavy chain of a pathogenic anti-DNA Ab induces a lupus-like phenotype with expansion of anti-DNA B cells, elevation of anti-DNA Ab titers, and glomerular immunoglobulin deposition. To understand this loss of B cell tolerance, the effects of E2 on B cell development and activation were examined. A sustained increase in E2 resulted in an altered distribution of B cell subsets, with a diminished transitional population and an increase in marginal zone B cells. Depletion of CD4+ T cells did not abrogate these effects. Furthermore, the B cells that spontaneously secreted anti-DNA Abs displayed a marginal zone phenotype. Thus, a sustained increase in E2 alters B cell development, leading to the survival, expansion, and activation of a population of autoreactive marginal zone B cells implicating this B cell subset in autoimmunity.
Role of CD4+ and CD8+ T Cells in Allorecognition: Lessons from Corneal Transplantation
Authors: Boisgérault Florence , Liu Ying , Anosova Natalie , Ehrlich Elana , Dana M. Reza , Benichou Gilles 
Published: April 2014

Abstract
Corneal transplantation represents an interesting model to investigate the contribution of direct vs indirect Ag recognition pathways to the alloresponse. Corneal allografts are naturally devoid of MHC class II+ APCs. In addition, minor Ag-mismatched corneal grafts are more readily rejected than their MHC-mismatched counterparts. Accordingly, it has been hypothesized that these transplants do not trigger direct T cell alloresponse, but that donor Ags are presented by host APCs, i.e., in an indirect fashion. Here, we have determined the Ag specificity, frequency, and phenotype of T cells activated through direct and indirect pathways in BALB/c mice transplanted orthotopically with fully allogeneic C57BL/6 corneas. In this combination, only 60% of the corneas are rejected, while the remainder enjoy indefinite graft survival. In rejecting mice the T cell response was mediated by two T cell subsets: 1) CD4+ T cells that recognize alloantigens exclusively through indirect pathway and secrete IL-2, and 2) IFN-γ-producing CD8+ T cells recognizing donor MHC in a direct fashion. Surprisingly, CD8+ T cells activated directly were not required for graft rejection. In nonrejecting mice, no T cell responses were detected. Strikingly, peripheral sensitization to allogeneic MHC molecules in these mice induced acute rejection of corneal grafts. We conclude that only CD4+ T cells activated via indirect allorecognition have the ability to reject allogeneic corneal grafts. Although alloreactive CD8+ T cells are activated via the direct pathway, they are not fully competent and cannot contribute to the rejection unless they receive an additional signal provided by professional APCs in the periphery.
Human Cytomegalovirus Circumvents NF-κB Dependence in Retinal Pigment Epithelial Cells
Authors: Cinatl Jindrich , Margraf Stefan , Vogel Jens-Uwe , Scholz Martin , Cinatl Jaroslav , Doerr Hans Wilhelm 
Published: April 2014

Abstract
The human CMV (HCMV) is a persistent virus that may cause severe inflammatory responses especially in immunocompromised hosts. In different cell types, HCMV infection leads to the activation of the pleiotropic transcription factor, NF-κB, which triggers virus replication but also propagates cell-mediated inflammatory mechanisms that largely depend on PG synthesis. We investigated the interactions of HCMV and the NF-κB-dependent PG synthesis pathway in cultures of retinal pigment epithelial (RPE) cells that are known to be infected in HCMV retinitis patients. Unlike in other cell types, HCMV increased neither NF-κB activity nor p65 and p105/50 mRNA levels in RPE cells. Both TNF-α and phorbol ester 12,0-tetradecanoylphorbol 13-acetate (TPA) enhanced NF-κB activity but only TPA increased HCMV replication. Cyclooxygenase-2 expression and PGE2 release was increased by TPA and TNF-α but not by HCMV infection. Stimulatory activity of TPA on HCMV replication was suppressed by protein kinase C inhibitors and inhibitors of p42/44 and p38 mitogen-activated protein kinases but not by NF-κB inhibitors. In conclusion, HCMV circumvents the NF-κB route in favor of the protein kinase C-dependent mitogen-activated protein kinase pathway in RPE cells. This virus/host cell interaction might be a mechanism that promotes HCMV persistence in immune-privileged organs such as the eye.
Differential Roles of Cytokine Receptors in the Development of Epidermal γδ T Cells
Authors: Ye Sang-Kyu , Maki Kazushige , Lee Hai-Chon , Ito Akiko , Kawai Kazuhiro , Suzuki Haruhiko , Mak Tak W. , Chien Yueh-hsiu , Honjo Tasuku , Ikuta Koichi 
Published: April 2014

