bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunization with a Mimotope of GD2 Ganglioside Induces CD8+ T Cells That Recognize Cell Adhesion Molecules on Tumor Cells
Authors: Wierzbicki Andrzej , Gil Margaret , Ciesielski Michael , Fenstermaker Robert A. , Kaneko Yutaro , Rokita Hanna , Lau Joseph T. , Kozbor Danuta 
Published: April 2014

Abstract
The GD2 ganglioside expressed on neuroectodermal tumor cells has been used as a target for passive and active immunotherapy in patients with malignant melanoma and neuroblastoma. We have reported that immunization of mice with a 47-LDA mimotope of GD2, isolated from a phage display peptide library with anti-GD2 mAb 14G2a, induces MHC class I-restricted CD8+ T cell responses to syngeneic neuroblastoma tumor cells. The cytotoxic activity of the vaccine-induced CTLs was independent of GD2 expression, suggesting recognition of a novel tumor-associated Ag cross-reacting with 47-LDA. Glycan microarray and immunoblotting studies using 14G2a mAb demonstrated that this Ab is highly specific for the entire carbohydrate motif of GD2 but also cross-reacts with a 105 kDa glycoprotein expressed by GD2+ and GD2− neuroblastoma and melanoma cells. Functional studies of tumor cells grown in three-dimensional collagen cultures with 14G2a mAb showed decreases in matrix metalloproteinase-2 activation, a process regulated by the 105 kDa-activated leukocyte cell adhesion molecule (ALCAM/CD166). A recombinant CD166 glycoprotein was shown to be recognized by 14G2a Ab and inhibition of CD166 expression by RNA interference ablated the cell sensitivity to lysis by 47-LDA-induced CD8+ T cells in vitro and in vivo. The binding of 14G2a to CD166 was not disruptable by a variety of exo- and endo-glycosidases, implying recognition of a non-glycan epitope on CD166. These results suggest that the vaccine-induced CTLs recognize a 47-LDA cross-reactive epitope expressed by CD166, and reveal a novel mechanism of induction of potent tumor-specific cellular responses by mimotopes of tumor-associated carbohydrate Ags.
Bone Marrow-Derived IFN-Producing Killer Dendritic Cells Account for the Tumoricidal Activity of Unpulsed Dendritic Cells
Authors: Himoudi Nourredine , Nabarro Stephen , Buddle Jo , Eddaoudi Ayad , Thrasher Adrian J. , Anderson John 
Published: April 2014

Abstract
The CD11cintB220+NK1.1+CD49+ subset of cells has recently been described as IFN-producing killer dendritic cells (IKDC), which share phenotypic and functional properties of dendritic cells and NK cells. Herein we show that bone marrow-derived murine dendritic cell preparations contain abundant CD11cintB220+NK1.1+CD49+ cells, the removal of which results in loss of tumoricidal activity of unpulsed dendritic cells in vivo. Moreover, following s.c. injection, as few as 5 × 103 highly pure bone marrow-derived IKDC cells are capable of shrinking small contralateral syngeneic tumors in C57BL/6 mice, but not in immunodeficient mice, implying the obligate involvement of host effector cells in tumor rejection. Our data suggest that bone marrow-derived IKDC represent a population that has powerful tumoricidal activity in vivo.
Crucial Role of Aspartic Acid at Position 265 in the CH2 Domain for Murine IgG2a and IgG2b Fc-Associated Effector Functions
Authors: Baudino Lucie , Shinohara Yasuro , Nimmerjahn Falk , Furukawa Jun-Ichi , Nakata Munehiro , Martínez-Soria Eduardo , Petry Franz , Ravetch Jeffery V. , Nishimura Shin-Ichiro , Izui Shozo 
Published: April 2014

