bluuebunny/crossref_metadata_2025_split huggingface dataset:
The IL-4 Receptor α-Chain-Binding Cytokines, IL-4 and IL-13, Induce Forkhead Box P3-Expressing CD25+CD4+ Regulatory T Cells from CD25−CD4+ Precursors
Authors: Skapenko Alla , Kalden Joachim R. , Lipsky Peter E. , Schulze-Koops Hendrik 
Published: April 2014

Abstract
The mechanisms underlying the extrathymic generation of CD25+CD4 regulatory T cells (Tregs) are largely unknown. In this study the IL-4R α-chain-binding cytokines, IL-4 and IL-13, were identified as inducers of CD25+ Tregs from peripheral CD25−CD4 naive T cells. IL-4-induced CD25+ Tregs phenotypically and functionally resemble naturally occurring Tregs in that they are anergic to mitogenic stimulation, inhibit the proliferation of autologous responder T cells, express high levels of the Forkhead box P3 and the surface receptors glucocorticoid-induced TNFR family-related protein and CTLA-4, and inhibit effector T cells in a contact-dependent, but cytokine-independent, manner. The IL-4-induced generation of peripheral Tregs was independent of the presence of TGF-β or IL-10, but was dependent on Ag-specific stimulation and B7 costimulation. The significance of the IL-4Rα-binding cytokines in the generation of Ag-specific Tregs was emphasized in a mouse model of oral tolerance, in which neutralization of IL-4 and IL-13 in mice transgenic for the TCR specific for OVA completely inhibited the expansion of OVA-specific Tregs that can be induced in untreated mice by feeding the nominal Ag. Together, our results demonstrate that IL-4 and IL-13 play an important role in generating Forkhead box P3-expressing CD25+ Tregs extrathymically in an Ag-dependent manner and therefore provide an intriguing link between the well-established immunoregulatory capacity of Th2 cells and the powerful CD25+ Treg population. Moreover, our findings might provide the basis for the design of novel therapeutic approaches for targeted immunotherapy with Tregs to known Ags in autoimmune diseases or graft-vs-host reactions.
Selection of T Cell Clones Expressing High-Affinity Public TCRs within Human Cytomegalovirus-Specific CD8 T Cell Responses
Authors: Trautmann Lydie , Rimbert Marie , Echasserieau Klara , Saulquin Xavier , Neveu Bérangère , Dechanet Julie , Cerundolo Vincenzo , Bonneville Marc 
Published: April 2014

Abstract
Assessment of clonal diversity of T cell responses against human CMV (HCMV), a major cause of morbidity in immunodepressed patients, provides important insights into the molecular basis of T cell immunodominance, and has also clinical implications for the immunomonitoring and immunotherapy of HCMV infections. We performed an in-depth molecular and functional characterization of CD8 T cells directed against an immunodominant HLA-A2-restricted epitope derived from HCMV protein pp65 (NLV/A2) in steady state and pathological situations associated with HCMV reactivation. NLV/A2-specific T cells in healthy HCMV-seropositive donors showed limited clonal diversity and usage of a restricted set of TCR Vβ regions. Although TCRβ-chain junctional sequences were highly diverse, a large fraction of NLV/A2-specific T cells derived from distinct individuals showed several recurrent (so-called “public”) TCR features associated in some cases with full conservation of the TCRα chain junctional region. A dramatic clonal focusing of NLV/A2-specific T cells was observed in situations of HCMV reactivation and/or chronic inflammation, which resulted in selection of a single clonotype displaying similar public TCR features in several patients. In most instances the NLV/A2-specific dominant clonotypes showed higher affinity for their Ag than subdominant ones, thus suggesting that TCR affinity/avidity is the primary driving force underlying repertoire focusing along chronic antigenic stimulation.
Innate Immunity and Human B Cell Clonal Expansion: Effects on the Recirculating B2 Subpopulation
Authors: Mongini Patricia K. A. , Inman John K. , Han Hanna , Kalled Susan L. , Fattah Rasem J. , McCormick Steven 
Published: April 2014

