bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Novel Subdominant Epitopes on the Carcinoembryonic Antigen Recognized by CD4+ T Cells of Lung Cancer Patients
Authors: Crosti Mariacristina , Longhi Renato , Consogno Giuseppe , Melloni Giulio , Zannini Piero , Protti Maria Pia 
Published: April 2014

AbstractThe carcinoembryonic Ag (CEA) is an attractive target for immunotherapy because of its expression profile and role in tumor progression. To verify the existence of spontaneous anti-CEA CD4+ T cells in lung cancer patients, we first identified CEA sequences forming naturally processed epitopes, and then used the identified epitopes to test their recognition by CD4+ T cells from the patients. We had previously identified CEA177–189/355–367 as an immunodominant epitope recognized by CD4+ T cells in association with several HLA-DR alleles. In this study, we identified four additional subdominant CEA sequences (CEA99–111, CEA425–437, CEA568–582, and CEA666–678), recognized in association with one or more HLA-DR alleles. Peptide-specific CD4+ T cells produced proinflammatory cytokines when challenged with the native protein and CEA-expressing tumor cells, thus demonstrating that the identified CEA sequences contain naturally processed epitopes. However, CEA is expressed in the thymus and belongs to the CD66 family that comprises highly homologous molecules expressed on hemopoietic cells, raising concerns about tolerance interfering with the in vivo development of anti-CEA immunity. We thus tested the spontaneous reactivity to the identified epitopes of peripheral blood CD4+ T lymphocytes from eight early-stage lung cancer patients bearing CEA-positive tumors. We found GM-CSF- and IFN-γ- producing CD4+ T cells in two patients. Our data indicate that CD4+ immune responses against CEA develop in neoplastic patients, suggesting that tolerance toward CEA or cross-reactive CD66 homologous molecules might be either not absolute or be overcome in the neoplastic disease.
BCR/ABL Oncogene Directly Controls MHC Class I Chain-Related Molecule A Expression in Chronic Myelogenous Leukemia
Authors: Boissel Nicolas , Rea Delphine , Tieng Vannary , Dulphy Nicolas , Brun Manuel , Cayuela Jean-Michel , Rousselot Philippe , Tamouza Ryad , Le Bouteiller Philippe , Mahon François-Xavier , Steinle Alexander , Charron Dominique , Dombret Hervé , Toubert Antoine 
Published: April 2014

Abstract
MHC class I chain-related molecules (MIC) participate in immune surveillance of cancer through engagement of the NKG2D-activating receptor on NK and T cells. Decreased NKG2D expression and function upon chronic exposure to NKG2D ligands and/or soluble forms of MIC (sMIC) may participate in immune escape. In chronic myeloid leukemia, a malignancy caused by the BCR/ABL fusion oncoprotein, we showed cell surface expression of MICA on leukemic, but not healthy, donor hemopoietic CD34+ cells. At diagnosis, chronic myeloid leukemia patients had abnormally high serum levels of sMICA and weak NKG2D expression on NK and CD8+ T cells, which were restored by imatinib mesylate (IM) therapy. In the BCR/ABL+ cell line K562, IM decreased both surface MICA/B expression and NKG2D-mediated lysis by NK cells. Silencing BCR/ABL gene expression directly evidenced its role in the control of MICA expression. IM did not affect MICA mRNA levels, but decreased MICA protein production and release. Sucrose density gradient fractionation of K562 cytoplasmic extracts treated with IM showed a shift in the distribution of MICA mRNA from the polysomal toward the monosomal fractions, consistent with decreased translation. Among the major pathways activated by BCR/ABL that regulate translation, PI3K and mammalian target of rapamycin were shown to control MICA expression. These data provide evidence for direct control of MICA expression by an oncogene in human malignancy and indicate that posttranscriptional mechanisms may participate in the regulation of MICA expression.
Cutting Edge: Cognate CD4 Help Promotes Recruitment of Antigen-Specific CD8 T Cells around Dendritic Cells
Authors: Beuneu Hélène , Garcia Zacarias , Bousso Philippe 
Published: April 2014