Abstract
IL-7 and IL-15 play important roles in γδ T cell development. These receptors transmit proliferation and/or survival signals in γδ T cells. In addition, the IL-7R promotes recombination and transcription in the TCR γ locus. To clarify the role of the cytokine receptors in the development of epidermal γδ T cells, we introduced a Vγ3/Vδ1 TCR transgene, derived from Thy-1+ dendritic epidermal T cells (DETC), into IL-7Rα-deficient mice, and we found that they partly rescued γδ T cells in the adult thymus but not in the spleen. Introduction of an additional Bcl-2 transgene had a minimal effect on γδ T cells in the adult thymus of these mice. In contrast to the adult thymus, the introduction of the Vγ3/Vδ1 TCR transgene into IL-7Rα−/− mice completely restored Vγ3+ T cells in the fetal thymus and DETC in the adult skin. On the contrary, the same Vγ3/Vδ1 TCR transgene failed to rescue DETC in the skin of IL-2Rβ-deficient mice, even with the additional Bcl-2 transgene. These results suggest that the IL-2/IL-15R, rather than the IL-7R, plays an essential role in proliferation and survival of DETC in the fetal thymus and the skin. In contrast, the IL-7R is probably essential in the induction of V-J recombination of TCRγ genes. Thus, this study proves that IL-7R and IL-2/IL-15R serve differential functions in epidermal γδ T cell development.
Impairment in the Expression and Activity of Fyn During Differentiation of Naive CD4+ T Cells into the Th2 Subset
Authors: Tamura Toshiki , Igarashi Osamu , Hino Ayako , Yamane Hidehiro , Aizawa Shinichi , Kato Takuma , Nariuchi Hideo 
Published: April 2014

Abstract
We previously showed that the amounts of Fyn protein in Th2 clones were approximately one-third to one-fifth of those in Th1 clones. In this study we examined the role of Fyn in the polarization of naive CD4+ T cells toward the Th2 subset using fyn−/− mice. The fyn−/− naive CD4+ T cells efficiently produced Th2 cytokines and polarized toward the Th2 subset even in the absence of IL-4 and IL-13. The expression of Fyn in wild-type CD4+ T cells decreased at a transcription level concomitant with polarization toward the Th2 subset. These results suggest that Fyn plays a role in the down-regulation of the differentiation of naive CD4+ T cells into the Th2 subset.
Impairment of Bleomycin-Induced Lung Fibrosis in CD28-Deficient Mice
Authors: Okazaki Tatsuma , Nakao Atsuhito , Nakano Hiroyasu , Takahashi Fumiyuki , Takahashi Kazuhisa , Shimozato Osamu , Takeda Kazuyoshi , Yagita Hideo , Okumura Ko 
Published: April 2014

Abstract
Lung fibrosis is an important pulmonary disease with a high mortality rate, but its pathophysiological mechanism has not been fully clarified. Various types of cells have been implicated in the development of lung fibrosis, including T cells. However, the contribution of functional molecules expressed on T cells to the development of lung fibrosis remains largely unknown. In this study, we determined whether costimulation via CD28 on T cells was crucial for the development of lung fibrosis by intratracheally administering bleomycin into CD28-deficient mice. Compared with wild-type mice, the CD28-deficient mice showed markedly impaired lung fibrosis after injection with low doses of bleomycin, as judged by histological changes and hydroxyproline content in the lungs. In addition, bleomycin-induced T cell infiltration into the airways and production of several cytokines and chemokines including IL-5 were also impaired in the CD28-deficient mice. Furthermore, adoptive transfer of CD28-positive T cells from wild-type mice recovered the impaired bleomycin-induced lung fibrosis in CD28-deficient mice. These findings suggest that the CD28-mediated T cell costimulation plays a critical role in the development of lung fibrosis, possibly by regulating the production of cytokines and chemokines in the lung. Thus, manipulation of the CD28-mediated costimulation could be a potential therapeutic strategy for the prevention of lung fibrosis.
CD8− Dendritic Cell Activation Status Plays an Integral Role in Influencing Th2 Response Development
Authors: MacDonald Andrew S. , Straw Amy D. , Bauman Beverley , Pearce Edward J. 
Published: April 2014