AbstractFoci of autoantigen-specific B lymphocytes in nonlymphoid tissues have been associated with development of autoimmune disease. To better understand the genesis of such ectopic lymphoid tissue, this study investigated whether several B cell-tropic innate immune system molecules, known to be elevated in response to inflammatory stimuli, can cooperate in fostering the T cell-independent clonal expansion of mature human B2 cells under conditions of limiting BCR engagement. Notable synergy was observed between BCR coligation with the C3dg-binding CD21/CD19 costimulatory complex, B cell-activating factor belonging to the TNF family (BAFF), and IL-4 in generating B cell progeny with sustained CD86 and DR expression. The synergy was observed over a wide range of BCR:ligand affinities and involved: 1) cooperative effects at promoting early cell cycle progression and viability; 2) BCR:CD21 coligation-promoted increases in BAFF receptors that were highly regulated by IL-4; 3) reciprocal effects of IL-4 and BAFF at dampening daughter cell apoptosis typical of stimulation by BCR:CD21 and either cytokine alone; and 4) BAFF-sustained expression of antiapoptotic Mcl-1 within replicating lymphoblasts. The results suggest that significant clonal proliferation of recirculating B2 cells occurs upon limited binding to C3dg-coated Ag in an inflammatory in vivo milieu containing both BAFF and IL-4. When rare autoantigen-presenting B cells undergo such expansions, both B cell and T cell autoimmunity may be promoted.
A Role for B Cell-Activating Factor of the TNF Family in Chemically Induced Autoimmunity
Authors: Zheng Yan , Gallucci Stefania , Gaughan John P. , Gross Jane A. , Monestier Marc 
Published: April 2014

Abstract
After exposure to subtoxic doses of heavy metals such as mercury, H-2s mice develop an autoimmune syndrome consisting of the rapid production of IgG autoantibodies that are highly specific for nucleolar autoantigens and a polyclonal increase in serum IgG1 and IgE. In this study, we observe that HgCl2 administration in susceptible mice results in the elevated production of B cell-activating factor of the TNF family ((BAFF) also known as BLyS, TALL-1, zTNF-4, THANK, and TNSF13B), a B cell growth factor belonging to the TNF family. A transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI)-Ig fusion protein (which neutralizes both BAFF and a proliferation-inducing ligand (APRIL), another TNF family member) inhibited Hg-induced autoantibody or serum IgE production. These results are discussed in the context of the inhibitory effect of TACI-Ig on B cell maturation at the transitional stage.
Tumor Progression Can Occur despite the Induction of Very High Levels of Self/Tumor Antigen-Specific CD8+ T Cells in Patients with Melanoma
Authors: Rosenberg Steven A. , Sherry Richard M. , Morton Kathleen E. , Scharfman William J. , Yang James C. , Topalian Suzanne L. , Royal Richard E. , Kammula Udai , Restifo Nicholas P. , Hughes Marybeth S. , Schwartzentruber Douglas , Berman David M. , Schwarz Susan L. , Ngo Lien T. , Mavroukakis Sharon A. , White Donald E. , Steinberg Seth M. 
Published: April 2014