Abstract
The cellular orchestration underlying help provided by CD4 T lymphocytes to CD8 T cell responses is not fully understood. We documented that the formation of three-cell clusters occurred as soon as day 1 and relied on long-lasting CD4 and CD8 T cell interactions with dendritic cells (DCs). The influence of CD4 help on CD8 T cell differentiation could be observed as early as the second round of cell division. Importantly, our results identify a new facet to the phenomenon of CD4 help in which DCs, upon cognate interactions with CD4 T cells, increase their ability to attract/retain Ag-specific CD8 T cells. Our results support a model in which CD4 help operates rapidly, in part by favoring CD8 T cells recruitment around those DCs that are the most competent for priming.
Cutting Edge: Central Memory T Cells Do Not Show Accelerated Proliferation or Tissue Infiltration in Response to Localized Herpes Simplex Virus-1 Infection
Authors: Stock Angus T. , Jones Claerwen M. , Heath William R. , Carbone Francis R. 
Published: April 2014

Abstract
Memory T cells mount an enhanced response to secondary infections. Such an enhancement has been attributed in part to the ability of memory cells to more rapidly respond to cognate stimulation. In this study we have examined the rapidity with which murine CD8+ memory T cells respond to a localized infection with HSV. Although central memory T cells (TcM), but not the effector memory T cells, mounted a strong recall response to secondary infection, the kinetics of TcM proliferation, the magnitude of their expansion, and their infiltration into infected nonlymphoid tissues were not advanced compared with that observed for naive T cells. These findings imply that it is the lack of accelerated proliferation kinetics and the subsequent delayed dissemination into the periphery that limits the ability of TcM to rapidly control localized virus replication.
Cutting Edge: IFN-γ Regulates the Induction and Expansion of IL-17-Producing CD4 T Cells during Mycobacterial Infection
Authors: Cruz Andrea , Khader Shabaana A. , Torrado Egidio , Fraga Alexandra , Pearl John E. , Pedrosa Jorge , Cooper Andrea M. , Castro António G. 
Published: April 2014

AbstractT cell responses are important to the control of infection but are deleterious if not regulated. IFN-γ-deficient mice infected with mycobacteria exhibit enhanced accumulation of activated effector T cells and neutrophils within granulomatous lesions. These cells do not control bacterial growth and compromise the integrity of the infected tissue. We show that IFN-γ-deficient mice have increased numbers of IL-17-producing T cells following infection with Mycobacterium bovis bacille Calmette Guérin. Furthermore, exogenous IFN-γ increases IL-12 and decreases IL-23 production by bacille Calmette Guérin-infected bone marrow-derived dendritic cells and reduces the frequency of IL-17-producing T cells induced by these bone marrow-derived dendritic cells. These data support the hypothesis that, during mycobacterial infection, both IFN-γ- and IL-17-producing T cells are induced, but that IFN-γ serves to limit the IL-17-producing T cell population. This counterregulation pathway may be an important factor in limiting mycobacterially associated immune-mediated pathology.
EBV-Specific CD4+ T Cell Clones Exhibit Vigorous Allogeneic Responses
Authors: Landais Elise , Morice Alexis , Long Heather M. , Haigh Tracey A. , Charreau Béatrice , Bonneville Marc , Taylor Graham S. , Houssaint Elisabeth 
Published: April 2014

AbstractAlloreactive T cells play a key role in mediating graft-vs-host disease and allograft rejection, and recent data suggest that most T cell alloreactivity resides within the CD4 T cell subset. Particularly, T cell responses to herpesvirus can shape the alloreactive repertoire and influence transplantation outcomes. In this study, we describe six distinct EBV-specific CD4+ T cell clones that cross-reacted with EBV-transformed lymphoblastoid cell lines (LCLs), dendritic cells, and endothelial cells expressing MHC class II alleles commonly found in the population. Allorecognition showed exquisite MHC specificity. These CD4+ T cell clones efficiently killed dendritic cells or LCLs expressing the cross-reactive allogeneic MHC class II molecules, whereas they did not kill autologous LCLs. Endothelial cells expressing the proper allogeneic MHC molecules were poorly killed, but they induced high-level TNF-α production by the EBV-specific CD4+ T cell clones. As already proposed, the strong alloreactivity toward LCLs suggest that these cells could be used for selective depletion of alloreactive T cells.
Tripeptidyl Peptidase II Is the Major Peptidase Needed to Trim Long Antigenic Precursors, but Is Not Required for Most MHC Class I Antigen Presentation
Authors: York Ian A. , Bhutani Nidhi , Zendzian Sophia , Goldberg Alfred L. , Rock Kenneth L. 
Published: April 2014