AbstractWhether dendritic cells (DC) play a passive or active role in Th2 response induction is poorly understood. In this study, we show that CD8− DC pulsed with Th2-polarizing Ag (soluble egg Ag (SEA)) from Schistosoma mansoni potently stimulate Th2 responses in vivo and in vitro while failing to undergo a conventional maturation process. Thus, in contrast to DC pulsed with the Th1 response inducing Ag Propionebacterium acnes, SEA-exposed DC exhibit a phenotype that is most similar to that of immature DC, failing to up-regulate expression of CD40, CD54, CD80, CD86, or OX40L; producing no detectable IL-4, IL-10, or IL-12; and displaying only a minor increase in MHC class II expression. Importantly, in vitro derived DC exposed to SEA were phenotypically similar to CD8− DC isolated from active S. mansoni infection. By discriminating between different types of pathogen and responding appropriately, CD8− DC play a major role in the decision process to mount either a Th1 or Th2 response.
The Source of Early IFN-γ That Plays a Role in Th1 Priming
Authors: Das Gobardhan , Sheridan Scott , Janeway Charles A. 
Published: April 2014

Abstract
When naive CD4 T cells are primed, they rapidly differentiate into polarized Th1 and/or Th2 phenotypes. A major factor in producing such polarization is the early production of cytokines (IL-12 and IFN-γ in the case of Th1 cells and IL-4 in the case of Th2 cells). One issue that remains unresolved is the source of the early IFN-γ that synergizes with IL-12 to fully polarize CD4 T cells into Th1 cells. We have examined this question by injecting mice with anti-CD3 and examining cells from normal and various MHC-knockout mice. We found that IFN-γ is induced rapidly in a small subset of CD8 T cells. This subset is absent in mice that lack β2-microglobulin, but not in KbDb-double-knockout mice, indicating that these CD8 T cells are dependent on nonclassical MHC class Ib molecules. The early burst of IFN-γ polarizes CD4 T cells toward Th1 cells, in part by stimulating the release of IL-12 from APC. We also use TAP- and CD1-knockout mice to show that such cells are not CD1-restricted NK T cells, nor are they dependent on TAP-1 transport for surface expression of the relevant MHC class Ib molecule. Therefore, they arise on MHC class Ib molecules that do not depend on TAP-1 transporters.
EBV-Specific CD8+ T Cell Memory: Relationships Between Epitope Specificity, Cell Phenotype, and Immediate Effector Function
Authors: Hislop Andrew D. , Gudgeon Nancy H. , Callan Margaret F. C. , Fazou Chrysoula , Hasegawa Hitoshi , Salmon Michael , Rickinson Alan B. 
Published: April 2014

Abstract
EBV infection in humans induces CD8+ T cell memory to viral epitopes derived from both lytic and latent cycle Ags. We have analyzed the relationship between the phenotype and function of the memory pool of T cells specific for these Ags. Lytic epitope-specific populations were heterogeneous in terms of CD45RO/RA and CD28 expression, whereas latent epitope-specific populations were uniformly CD45RO+ and CD28+, consistent with the higher antigenic challenge from lytic epitopes driving some memory cells toward a CD45RA+, CD28− phenotype. However, both types of memory population showed immediate epitope-specific cytotoxicity and type 1 cytokine production in ex vivo assays. Cytotoxic function was not associated with preactivated T cells, as EBV-specific populations were negative for activation markers such as CD69 or CD38, nor could cytotoxic function be ascribed to CD27− or CD56+ subsets, as such cells were not detected in EBV-specific memory. Furthermore, cytotoxicity was not limited to CD45RA+ and/or CD28− fractions, but also was observed in CD45RO+, CD28+ populations in lytic and latent epitope-specific memory. Cytokine (IFN-γ, TNF-α) responses, measured by intracytoplasmic staining after peptide stimulation, also were detectable in CD45RO+ and RA+ subsets as well as CD28+ and CD28− subsets. Of other markers that were heterogeneous in both lytic and latent epitope populations, CCR7 gave the best discrimination of functionality; thus, CCR7+ cells consistently failed to give an IFN-γ or TNF-α response, whereas many CCR7− cells were responsive. Our data are consistent with effector functions having a broad distribution among phenotypically distinct subsets of “effector memory” cells that have lost the CCR7 marker.
A Central Role for Death Receptor-Mediated Apoptosis in the Rejection of Tumors by NK Cells
Authors: Screpanti Valentina , Wallin Robert P. A. , Ljunggren Hans-Gustaf , Grandien Alf 
Published: April 2014