Abstract
The identification of many tumor-associated epitopes as nonmutated “self” Ags led to the hypothesis that the induction of large numbers of self/tumor Ag-specific T cells would be prevented because of central and peripheral tolerance. We report in this study on vaccination efforts in 95 HLA-A*0201 patients at high risk for recurrence of malignant melanoma who received prolonged immunization with the “anchor-modified” synthetic peptide, gp100209–217(210M). Vaccination using this altered peptide immunogen was highly effective at inducing large numbers of self/tumor-Ag reactive T cells in virtually every patient tested, with levels as high as 42% of all CD8+ T cells assessed by tetramer analysis. From 1 to 10% of all CD8+ cells were tumor-Ag reactive in 44% of patients and levels &gt;10% were generated in 17% of patients. These studies were substantiated using the ELISPOT assay and a bulk cytokine release assay. Although our data regarding “tumor escape” were inconclusive, some patients had growing tumors that expressed Ag and HLA-A*0201 in the presence of high levels of antitumor T cells. There was no difference in the levels of antitumor Ag-specific T cells in patients who recurred compared with those that remained disease-free. Thus, the mere presence of profoundly expanded numbers of vaccine-induced, self/tumor Ag-specific T cells cannot by themselves be used as a “surrogate marker” for vaccine efficacy. Further, the induction of even high levels of antitumor T cells may be insufficient to alter tumor progression.
Increased Susceptibility to Complement Attack due to Down-Regulation of Decay-Accelerating Factor/CD55 in Dysferlin-Deficient Muscular Dystrophy
Authors: Wenzel Katrin , Zabojszcza Joanna , Carl Miriam , Taubert Semjon , Lass Antje , Harris Claire L. , Ho Mengfatt , Schulz Herbert , Hummel Oliver , Hubner Norbert , Osterziel Karl Josef , Spuler Simone 
Published: April 2014

AbstractDysferlin is expressed in skeletal and cardiac muscles. However, dysferlin deficiency results in skeletal muscle weakness, but spares the heart. We compared intraindividual mRNA expression profiles of cardiac and skeletal muscle in dysferlin-deficient SJL/J mice and found down-regulation of the complement inhibitor, decay-accelerating factor/CD55, in skeletal muscle only. This finding was confirmed on mRNA and protein levels in two additional dysferlin-deficient mouse strains, A/J mice and Dysf−/− mice, as well as in patients with dysferlin-deficient muscular dystrophy. In vitro, the absence of CD55 led to an increased susceptibility of human myotubes to complement attack. Evidence is provided that decay-accelerating factor/CD55 is regulated via the myostatin-SMAD pathway. In conclusion, a novel mechanism of muscle fiber injury in dysferlin-deficient muscular dystrophy is demonstrated, possibly opening therapeutic avenues in this to date untreatable disorder.
A Suppressive Oligodeoxynucleotide Enhances the Efficacy of Myelin Cocktail/IL-4-Tolerizing DNA Vaccination and Treats Autoimmune Disease
Authors: Ho Peggy P. , Fontoura Paulo , Platten Michael , Sobel Raymond A. , DeVoss Jason J. , Lee Lowen Y. , Kidd Brian A. , Tomooka Beren H. , Capers Julien , Agrawal Ashish , Gupta Rohit , Zernik Jonathan , Yee Michael K. , Lee Byung J. , Garren Hideki , Robinson William H. , Steinman Lawrence 
Published: April 2014

AbstractTargeting pathogenic T cells with Ag-specific tolerizing DNA vaccines encoding autoantigens is a powerful and feasible therapeutic strategy for Th1-mediated autoimmune diseases. However, plasmid DNA contains abundant unmethylated CpG motifs, which induce a strong Th1 immune response. We describe here a novel approach to counteract this undesired side effect of plasmid DNA used for vaccination in Th1-mediated autoimmune diseases. In chronic relapsing experimental autoimmune encephalomyelitis (EAE), combining a myelin cocktail plus IL-4-tolerizing DNA vaccine with a suppressive GpG oligodeoxynucleotide (GpG-ODN) induced a shift of the autoreactive T cell response toward a protective Th2 cytokine pattern. Myelin microarrays demonstrate that tolerizing DNA vaccination plus GpG-ODN further decreased anti-myelin autoantibody epitope spreading and shifted the autoreactive B cell response to a protective IgG1 isotype. Moreover, the addition of GpG-ODN to tolerizing DNA vaccination therapy effectively reduced overall mean disease severity in both the chronic relapsing EAE and chronic progressive EAE mouse models. In conclusion, suppressive GpG-ODN effectively counteracted the undesired CpG-induced inflammatory effect of a tolerizing DNA vaccine in a Th1-mediated autoimmune disease by skewing both the autoaggressive T cell and B cell responses toward a protective Th2 phenotype. These results demonstrate that suppressive GpG-ODN is a simple and highly effective novel therapeutic adjuvant that will boost the efficacy of Ag-specific tolerizing DNA vaccines used for treating Th1-mediated autoimmune diseases.
Cutting Edge: Monovalency of CD28 Maintains the Antigen Dependence of T Cell Costimulatory Responses
Authors: Dennehy Kevin M. , Elias Fernando , Zeder-Lutz Gabrielle , Ding Xin , Altschuh Danièle , Lühder Fred , Hünig Thomas 
Published: April 2014