AbstractRecent reports concluded that tripeptidyl peptidase (TPPII) is essential for MHC class I Ag presentation and that the proteasome in vivo mainly releases peptides 16 residues or longer that require processing by TPPII. However, we find that eliminating TPPII from human cells using small interfering RNA did not decrease the overall supply of peptides to MHC class I molecules and reduced only modestly the presentation of SIINFEKL from OVA, while treatment with proteasome inhibitors reduced these processes dramatically. Purified TPPII digests peptides from 6 to 30 residues long at similar rates, but eliminating TPPII in cells reduced the processing of long antigenic precursors (14–17 residues) more than short ones (9–12 residues). Therefore, TPPII appears to be the major peptidase capable of processing proteasome products longer than 14 residues. However, proteasomes in vivo (like purified proteasomes) release relatively few such peptides, and these peptides processed by TPPII require further trimming in the endoplasmic reticulum (ER) by ER aminopeptidase 1 for presentation. Taken together, these observations demonstrate that TPPII plays a specialized role in Ag processing and one that is not essential for the generation of most presented peptides. Moreover, these findings reveal that three sequential proteolytic steps (by proteasomes, TPPII, and then ER aminopepsidase 1) are required for the generation of a subset of epitopes.
Reconstitution of Allogeneic Hemopoietic Stem Cells: The Essential Role of FcRγ and the TCR β-Chain-FCp33 Complex
Authors: Taylor Kendra N. , Shinde Patil Vivek R. , Colson Yolonda L. 
Published: April 2014

AbstractTransplantation of purified allogeneic hemopoietic stem cells (SC) alone is characterized by a decreased risk of graft-vs-host disease but increased incidence of engraftment failure. It has been established that the facilitating cell (FC) promotes allogeneic SC reconstitution and results in donor-specific transplantation tolerance across MHC disparities, without graft-vs-host disease. Although the requirements for this facilitating function are not well-characterized, it is known that facilitation is dependent on FC expression of a unique heterodimer consisting of the TCR β-chain (TCRβ) and a 33-kDa protein, FCp33. The current study confirms that CD3ε and TCRβ expression are present on the FC at the time of transplantation and demonstrates that the majority of cells in the FC population express the TCR signaling molecule, FcRγ, rather than the more conventional CD3ζ receptor. Of particular significance, we have now demonstrated that FC-mediated allogeneic SC reconstitution is critically dependent on FcRγ expression and that FcRγ coprecipitates with the TCRβ-FCp33 heterodimer. The mandatory requirement of TCRβ and FcRγ for FC function provides the first evidence of a previously undescribed role for FcRγ in the facilitation of allogeneic SC reconstitution and establishes that FcRγ is part of the TCRβ-FCp33 complex uniquely expressed on FC.
Dendritic Cells Can Turn CD4+ T Lymphocytes into Vascular Endothelial Growth Factor-Carrying Cells by Intercellular Neuropilin-1 Transfer
Authors: Bourbié-Vaudaine Sarah , Blanchard Nicolas , Hivroz Claire , Roméo Paul-Henri 
Published: April 2014

AbstractNeuropilin-1 (NRP1) is a transmembrane protein expressed on neuronal and endothelial cells where it plays a crucial role in guiding axons and regulating angiogenesis. We have recently shown that NRP1 also is expressed on dendritic cells (DC) in the human immune system and have proposed a role for NRP1 in the first stages of the immune response. In these studies, we show that NRP1 can be transferred with a high efficiency from human DC to T lymphocytes by trogocytosis. The NRP1 transfer can occur independently of T lymphocyte activation; the amount of NRP1 transferred depends on the NRP1 expression level on APC and is enhanced when T cells are activated through the TCR. Moreover, the NRP1 transfer occurs between specific donor and recipient cells, because no NRP1 transfer is observed between endothelial cells and T lymphocytes or between APCs and CD34+ hemopoietic cells. Finally, we show that a major NRP1 ligand, vascular endothelial growth factor (VEGF)165, is secreted by mature human DCs and binds to NRP1 captured by T lymphocytes. These results show that NRP1 transfer to T lymphocytes during the immune synapse can convert T lymphocytes into VEGF165-carrying cells. Together with the enhanced signaling of VEGF-R2 on endothelial cells in the presence, in trans, of the NRP1–VEGF165 complex, our results suggest that the intercellular transfer of NRP1 might participate in the Ag-independent remodelling of the endothelial vessels in secondary lymphoid organs during inflammation.
The Cytoplasmic Domain of Fas Ligand Costimulates TCR Signals
Authors: Sun Mingyi , Ames Kristina T. , Suzuki Ivy , Fink Pamela J. 
Published: April 2014

AbstractProductive T cell activation generally requires costimulation in addition to a signal delivered through the TCR. Although FasL is well-characterized for its capacity to deliver a death signal through Fas, this TNF family member can also transmit a reverse signal to enhance Ag-driven T cell proliferation. In this study, we define this reverse signal through FasL as costimulation by showing it requires TCR coengagement and is CD28 independent. We demonstrate that FasL-mediated costimulation drives FasL recruitment into lipid rafts and association with select Src homology 3 (SH3)-containing proteins. We further show that the proline-rich intracellular domain of FasL is sufficient to costimulate by enhancing the phosphorylation of Akt, ERK1/2, JNK, and FasL itself, by activating the transcription factors NFAT and AP-1, and by enhancing IFN-γ production. These results elucidate the pathway of costimulation through the death inducer FasL, and comprise the first mechanistic analysis of a newly emerging group of costimulators, the TNF family.
Delayed Expansion and Contraction of CD8+ T Cell Response during Infection with VirulentSalmonella typhimurium
Authors: Luu Rachel A. , Gurnani Komal , Dudani Renu , Kammara Rajagopal , van Faassen Henk , Sirard Jean-Claude , Krishnan Lakshmi , Sad Subash 
Published: April 2014

AbstractAg presentation to CD8+ T cells often commences immediately after infection, which facilitates their rapid expansion and control of infection. Subsequently, the primed cells undergo rapid contraction. We report that this paradigm is not followed during infection with virulent Salmonella enterica, serovar Typhimurium (ST), an intracellular bacterium that replicates within phagosomes of infected cells. Although susceptible mice die rapidly (∼7 days), resistant mice (129×1SvJ) harbor a chronic infection lasting ∼60–90 days. Using rOVA-expressing ST (ST-OVA), we show that T cell priming is considerably delayed in the resistant mice. CD8+ T cells that are induced during ST-OVA infection undergo delayed expansion, which peaks around day 21, and is followed by protracted contraction. Initially, ST-OVA induces a small population of cycling central phenotype (CD62LhighIL-7RαhighCD44high) CD8+ T cells. However, by day 14–21, majority of the primed CD8+ T cells display an effector phenotype (CD62LlowIL-7RαlowCD44high). Subsequently, a progressive increase in the numbers of effector memory phenotype cells (CD62LlowIL-7RαhighCD44high) occurs. This differentiation program remained unchanged after accelerated removal of the pathogen with antibiotics, as majority of the primed cells displayed an effector memory phenotype even at 6 mo postinfection. Despite the chronic infection, CD8+ T cells induced by ST-OVA were functional as they exhibited killing ability and cytokine production. Importantly, even memory CD8+ T cells failed to undergo rapid expansion in response to ST-OVA infection, suggesting a delay in T cell priming during infection with virulent ST-OVA. Thus, phagosomal lifestyle may allow escape from host CD8+ T cell recognition, conferring a survival advantage to the pathogen.
Immunoediting of Cancers May Lead to Epithelial to Mesenchymal Transition
Authors: Knutson Keith L. , Lu Hailing , Stone Brad , Reiman Jennifer M. , Behrens Marshall D. , Prosperi Christine M. , Gad Ekram A. , Smorlesi Arianna , Disis Mary L. 
Published: April 2014

Abstract
Tumors evade both natural and pharmacologically induced (e.g., vaccines) immunity by a variety of mechanisms, including induction of tolerance and immunoediting. Immunoediting results in reshaping the immunogenicity of the tumor, which can be accompanied by loss of Ag expression and MHC molecules. In this study, we evaluated immunoediting in the neu-transgenic mouse model of breast cancer. A tumor cell line that retained expression of rat neu was generated from a spontaneous tumor of the neu-transgenic mouse and, when injected into the non-transgenic parental FVB/N mouse, resulted in the development of a strong immune response, initial rejection, and ultimately the emergence of neu Ag-loss variants. Morphologic and microarray data revealed that the immunoedited tumor cells underwent epithelial to mesenchymal transition accompanied by an up-regulation of invasion factors and increased invasiveness characteristic of mesenchymal tumor cells. These results suggest that immunoediting of tumor results in cellular reprogramming may be accompanied by alterations in tumor characteristics including increased invasive potential. Understanding the mechanisms by which tumors are immunoedited will likely lead to a better understanding of how tumors evade immune detection.
Differential Polarization of Immune Responses by Plant 2S Seed Albumins, Ber e 1, and SFA8
Authors: Kean Dorothy E. , Goodridge Helen S. , McGuinness Stephen , Harnett Margaret M. , Alcocer Marcos J. C. , Harnett William 
Published: April 2014