AbstractNK cells provide a line of defense against tumors and virus-infected cells that have lost the expression of one or more MHC class I isoforms. Here, we investigate whether inhibitors of apoptosis can block the rejection of tumors mediated by NK cells, by introducing the long form of Fas-associated death domain-like IL-1β-converting enzyme-associated inhibitory protein (FLIPL) and poxvirus cytokine response modifier A (CrmA) into the MHC class I-deficient T lymphoma cell line RMA-S. RMA-S cells do not normally express Fas in vitro, and it was previously postulated that the rejection of these tumors by NK cells is strictly perforin dependent. We show that perforin-deficient NK cells directly mediate Fas up-regulation on RMA-S cells and thereafter kill the cells in a Fas-dependent manner, and that RMA-S FLIPL and RMA-S CrmA are protected from such killing. When injected in immunocompetent recipients, RMA-S cells up-regulate Fas, rendering in vivo-passed mock-transduced cells sensitive to Fas-mediated apoptosis. Moreover, RMA-S FLIPL and RMA-S CrmA cells establish aggressive tumors, in contrast to RMA-S mock cells that are rejected. These results demonstrate that FLIPL and CrmA function as tumor progression factors by protecting MHC class I-deficient tumors from rejection mediated by NK cells. Moreover, our data indicate that death receptor-mediated apoptosis has a more prominent role in the clearance of NK-sensitive tumors than previously suggested.
IL-17 Mobilizes Peripheral Blood Stem Cells with Short- and Long-Term Repopulating Ability in Mice
Authors: Schwarzenberger Paul , Huang Weitao , Oliver Peter , Byrne Patrick , La Russa Vincent , Zhang Zili , Kolls Jay K. 
Published: April 2014

Abstract
Autologous and allogeneic bone marrow transplantations have evolved as important cancer therapy modalities. For both indications, peripheral blood has been shown to have distinct advantages over bone marrow as the stem cell source. Cytokine combinations for mobilization have enhanced stem cell yield and accelerated engraftment. However, novel mobilizing agents and strategies are needed to further improve clinical outcomes. Within the donor graft, the dynamic equilibrium between T cells and stem cells critically influences engraftment and transplantation results. IL-17 is a cytokine produced almost exclusively from activated T cells. IL-17 was expressed in vivo with adenovirus technology. Here, proof-of-principle studies demonstrate that IL-17 effectively mobilizes hemopoietic precursor cells (CFU-granulocyte-erythrocyte-macrophage-monocyte, CFU-high proliferative potential) and primitive hemopoietic stem cells (Lin−/lowc-kit+Sca1+). Moreover, mouse IL-17 adenovirus-mobilized peripheral blood stem cells rescued lethally irradiated mice. Bone marrow was found to be 45–75% of donor origin at 1 year. In secondary recipients, donor-derived bone marrow cells ranged from 45 to 95%. These data show that IL-17 mobilizes stem cells in mice with short- and long-term reconstituting capacity. Additional comparative studies are needed as well as studies in tumor models to refine distinct potential clinical applications for IL-17-mobilized peripheral blood stem cells.
Predominance of NK1.1+TCRαβ+ or DX5+TCRαβ+ T Cells in Mice Conditioned with Fractionated Lymphoid Irradiation Protects Against Graft-Versus-Host Disease: “Natural Suppressor” Cells
Authors: Lan Fengshuo , Zeng Defu , Higuchi Masanori , Huie Philip , Higgins John P. , Strober Samuel 
Published: April 2014