Abstract
CD28 and CTLA-4 are the major costimulatory receptors on naive T cells. But it is not clear why CD28 is monovalent whereas CTLA-4 is bivalent for their shared ligands CD80/86. We generated bivalent CD28 constructs by fusing the extracellular domains of CTLA-4 or CD80 with the intracellular domains of CD28. Bivalent or monovalent CD28 constructs were ligated with recombinant ligands with or without TCR coligation. Monovalent CD28 ligation did not induce responses unless the TCR was coligated. By contrast, bivalent CD28 ligation induced responses in the absence of TCR engagement. To extend these findings to primary cells, we used novel superagonistic and conventional CD28 Abs. Superagonistic Ab D665, but not conventional Ab E18, predominantly ligates CD28 bivalently at low CD28/Ab ratios and induces Ag-independent T cell proliferation. Monovalency of CD28 for its natural ligands is thus essential to provide costimulation without inducing responses in the absence of TCR engagement.
Regulation of T Cell Responses in the Developing Human Fetus
Authors: Michaëlsson Jakob , Mold Jeff E. , McCune Joseph M. , Nixon Douglas F. 
Published: April 2014

Abstract
Although human T cells enter the peripheral lymphoid tissues early during fetal development, the adaptive immune system in the fetus has largely been regarded as functionally immature and unresponsive to stimulation. In this study, we show that depletion of fetal CD4+CD25high T regulatory (TReg) cells, which are present at high frequency in fetal lymphoid tissues, results in vigorous T cell proliferation and cytokine production in vitro, even in the absence of exogenous stimulation. Analysis of CD4+ and CD8+ T cell populations revealed a large subset of cells that expressed the early activation Ag, CD69. We show that this population represents a subset of highly reactive fetal T cells actively suppressed by fetal CD4+CD25high TReg cells during development. These findings indicate that fetal T cells are, in the absence of CD4+CD25high TReg cells, highly responsive to stimulation and provide evidence for an important role for CD4+CD25high TReg cells in controlling T cell responses in utero.
Redundant Role of Chemokines CCL25/TECK and CCL28/MEC in IgA+ Plasmablast Recruitment to the Intestinal Lamina Propria After Rotavirus Infection
Authors: Feng Ningguo , Jaimes María C. , Lazarus Nicole H. , Monak Denise , Zhang Caiqui , Butcher Eugene C. , Greenberg Harry B. 
Published: April 2014

Abstract
Rotaviruses (RV) are the most important cause of severe childhood diarrheal disease. In suckling mice, infection with RV results in an increase in total and virus-specific IgA+ plasmablasts in the small intestinal lamina propria (LP) soon after infection, providing a unique opportunity to study the mechanism of IgA+ cell recruitment into the small intestine. In this study, we show that the increase in total and RV-specific IgA+ plasmablasts in the LP after RV infection can be blocked by the combined administration of Abs against chemokines CCL25 and CCL28, but not by the administration of either Ab alone. RV infection in CCR9 knockout mice still induced a significant accumulation of IgA+ plasmablasts in the LP, which was blocked by the addition of anti-CCL28 Ab, confirming the synergistic role of CCL25 and CCL28. The absence of IgA+ plasmablast accumulation in LP following combined anti-chemokine treatment was not due to changes in proliferation or apoptosis in these cells. We also found that coadministration of anti-CCL25 and anti-CCL28 Abs with the addition of anti-α4 Ab did not further inhibit IgA+ cell accumulation in the LP and that the CCL25 receptor, CCR9, was coexpressed with the intestinal homing receptor α4β7 on IgA+ plasmablasts. Finally, we showed that RV infection was associated with an increase in both CCL25 and CCL28 in the small intestine. Hence, our findings indicate that α4β7 along with either CCR9 or CCR10 are sufficient for mediating the intestinal migration of IgA+ plasmablasts during RV infection.
Regulatory T Cells Inhibit Protein Kinase Cθ Recruitment to the Immune Synapse of Naive T Cells with the Same Antigen Specificity
Authors: Sumoza-Toledo Adriana , Eaton Alfred D. , Sarukhan Adelaida 
Published: April 2014