Abstract
Replacement of aspartic acid by alanine at position 265 (D265A) in mouse IgG1 results in a complete loss of interaction between this isotype and low-affinity IgG Fc receptors (FcγRIIB and FcγRIII). However, it has not yet been defined whether the D265A substitution could exhibit similar effects on the interaction with two other FcγR (FcγRI and FcγRIV) and on the activation of complement. To address this question, 34-3C anti-RBC IgG2a and IgG2b switch variants bearing the D265A mutation were generated, and their effector functions and in vivo pathogenicity were compared with those of the respective wild-type Abs. The introduction of the D265A mutation almost completely abolished the binding of 34-3C IgG2a and IgG2b to all four classes of FcγR and the activation of complement. Consequently, these mutants were hardly pathogenic. Although oligosaccharide side chains of these mutants were found to contain higher levels of sialic acids than those of wild-type Abs, the analysis of enzymatically desialylated D265A variants ruled out the possibility that very poor Fc-associated effector functions of the D265A mutants were due to an increased level of the mutant Fc sialylation. Thus, our results demonstrate that aspartic acid at position 265 is a residue critically implicated in triggering the Fc-associated effector functions of IgG, probably by defining a crucial three-dimensional structure of the Fc region.
CD69+CD4+CD25− T Cells, a New Subset of Regulatory T Cells, Suppress T Cell Proliferation through Membrane-Bound TGF-β1
Authors: Han Yanmei , Guo Qiuli , Zhang Minggang , Chen Zhubo , Cao Xuetao 
Published: April 2014

Abstract
The underlying mechanisms of tumor-induced immune suppression need to be fully understood. Regulatory T (Treg) cells have been shown to play an important role in tumor immune escape. Until now, many subsets of Treg cells have been described that can suppress T cell response via different mechanisms. CD69 is generally regarded as one of the activating markers; however, recent studies show that CD69 may exert regulatory function in the immune response. In this study, we have identified tumor-induced CD69+CD4+CD25− T cells as a new subset of CD4+ Treg cells. CD69+CD4+CD25− T cells increase dramatically along tumor progression, with up to 40% of CD4+ T cells in the advanced tumor-bearing mice. Distinct from the previously described CD4+ Treg cell subsets, CD69+CD4+CD25− T cells express high CD122, but they do not express Foxp3 and secrete IL-10, TGF-β1, IL-2, and IFN-γ. CD69+CD4+CD25− T cells are hyporesponsive and can suppress CD4+ T cell proliferation in a cell-cell contact manner. Interestingly, the fixed CD69+CD4+CD25− T cells still have suppressive activity, and neutralizing Abs against TGF-β1 can block their suppressive activity. We found that CD69+CD4+CD25− T cells express membrane-bound TGF-β1, which mediates suppression of T cell proliferation. Furthermore, engagement of CD69 maintains high expression of membrane-bound TGF-β1 on CD69+CD4+CD25− T cells via ERK activation. Our results demonstrate that CD69+CD4+CD25− T cells act as a new subset of regulatory CD4+ T cells, with distinct characteristics of negative expression of Foxp3, no secretion of IL-10, but high expression of CD122 and membrane-bound TGF-β1. Our data contribute to the better understanding of mechanisms for tumor immune escape.
An Essential Role for the Stalk Region of CD8β in the Coreceptor Function of CD8
Authors: Rettig Lorna , McNeill Louise , Sarner Nitza , Guillaume Philippe , Luescher Immanuel , Tolaini Mauro , Kioussis Dimitris , Zamoyska Rose 
Published: April 2014

Abstract
The CD8αβ heterodimer is integral to the selection of the class I-restricted lineage in the thymus; however, the contribution of the CD8β chain to coreceptor function is poorly understood. To understand whether the CD8β membrane proximal stalk region played a role in coreceptor function, we substituted it with the corresponding sequence from the CD8α polypeptide and expressed the hybrid molecule in transgenic mice in place of endogenous CD8β. Although the stalk-swapped CD8β was expressed on the cell surface as a disulfide-bonded heterodimer at equivalent levels of expression to an endogenous CD8β molecule, it failed to restore selection of CD8+ class I MHC-restricted T cells and it altered the response of peripheral T cells. Thus, the stalk region of the CD8β polypeptide has an essential role in ensuring functionality of the CD8αβ heterodimer and its replacement compromises the interaction of CD8 with peptide-MHC complexes.
Checkpoints in the Development of Thymic Cortical Epithelial Cells
Authors: Shakib Saba , Desanti Guillaume E. , Jenkinson William E. , Parnell Sonia M. , Jenkinson Eric J. , Anderson Graham 
Published: April 2014