Abstract
The plant 2S seed albumins Ber e 1 and SFA8, although structurally very similar, vary with respect to their allergenic properties. Whereas the former represents a major allergen, the latter appears to promote only weak allergenic responses. The aim of this investigation was to determine whether the allergenic properties of Ber e 1 and SFA8 reflected differential polarization of dendritic cell (DC) and Th cell responses. We thus investigated the effect of recombinant forms of both allergens on DC and Th cell responses as indicated by cell surface phenotype and cytokine production. Exposure of murine DCs to SFA8, but not Ber e 1, resulted in production of the cytokines IL-12 p40 and TNF-α by a mechanism independent of recognition by TLRs. Furthermore, depending on the mouse strain used, increased expression of MHC class II and costimulatory molecules such as CD40, CD80, and CD86 was associated with exposure to SFA8, but not Ber e 1. In coculture experiments using the DO11.10 transgenic T cell that recognizes OVA peptide, DCs exposed to both allergens induced T cells to produce IFN-γ, but only Ber e 1 could induce significant production of IL-4 and IL-5. Likewise, analysis of transcription factors shows increased T-bet with respect to both allergens, but also GATA-3 with respect to Ber e 1. Overall, our data are consistent with the idea that the ability of Ber e 1, but not SFA8, to act as a potent allergen may reflect differences in their ability to induce IL-12 production.
Kinetics of B Cell Receptor Signaling in Human B Cell Subsets Mapped by Phosphospecific Flow Cytometry
Authors: Irish Jonathan M. , Czerwinski Debra K. , Nolan Garry P. , Levy Ronald 
Published: April 2014

Abstract
Differences in BCR signaling may govern outcomes as diverse as proliferation and cell death. We profiled BCR signaling kinetics in subsets of primary human B cells using flow cytometry. In the predominant population expressing IgM, BCR cross-linking led to a quick burst of Syk, ERK1/2, and p38 signaling. In contrast, IgG B cells sustained higher per-cell ERK1/2 phosphorylation over time. This dichotomy suggested a mechanism for dampening signals transmitted by IgM. Regulatory phosphatase activity in IgM B cells was BCR-mediated and initiated more slowly than kinase activity. This BCR-mediated phosphatase activity was sensitive to inhibition by H2O2 and required to attenuate IgM BCR signaling. These results provide the first kinetic maps of BCR signaling in primary human B cell subsets and enable new studies of signaling in B cell disorders, such as autoimmunity and cancer.
CD8αα-Mediated Intraepithelial Lymphocyte Snatching of Thymic Leukemia MHC Class Ib Molecules In Vitro and In Vivo
Authors: Pardigon Nathalie , Takeda Kazuyo , Saunier Bertrand , Hornung Felicita , Gibbs James , Weisberg Andrea , Contractor Nikhat , Kelsall Brian , Bennink Jack R. , Yewdell Jonathan W. 
Published: April 2014

Abstract
Thymic leukemia (TL) is a MHC class Ib molecule that interacts with CD8αα homodimers. CD8αα is abundantly expressed by intraepithelial T lymphocytes (IELs) located in close proximity to TL-expressing intestinal epithelial cells. In this study, we show that CD8αα+ IELs “snatch” TL from the plasma membrane of TL-expressing cells and express TL in its proper orientation on their own cell surface. TL snatching is enhanced by cross-linking of IEL TCRs in a phosphatidylinositol kinase-dependent manner, and results in overall alterations to the IEL cell surface detected by enhanced binding of peanut agglutinin lectin. Induction of bowel inflammation results in the presence of TL on IELs, probably via in vivo snatching, providing the initial evidence for the interaction of CD8αα IELs with intestinal cells.