Abstract
The precise mechanisms by which regulatory T cells operate, particularly their effect on signaling pathways leading to T cell activation, are poorly understood. In this study we have used regulatory T (Treg) cells of known Ag specificity, generated in vivo, to address their effects on early activation events occurring in naive T cells of the same Ag specificity. We found that the Treg cells need to be present at the moment of priming to suppress activation and proliferation of the naive T cell. Furthermore, the Treg cells significantly inhibit the recruitment of protein kinase Cθ (PKCθ) to the immune synapse of the naive T cell as long as both T cells are of the same Ag specificity and are contacting the same APC. Finally, naturally occurring CD4+25+ T cells seem to have the same effect on PKCθ recruitment in CD25− T cells of the same Ag specificity. These results suggest that although additional mechanisms of regulation are likely to exist, inhibition of PKCθ recruitment in the effector T cell may be a common regulatory pathway leading to the absence of NF-κB activation and contributing to the block of IL-2 secretion characteristic of immune suppression.
ERK1−/− Mice Exhibit Th1 Cell Polarization and Increased Susceptibility to Experimental Autoimmune Encephalomyelitis
Authors: Agrawal Anshu , Dillon Stephanie , Denning Timothy L. , Pulendran Bali 
Published: April 2014

Abstract
Activation of MAPK ERK1/2 has been shown to play an important role in Th1/Th2 polarization and in regulating cytokine production from APCs. The ERK family consists of two members ERK1 and ERK2, which share ∼84% identity at the amino acid level and can compensate for each other for most functions. Despite these features, ERK1 and ERK2 do serve different functions, but there is very little information on the contribution of individual forms of ERK on innate and adaptive immune responses. In this study, we describe that ERK1−/− mice display a bias toward Th1 type immune response. Consistent with this observation, dendritic cells from ERK1−/− mice show enhanced IL-12p70 and reduced IL-10 secretion in response to TLR stimulation. Furthermore, serum from ERK1−/− mice had 100-fold higher total IgG2b and 10-fold higher total IgG2a and IgG1 Ab isotype titers, and enhanced levels of Ag-specific IgG2b Ab titers, compared with wild-type mice. Consistent with this enhanced Th1 bias, ERK1−/− mice showed enhanced susceptibility to myelin oligodendrocyte glycoprotein (MOG)35–55 peptide-induced experimental autoimmune encephalomyelitis (EAE) and developed EAE earlier, and with increased severity, compared with wild-type mice. Importantly, there was a profound skewing toward Th1 responses in ERK1−/− mice, with higher IFN-γ production and lower IL-5 production in MOG35–55-primed T cells, as well as an augmentation in the MOG-specific IgG2a and IgG2b Th1 Ab isotypes. Finally, increased infiltrating cells and myelin destruction was observed in the spinal cord of ERK1−/− mice. Taken together, our data suggest that deficiency of ERK1 biases the immune response toward Th1 resulting in increased susceptibility to EAE.
Striking Immunodominance Hierarchy of Naturally Occurring CD8+ and CD4+ T Cell Responses to Tumor Antigen NY-ESO-1
Authors: Jackson Heather , Dimopoulos Nektaria , Mifsud Nicole A. , Tai Tsin Yee , Chen Qiyuan , Svobodova Suzanne , Browning Judy , Luescher Immanuel , Stockert Lisa , Old Lloyd J. , Davis Ian D. , Cebon Jonathan , Chen Weisan 
Published: April 2014