Abstract
In the thymus, interactions between immature thymocytes and thymic epithelial cells (TECs) regulate the development and selection of self-tolerant MHC-restricted T cells. Despite the importance of cortical (cTEC) and medullary (mTEC) thymic epithelial cells in fostering T cell production, events in TEC development are still unclear. Although precursor-product relationships during mTEC development have been reported, and some genetic regulators of mTEC development have been identified, stages in cTEC development occurring downstream of recently identified bipotent cTEC/mTEC progenitors remain poorly defined. In this study, we combine analysis of differentiation, proliferation, and gene expression of TECs in the murine thymus, that has enabled us to identify cTEC progenitors, define multiple stages in cTEC development, and identify novel checkpoints in development of the cTEC lineage. We show an essential requirement for FoxN1 in the initial development of cTEC from bipotent progenitors, and demonstrate a stage-specific requirement for CD4−8− thymocytes in later stages of cTEC development. Collectively, our data establish a program of cTEC development that should provide insight into the formation and function of the thymic cortex for T cell development.
Deviation of the B Cell Pathway in Senescent Mice Is Associated with Reduced Surrogate Light Chain Expression and Altered Immature B Cell Generation, Phenotype, and Light Chain Expression
Authors: Alter-Wolf Sarah , Blomberg Bonnie B. , Riley Richard L. 
Published: April 2014

Abstract
B lymphopoiesis in aged mice is characterized by reduced B cell precursors and an altered Ab repertoire. This likely results, in part, from reduced surrogate L chains in senescent B cell precursors and compromised pre-BCR checkpoints. Herein, we show that aged mice maintain an ordinarily minor pool of early c-kit+ pre-B cells, indicative of poor pre-BCR expression, even as pre-BCR competent early pre-B cells are significantly reduced. Therefore, in aged mice, B2 B lymphopoiesis shifts from dependency on pre-BCR expansion and selection to more pre-BCR-deficient pathways. B2 c-kit+ B cell precursors, from either young or aged mice, generate new B cells in vitro that are biased to larger size, higher levels of CD43, and decreased κ L chain expression. Notably, immature B cells in aged bone marrow exhibit a similar phenotype in vivo. We hypothesize that reduced surrogate L chain expression contributes to decreased pre-B cells in aged mice. The B2 pathway is partially blocked with limited B cell development and reduced pre-BCR expression and signaling. In old age, B2 pathways have limited surrogate L chain and increasingly generate new B cells with altered phenotype and L chain expression.
Levels of Foxp3 in Regulatory T Cells Reflect Their Functional Status in Transplantation
Authors: Chauhan Sunil K. , Saban Daniel R. , Lee Hyung K. , Dana Reza 
Published: April 2014

Abstract
Foxp3 expressing CD4+CD25+ regulatory T cells (Tregs) have been shown to prevent allograft rejection in clinical and animal models of transplantation. However, the role of Foxp3 in regulating Treg function, and the kinetics and mechanism of action of Tregs in inducing allograft tolerance in transplantation, are still not fully understood. Thus, we investigated the kinetics and function of Tregs in a mouse model of orthotopic corneal transplantation, the most common form of tissue grafting worldwide. In this study, using in vitro functional assays and in vivo Treg adoptive transfer assays, we show that far more relevant than Treg frequency is their level of Foxp3 expression, which is directly associated with the potential of Tregs to prevent allograft rejection by producing regulatory cytokines and suppressing effector T cell activation. In addition, our data clearly demonstrate that Tregs primarily suppress the induction of alloimmunity in regional draining lymph nodes rather than suppressing the effector phase of the immune response in the periphery. These findings provide new insights on Treg dynamics in transplantation, which are crucial for designing therapeutic strategies to modulate Treg function and to optimize Treg-based cell therapies for clinical translation.
TCRμ Recombination and Transcription Relative to the Conventional TCR during Postnatal Development in Opossums
Authors: Parra Zuly E. , Baker Michelle L. , Lopez April M. , Trujillo Jonathan , Volpe Joseph M. , Miller Robert D. 
Published: April 2014

AbstractMarsupials are a distinct lineage of mammals notable for giving birth to highly altricial (relatively less developed) young. The recent discovery of a unique TCR chain in marsupials, TCRμ, raises questions about its possible role in early development. Here we compare the timing of V(D)J recombination and appearance of TCRμ transcripts relative to the conventional TCRα, β, γ, and δ mRNA during postnatal development in the opossum. There are two TCRμ transcript isoforms, TCRμ1.0 and TCRμ2.0. TCRμ1.0, which uses prejoined V(D)J segments, is detectable as early as day 1, when the thymus is primarily undifferentiated epithelium. The other isoform, TCRμ2.0, which requires V(D)J recombination and contains an unusual double V configuration, is not detectable until day 13 when the thymus is histologically mature. Surprisingly, we were able to detect TCRα, β, and δ mRNA transcribed from loci that had completed V(D)J recombination as early as day 1 as well. At this early age there is apparent evidence for preference in the V segments used in the TCRα and β genes. In the case of Vα this preference appears to be associated with position in the TCRα/δ locus. In Vβ, however, preference may be due to the use of microhomology in the V, D, and J segments. Mature TCRγ transcripts were not detected until day 8, suggesting that, in contrast to eutherian mammals, in the opossum αβ T cell development precedes γδ T cell development. The results support that there may be differences in T cell subset development between marsupials and placental mammals.
Ly49D Engagement on T Lymphocytes Induces TCR-Independent Activation and CD8 Effector Functions That Control Tumor Growth
Authors: Merck Estelle , Voyle Roger B. , MacDonald H. Robson 
Published: April 2014