Abstract
We developed a nonmyeloablative host conditioning regimen in a mouse model of MHC-mismatched bone marrow transplantation that not only reduces radiation toxicity, but also protects against graft-vs-host disease. The regimen of fractionated irradiation directed to the lymphoid tissues and depletive anti-T cell Abs results in a marked change in the residual host T cells, such that NK1.1+ or DX5+asialo-GM1+ T cells become the predominant T cell subset in the lymphoid tissues of C57BL/6 and BALB/c mice, respectively. The latter “natural suppressor” T cells protect hosts from graft-vs-host disease after the infusion of allogeneic bone marrow and peripheral blood cells that ordinarily kill hosts conditioned with sublethal or lethal total body irradiation. Protected hosts become stable mixed chimeras, but fail to show the early expansion and infiltration of donor T cells in the gut, liver, and blood associated with host tissue injury. Cytokine secretion and adoptive transfer studies using wild-type and IL-4−/− mice showed that protection afforded by NK1.1+ and DX5+asialo-GM1+ T cells derived from either donors or hosts conditioned with lymphoid irradiation is dependent on their secretion of high levels of IL-4.
Tapasin Enhances Peptide-Induced Expression of H2-M3 Molecules, but Is Not Required for the Retention of Open Conformers
Authors: Lybarger Lonnie , Yu Yik Yeung L. , Chun Taehoon , Wang Chyung-Ru , Grandea Andres G. , Van Kaer Luc , Hansen Ted H. 
Published: April 2014

AbstractH2-M3 is a class Ib MHC molecule that binds a highly restricted pool of peptides, resulting in its intracellular retention under normal conditions. However, addition of exogenous M3 ligands induces its escape from the endoplasmic reticulum (ER) and, ultimately, its expression at the cell surface. These features of M3 make it a powerful and novel model system to study the potentially interrelated functions of the ER-resident class I chaperone tapasin. The functions ascribed to tapasin include: 1) ER retention of peptide-empty class I molecules, 2) TAP stabilization resulting in increased peptide transport, 3) direct facilitation of peptide binding by class I, and 4) peptide editing. We report in this study that M3 is associated with the peptide-loading complex and that incubation of live cells with M3 ligands dramatically decreased this association. Furthermore, high levels of open conformers of M3 were efficiently retained intracellularly in tapasin-deficient cells, and addition of exogenous M3 ligands resulted in substantial surface induction that was enhanced by coexpression of either membrane-bound or soluble tapasin. Thus, in the case of M3, tapasin directly facilitates intracellular peptide binding, but is not required for intracellular retention of open conformers. As an alternative approach to define unique aspects of M3 biosynthesis, M3 was expressed in human cell lines that lack an M3 ortholog, but support expression of murine class Ia molecules. Unexpectedly, peptide-induced surface expression of M3 was observed in only one of two cell lines. These results demonstrate that M3 expression is dependent on a unique factor compared with class Ia molecules.
A Point Mutation in the IL-12Rβ2 Gene Underlies the IL-12 Unresponsiveness of Lps-Defective C57BL/10ScCr Mice
Authors: Poltorak Alexander , Merlin Thomas , Nielsen Peter J. , Sandra Olivier , Smirnova Irina , Schupp Ingo , Boehm Thomas , Galanos Chris , Freudenberg Marina A. 
Published: April 2014

Abstract
Lps-defective C57BL/10ScCr (Cr) mice are homozygous for a deletion encompassing Toll-like receptor 4 that makes them refractory to the biological activity of LPS. In addition, these mice exhibit an inherited IL-12 unresponsiveness resulting in impaired IFN-γ responses to different microorganisms. By positional cloning methods, we show here that this second defect of Cr mice is due to a mutation in a single gene located on mouse chromosome 6, in close proximity to the Igκ locus. The gene is IL-12Rβ2. Cr mice carry a point mutation creating a stop codon that is predicted to cause premature termination of the translated IL-12Rβ2 after a lysine residue at position 777. The truncated β2 chain can still form a heterodimeric IL-12R that allows phosphorylation of Janus kinase 2, but, unlike the wild-type IL-12R, can no longer mediate phosphorylation of STAT4. Because the phosphorylation of STAT4 is a prerequisite for the IL-12-mediated induction of IFN-γ, its absence in Cr mice is responsible for their defective IFN-γ response to microorganisms.