Abstract
Immunodominance has been well-demonstrated in many antiviral and antibacterial systems, but much less so in the setting of immune responses against cancer. Tumor Ag-specific CD8+ T cells keep cancer cells in check via immunosurveillance and shape tumor development through immunoediting. Because most tumor Ags are self Ags, the breadth and depth of antitumor immune responses have not been well-appreciated. To design and develop antitumor vaccines, it is important to understand the immunodominance hierarchy and its underlying mechanisms, and to identify the most immunodominant tumor Ag-specific T cells. We have comprehensively analyzed spontaneous cellular immune responses of one individual and show that multiple tumor Ags are targeted by the patient’s immune system, especially the “cancer-testis” tumor Ag NY-ESO-1. The pattern of anti-NY-ESO-1 T cell responses in this patient closely resembles the classical broad yet hierarchical antiviral immunity and was confirmed in a second subject.
Annexin V Associates with the IFN-γ Receptor and Regulates IFN-γ Signaling
Authors: Leon Carlos , Nandan Devki , Lopez Martin , Moeenrezakhanlou Alireza , Reiner Neil E. 
Published: April 2014

Abstract
Many of the biological activities of IFN-γ are mediated through the IFN-γR3-linked Jak-Stat1α pathway. However, regulation of IFN-γ signaling is not fully understood, and not all responses to IFN-γ are Stat1α dependent. To identify novel elements involved in IFN-γ cell regulation, the cytoplasmic domain of the R2 subunit of the human IFN-γR was used as bait in a yeast two-hybrid screen of a human monocyte cDNA library. This identified annexin A5 (AxV) as a putative IFN-γR binding protein. The interaction was confirmed in pull-down experiments in which a GST-R2 cytoplasmic domain fusion protein was incubated with macrophage lysates. Furthermore, immunoprecipitation using anti-IFN-γR2 Abs showed that AxV interacted with IFN-γR2 to form a stable complex following incubation of cells with IFN-γ. In 293T cells with reduced expression of AxV, brought about by small interfering RNA targeting, activation of Jak2 and Stat1α in response to IFN-γ was enhanced. Inhibition of cell proliferation, a hallmark of the IFN-γ response, also was potentiated in HeLa cells treated with small interfering RNA directed at AxV. Taken together, these results suggest that through an inducible association with the R2 subunit of the IFN-γR, AxV modulates cellular responses to IFN-γ by modulating signaling through the Jak-Stat1 pathway.
Peripheral Tolerance Via the Anterior Chamber of the Eye: Role of B Cells in MHC Class I and II Antigen Presentation
Authors: Ashour Hossam M. , Niederkorn Jerry Y. 
Published: April 2014

Abstract
Ags introduced into the anterior chamber (AC) of the eye induce a form of peripheral immune tolerance termed AC-associated immune deviation (ACAID). ACAID mitigates ocular autoimmune diseases and promotes corneal allograft survival. Ags injected into the AC are processed by F4/80+ APCs, which migrate to the thymus and spleen. In the spleen, ocular APCs induce the development of Ag-specific B cells that act as ancillary APCs and are required for ACAID induction. In this study, we show that ocular-like APCs elicit the generation of Ag-specific splenic B cells that induce ACAID. However, direct cell contact between ocular-like APCs and splenic B cells is not necessary for the induction of ACAID B cells. Peripheral tolerance produced by ACAID requires the participation of ACAID B cells, which induce the generation of both CD4+ regulatory T cells (Tregs) and CD8+ Tregs. Using in vitro and in vivo models of ACAID, we demonstrate that ACAID B cells must express both MHC class I and II molecules for the generation of Tregs. These results suggest that peripheral tolerance induced through the eye requires Ag-presenting B cells that simultaneously present Ags on both MHC class I and II molecules.