AbstractRecent data showing expression of activating NK receptors (NKR) by conventional T lymphocytes raise the question of their role in the triggering of TCR-independent responses that could be damaging for the host. Transgenic mice expressing the activating receptor Ly49D/DAP12 offer the opportunity to better understand the relevance of ITAM signaling in the biology of T cells. In vitro experiments showed that Ly49D engagement on T lymphocytes by a cognate MHC class I ligand expressed by Chinese hamster ovary (CHO) cells or by specific Ab triggered cellular activation of both CD4 and CD8 populations with modulation of activation markers and cytokine production. The forced expression of the ITAM signaling chain DAP12 is mandatory for Ly49D-transgenic T cell activation. In addition, Ly49D stimulation induced T lymphocyte proliferation, which was much stronger for CD8 T cells. Phenotypic analysis of anti-Ly49D-stimulated CD8 T cells and their ability to produce high levels of IFN-γ and to kill target cells indicate that Ly49D ligation generates effector cytotoxic CD8 T cells. Ly49D engagement by itself also triggered cytotoxic activity of activated CD8 T cells. Adoptive transfer experiments confirmed that Ly49D-transgenic CD8 T cells are able to control growth of CHO tumor cells or RMA cells transfected with Hm1-C4, the Ly49D ligand normally expressed by CHO. In conclusion, Ly49D engagement on T cells leads to T cell activation and to a full range of TCR-independent effector functions of CD8 T cells.
CD4+ Th-APC with Acquired Peptide/MHC Class I and II Complexes Stimulate Type 1 Helper CD4+ and Central Memory CD8+ T Cell Responses
Authors: Umeshappa Channakeshava Sokke , Huang Hui , Xie Yufeng , Wei Yangdou , Mulligan Sean J. , Deng Yulin , Xiang Jim 
Published: April 2014

Abstract
T cell-T cell Ag presentation is increasingly attracting attention. We previously showed that the in vitro OVA-pulsed dendritic cell (DCOVA)-activated CD4+ Th cells acquired OVA peptide/MHC (pMHC) class I and costimulatory molecules such as CD54 and CD80 from DCOVA and acted as CD4+ Th-APC capable of stimulating OVA-specific CD8+ CTL responses. In this study, we further applied the OVA-specific TCR-transgenic OT I and OT II mice with deficiency of various cytokines or costimulatory molecule genes useful for studying the molecular mechanisms underlying in Th-APC’s stimulatory effect. We demonstrated that DCOVA-stimulated OT II CD4+ Th-APC also acquired costimulatory molecules such as CD40, OX40L, and 4-1BBL and the functional pMHC II complexes by DCOVA activation. CD4+ Th-APC with acquired pMHC II and I were capable of stimulating CD4+ Th1 and central memory CD8+44+CD62LhighIL-7R+ T cell responses leading to antitumor immunity against OVA-expressing mouse B16 melanoma. Their stimulatory effect on CD8+ CTL responses and antitumor immunity is mediated by IL-2 secretion, CD40L, and CD80 signaling and is specifically targeted to CD8+ T cells in vivo via acquired pMHC I. In addition, CD4+ Th-APC expressing OVA-specific TCR, FasL, and perforin were able to kill DCOVA and neighboring Th-APC expressing endogenous and acquired pMHC II. Taken together, we show that CD4+ Th-APC can modulate immune responses by stimulating CD4+ Th1 and central memory CD8+ T cell responses and eliminating DCOVA and neighboring Th-APC. Therefore, our findings may have great impacts in not only the antitumor immunity, but also the regulatory T cell-dependent immune tolerance in vivo.
Insights into the Role of STAT3 in Human Lymphocyte Differentiation as Revealed by the Hyper-IgE Syndrome
Authors: Tangye Stuart G. , Cook Matthew C. , Fulcher David A. 
Published: April 2014

Abstract
“Experiments of nature” due to single gene mutations resulting in human immunodeficiency states have revealed critical roles for several genes in regulating lymphocyte development and the generation of protective immunity. Recently, heterozygous mutations in STAT3 were found to cause autosomal dominant hyper-IgE syndrome, a condition affecting not only the immune system but also other mesenchymal and ectodermal tissues, including bones, cranium, teeth, and skin. STAT proteins operate to integrate signals from surface receptors, including cytokine receptors, that regulate growth and differentiation of multiple cell lineages. In this article, we will review how the study of STAT3 deficiency in humans and mice has highlighted nonredundant roles of STAT3, and of specific cytokines, in diverse cellular processes such as antimicrobial immunity and protection at epithelial barriers, the generation of functional humoral immune responses, bone formation, and keratinocyte biology.
Follistatin-Like Protein 1 Promotes Arthritis by Up-Regulating IFN-γ
Authors: Clutter Suzanne D. , Wilson David C. , Marinov Anthony D. , Hirsch Raphael 
Published: April 2014

Abstract
Follistatin-like protein-1 (FSTL-1) is a poorly characterized protein that is up-regulated in the early stage of collagen-induced arthritis and that exacerbates arthritis when delivered by gene transfer. The current study was designed to determine the mechanism by which FSTL-1 promotes arthritis. FSTL-1 was injected into mouse paws, resulting in severe paw swelling associated with up-regulation of IFN-γ transcript and the IFN-γ-induced chemokine, CXCL10. Mice depleted of T cells were protected. A central role for IFN-γ was confirmed by the finding that mice deficient in IFN-γ failed to exhibit paw swelling in response to injection of FSTL-1. Furthermore, IFN-γ secretion from mouse spleen cells exposed to a weak TCR signal was increased 5-fold in the presence of FSTL-1. FSTL-1 could be induced by innate immune signals, including TLR4 agonists and the arthritogenic cytokine, IL-1β, via an NFκB pathway. Finally, FSTL-1 was found to be overexpressed in human arthritis and its neutralization inhibited murine collagen-induced arthritis and suppressed IFN-γ and CXCL10 production in arthritic joints. These findings demonstrate that FSTL-1 plays a critical role in arthritis by enhancing IFN-γ signaling pathways and suggest a mechanism by which FSTL-1 bridges innate and adaptive immune responses.
Epigenetic Regulation of Foxp3 Expression in Regulatory T Cells by DNA Methylation
Authors: Lal Girdhari , Zhang Nan , van der Touw William , Ding Yaozhong , Ju Wenjun , Bottinger Erwin P. , Reid St. Patrick , Levy David E. , Bromberg Jonathan S. 
Published: April 2014

Abstract
Foxp3, a winged-helix family transcription factor, serves as the master switch for CD4+ regulatory T cells (Treg). We identified a unique and evolutionarily conserved CpG-rich island of the Foxp3 nonintronic upstream enhancer and discovered that a specific site within it was unmethylated in natural Treg (nTreg) but heavily methylated in naive CD4+ T cells, activated CD4+ T cells, and peripheral TGFβ-induced Treg in which it was bound by DNMT1, DNMT3b, MeCP2, and MBD2. Demethylation of this CpG site using the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza) induced acetylation of histone 3, interaction with TIEG1 and Sp1, and resulted in strong and stable induction of Foxp3. Conversely, IL-6 resulted in methylation of this site and repression of Foxp3 expression. Aza plus TGFβ-induced Treg resembled nTreg, expressing similar receptors, cytokines, and stable suppressive activity. Strong Foxp3 expression and suppressor activity could be induced in a variety of T cells, including human CD4+CD25− T cells. Epigenetic regulation of Foxp3 can be predictably controlled with DNMT inhibitors to generate functional, stable, and specific Treg.
CTLA-4 Controls Regulatory T Cell Peripheral Homeostasis and Is Required for Suppression of Pancreatic Islet Autoimmunity
Authors: Schmidt Emily M. , Wang Chun Jing , Ryan Gemma A. , Clough Louise E. , Qureshi Omar S. , Goodall Margaret , Abbas Abul K. , Sharpe Arlene H. , Sansom David M. , Walker Lucy S. K. 
Published: April 2014

Abstract
The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3+ regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3+ cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity.