bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Third Signal in T Cell-Mediated Autoimmune Disease?
Authors: Darabi Kamruz , Karulin Alexey Y. , Boehm Bernhard O. , Hofstetter Harald H. , Fabry Zsuzsa , LaManna Joseph C. , Chavez Juan C. , Tary-Lehmann Magdalena , Lehmann Paul V. 
Published: April 2014

Abstract
The initial event in the pathogenesis of autoimmune disease is thought to be the priming of naive autoreactive T cells by an infection with a cross-reactive microorganism. Although such cross-reactive priming should be a common event, autoimmune disease does not frequently develop. This situation is reflected after the immunization of C57BL/6 mice with the neuroantigen myelin oligodendrocyte glycoprotein (MOG) with CFA, which primes a type 1 T cell response but does not lead to clinical or histological manifestation of experimental allergic encephalomyelitis unless pertussis toxin is injected in addition. We show in this study that, in MOG:CFA-primed mice, the autoimmune CNS pathology develops after intracerebral deposition of TLR9-activating CpG oligonucleotides, but not following non-CpG oligonucleotide injection or after aseptic cryoinjury of the brain. Thus, access of primed MOG-specific Th1 cells to the uninflamed CNS or to CNS undergoing sterile inflammation did not suffice to elicit autoimmune pathology; only if the APC in the target organ were activated in addition by the TLR9-stimulating microbial product did they exert local effector functions. The data suggest that such licensing of APC in the target organ by microbial stimuli represents a checkpoint for functional self-tolerance. Therefore, microorganisms unrelated to the cross-reactive agent that primes the autoreactive T cells could dictate the onset and exacerbation of autoimmune diseases.
TLR Signaling: An Emerging Bridge from Innate Immunity to Atherogenesis
Authors: Michelsen Kathrin S. , Doherty Terence M. , Shah Prediman K. , Arditi Moshe 
Published: April 2014

Abstract
Chronic inflammation and disordered lipid metabolism represent hallmarks of atherosclerosis. Considerable evidence suggests that innate immune defense mechanisms might interact with proinflammatory pathways and contribute to development of arterial plaques. The preponderance of such evidence has been indirect clinical and epidemiologic studies, with some support from experimental animal models of atherosclerosis. However, recent data now directly implicate signaling by TLR4 in the pathogenesis of atherosclerosis, establishing a key link between atherosclerosis and defense against both foreign pathogens and endogenously generated inflammatory ligands. In this study, we briefly review these and closely related studies, highlighting areas that should provide fertile ground for future studies aimed at a more comprehensive understanding of the interplay between innate immune defense mechanisms, atherosclerosis, and related vascular disorders.
Cutting Edge: Human Eosinophils Regulate T Cell Subset Selection through Indoleamine 2,3-Dioxygenase
Authors: Odemuyiwa Solomon O. , Ghahary Ahmad , Li Yunyuan , Puttagunta Lakshmi , Lee Joo Eun , Musat-Marcu Sorin , Ghahary Aziz , Moqbel Redwan 
Published: April 2014

Abstract
Allergy involves eosinophilia and Th2 polarization. Indoleamine 2,3-dioxygenase (IDO)-catalyzed conversion of tryptophan to kynurenines (KYN) regulates T cell function. We show that human eosinophils constitutively express IDO. Eosinophils treated with IFN-γ showed an 8-fold increase in IDO mRNA within 4 h; IL-3, IL-5, and GM-CSF had no effect on baseline IDO expression. IL-3 pretreatment of eosinophils reduced IFN-γ-induced IDO mRNA expression below baseline. Conversely, GM-CSF, but not IL-5, resulted in a 2-fold increase in IFN-γ-induced IDO. Treatment with IL-3, IL-5, GM-CSF, or IFN-γ alone expressed IDO enzymatic activity (the presence of KYN in supernatants 48 h postculture). CD28 cross-linking resulted in measurable KYN in culture supernatants, inhibitable by a neutralizing anti-IFN-γ. Coculture of eosinophils with an IFN-γ-producing T cell line, but not IL-4-producing T cell clone, led to apoptosis and inhibition of CD3 or CD3/CD28-induced proliferation. Eosinophils infiltrating asthmatic lung and associated lymphoid tissue exhibited intracellular IDO immunoreactivity. Eosinophils may, therefore, maintain Th2 bias through IDO.
Cutting Edge: Bone Morphogenetic Protein Antagonists Drm/Gremlin and Dan Interact with Slits and Act as Negative Regulators of Monocyte Chemotaxis
Authors: Chen Bo , Blair Donald G. , Plisov Sergei , Vasiliev Gennady , Perantoni Alan O. , Chen Qian , Athanasiou Meropi , Wu Jane Y. , Oppenheim Joost J. , Yang De 
Published: April 2014

AbstractDrm/Gremlin and Dan, two homologous secreted antagonists of bone morphogenic proteins, have been shown to regulate early development, tumorigenesis, and renal pathophysiology. In this study, we report that Drm and Dan physically and functionally interact with Slit1 and Slit2 proteins. Drm binding to Slits depends on its glycosylation and is not interfered with by bone morphogenic proteins. Importantly, Drm and Dan function as inhibitors for monocyte migration induced by stromal cell-derived factor 1α (SDF-1α) or fMLP. The inhibition of SDF-1α-induced monocyte chemotaxis by Dan is not due to blocking the binding of SDF-1α to its receptor. Thus, the results identify that Drm and Dan can interact with Slit proteins and act as inhibitors of monocyte chemotaxis, demonstrating a previously unidentified biological role for these proteins.
Cutting Edge: Immunity and IFN-γ Production during Listeria monocytogenes Infection in the Absence of T-bet
Authors: Way Sing Sing , Wilson Christopher B. 
Published: April 2014

Abstract
The T-box transcription factor T-bet is an important regulator of IFN-γ production in all cell types and is considered to be essential for the generation of CD4 Th1 T cells. IFN-γ in turn plays a critical role in immunity to many infectious agents. In this study, we demonstrate that T-bet is not required for host resistance to primary Listeria monocytogenes (LM) infection. In the innate immune phase, control of LM replication, serum IFN-γ, and numbers of IFN-γ-producing NK cells were similar in T-bet-deficient and control mice. In the adaptive immune phase, there was no defect in bacterial clearance or in the numbers of LM-specific IFN-γ-producing CD8 T cells in T-bet-deficient mice and only a modest, although significant, reduction in the numbers of Th1 CD4 T cells and IFN-γ secretion by CD4 T cells. Thus, host resistance and the generation of IFN-γ-producing cells in response to LM infection are not substantially compromised in the absence of T-bet.
Cutting Edge: Tumor-Specific CTL Are Constitutively Cross-Armed in Draining Lymph Nodes and Transiently Disseminate to Mediate Tumor Regression following Systemic CD40 Activation
Authors: Stumbles Philip A. , Himbeck Robyn , Frelinger Jeffrey A. , Collins Edward J. , Lake Richard A. , Robinson Bruce W. S. 
Published: April 2014

Abstract
The cross-arming of effector CTL in response to cross-presented tumor Ags is predicted to fail in the absence of CD40 stimulation. However, questions remain regarding the role of CD40 signaling and additional CD4+ T cell-derived signals in this process. To address this, we have analyzed the cross-arming of tumor-specific CTL effectors in vivo in a mouse model of established tumor and tumor regression following CD40 activation. We found that tumor-specific CTL were constitutively cross-armed in tumor-draining lymph nodes during tumor growth and that systemic CD40 activation did not alter CTL cross-arming in the tumor-draining lymph nodes. Rather, CD40 activation induced peripheral dissemination of tumor-specific CTL effectors that required continual CD40 stimulation to maintain peripheral CTL and tumor regression. These data indicate that CD40 activation enhances the peripheral survival of constitutively cross-armed CTL and that persistent CD4+ T cell signals are required for their long-term activity.
Eosinophil Adhesion to Cholinergic IMR-32 Cells Protects against Induced Neuronal Apoptosis
Authors: Morgan Ross K. , Kingham Paul J. , Walsh Marie Therese , Curran David C. , Durcan Niamh , McLean W. Graham , Costello Richard W. 
Published: April 2014

Abstract
Eosinophils release a number of mediators that are potentially toxic to nerve cells. However, in a number of inflammatory conditions, such as asthma and inflammatory bowel disease, it has been shown that eosinophils localize to nerves, and this is associated with enhanced nerve activity. In in vitro studies, we have shown that eosinophil adhesion via neuronal ICAM-1 leads to activation of neuronal NF-κB via an ERK1/2-dependent pathway. In this study, we tested the hypothesis that eosinophil adhesion to nerves promotes neural survival by protection from inflammation-associated apoptosis. Exposure of differentiated IMR-32 cholinergic nerve cells to IL-1β, TNF-α, and IFN-γ, or culture in serum-deprived medium, induced neuronal apoptosis, as detected by annexin V staining, caspase-3 activation, and DNA laddering. Addition of human eosinophils to IMR-32 nerve cells completely prevented all these features of apoptosis. The mechanism of protection by eosinophils was by an adhesion-dependent activation of ERK1/2, which led to the induced expression of the antiapoptotic gene bfl-1. Adhesion to nerve cells did not influence the expression of the related genes bax and bad. Thus, prevention of apoptosis by eosinophils may be a mechanism by which these cells regulate neural plasticity in the peripheral nervous system.
Impaired Receptor Editing in the Primary B Cell Repertoire of BASH-Deficient Mice
Authors: Hayashi Katsuhiko , Nojima Takuya , Goitsuka Ryo , Kitamura Daisuke 
Published: April 2014

AbstractThe editing of B cell Ag receptor (BCR) through successive rearrangements of Ig genes has been considered to be a major mechanism for the central B cell tolerance, which precludes appearance of self-reactive B cells, through studies using anti-self-Ig transgenic/knock-in mouse systems. However, contribution of the receptor editing in the development of the normal B cell repertoire remains unclear. In addition, the signaling pathway directing this event is unknown. In this study, we demonstrate that receptor editing in anti-DNA Ig knock-in mice is impaired in the absence of an adaptor protein BASH (BLNK/SLP-65) that is involved in BCR signaling. Remarkably, the supposed hallmarks of receptor editing such as Igλ chain expression, recombination sequence rearrangements at Igκ loci, and presence of in-frame VκJκ joins in the Igκ loci inactivated by the recombination sequence rearrangements, were all diminished in BASH-deficient mice with unmanipulated Ig loci. BCR ligation-induced Igλ gene recombination in vitro was also impaired in BASH-deficient B cells. Furthermore, the BASH-deficient mice showed an excessive Ab response to a DNA carrier immunization, suggesting the presence of unedited DNA-reactive B cells in the periphery. These results not only define a signaling pathway required for receptor editing but indicate that the BCR-signaled receptor editing indeed operates in the development of normal B cell repertoire and contributes to establishing the B cell tolerance.
Rescuing Melanoma Epitope-Specific Cytolytic T Lymphocytes from Activation-Induced Cell Death, by SP600125, an Inhibitor of JNK: Implications in Cancer Immunotherapy
Authors: Mehrotra Shikhar , Chhabra Arvind , Chattopadhyay Subhasis , Dorsky David I. , Chakraborty Nitya G. , Mukherji Bijay 
Published: April 2014

Abstract
Activation-induced cell death (AICD) as well as programmed cell death (PCD) serve to control the expansion of activated T cells to limit untoward side effects of continued effector responses by T cells and to maintain homeostasis. AICD of T cells in tumor immunotherapy can be counterproductive particularly if the activated T cells undergo apoptotic death after the very first secondary encounter of the specific epitope. We examined the extent to which tumor epitope-specific CTLs that are activated and expanded in an in vitro-matured dendritic cell-based primary stimulation protocol undergo AICD following their first secondary encounter of the cognate epitope. Using the MART-127–35 epitope as a prototype vaccine epitope, we also examined whether these CTLs could be rescued from AICD. Our results demonstrate that a substantial fraction of MART-127–35 epitope-specific primary CTLs undergo AICD upon the very first secondary encounter of the cognate epitope. The AICD in these CTLs is neither caspase dependent nor is it triggered by the extrinsic death signaling pathways (Fas, TNFR, etc.). These CTLs, interestingly, could be rescued from AICD by the JNK inhibitor, SP600125. We also found that SP600125 interferes with their IFN-γ response but does not block their cytolytic function. The rescued CTLs, however, regain their capacity to synthesize IFN-γ if continued in culture without the inhibitor. These observations have implications in tumor immunotherapy and in further studies for regulation of AICD in CTLs.
The Immunization Site of Cytokine-Secreting Tumor Cell Vaccines Influences the Trafficking of Tumor-Specific T Lymphocytes and Antitumor Efficacy against Regional Tumors
Authors: Chang Chun-Jung , Tai Kuo-Feng , Roffler Steve , Hwang Lih-Hwa 
Published: April 2014

Abstract
Tumor cells engineered to secrete cytokines, referred to as tumor cell vaccines, can often generate systemic antitumor immunity and, in many cases, cause tumor regression. We compared the efficacy of s.c. immunization or intrahepatic immunization of GM-CSF-expressing tumor cell vaccines on the growth of s.c. or orthotopic liver tumors. A chemically transformed hepatic epithelial cell line, GP7TB, derived from Fischer 344 rats, was used to generate tumor models and tumor cell vaccines. Our results demonstrated that two s.c. injections of an irradiated tumor cell vaccine significantly controlled the growth of s.c. tumors, but was completely ineffective against orthotopic liver tumors. Effector cell infiltration in liver tumors was markedly reduced compared with s.c. tumors. Enhanced apoptosis of some effector cells was observed in the liver tumors compared with the s.c. tumors. Furthermore, the T cells induced by s.c. immunization preferentially migrated to s.c. tumor sites, as demonstrated by adoptive transfer experiments. In contrast, intrahepatic immunization, using parental tumor cells admixed with adenoviruses carrying the GM-CSF gene, yielded significantly better therapeutic effects on the liver tumors than on the s.c. tumors. Adoptive transfer experiments further confirmed that the T cells induced by liver immunization preferentially migrated to the liver tumor sites. Our results demonstrate that distinct T cell populations are induced by different immunization routes. Thus, the homing behavior of T cells depends on the route of immunization and is an important factor determining the efficacy of immunotherapy for regional tumors.
Final Antigenic Melan-A Peptides Produced Directly by the Proteasomes Are Preferentially Selected for Presentation by HLA-A*0201 in Melanoma Cells
Authors: Chapatte Laurence , Servis Catherine , Valmori Danila , Burlet-Schiltz Odile , Dayer Johanna , Monsarrat Bernard , Romero Pedro , Lévy Frédéric 
Published: April 2014

Abstract
The melanoma-associated protein Melan-A contains the immunodominant CTL epitope Melan-A26/27–35/HLA-A*0201 against which a high frequency of T lymphocytes has been detected in many melanoma patients. In this study we show that the in vitro degradation of a polypeptide encompassing Melan-A26/27–35 by proteasomes produces both the final antigenic peptide and N-terminally extended intermediates. When human melanoma cells expressing the corresponding fragments were exposed to specific CTL, those expressing the minimal antigenic sequence were recognized more efficiently than those expressing the N-terminally extended intermediates. Using a tumor-reactive CTL clone, we confirmed that the recognition of melanoma cells expressing an N-terminally extended intermediate of Melan-A is inefficient. We demonstrated that the inefficient cytosolic trimming of N-terminally extended intermediates could offer a selective advantage for the preferred presentation of Melan-A peptides directly produced by the proteasomes. These results imply that both the proteasomes and postproteasomal peptidases limit the availability of antigenic peptides and that the efficiency of presentation may be affected by conditions that alter the ratio between fully and partially processed proteasomal products.
Antigen Targeting to CD11b Allows Efficient Presentation of CD4+ and CD8+ T Cell Epitopes and In Vivo Th1-Polarized T Cell Priming
Authors: Schlecht Géraldine , Loucka Jirina , Najar Hossain , Sebo Peter , Leclerc Claude 
Published: April 2014

Abstract
Bordetella pertussis adenylate cyclase (CyaA) is an invasive bacterial toxin that delivers its N-terminal catalytic domain into the cytosol of eukaryotic cells bearing the αMβ2 integrin (CD11b/CD18), such as myeloid dendritic cells. This allows use of engineered CyaA for targeted delivery of CD8+ T cell epitopes into the MHC class I pathway of APC and induction of robust and protective cytotoxic responses. In this study, we demonstrate that CyaA can efficiently codeliver both a CD8+ T cell epitope (OVA257–264) and a CD4+ T cell epitope (MalE100–114) into, respectively, the conventional cytosolic or endocytic routes of processing of murine bone marrow-derived dendritic cells. Upon CyaA delivery, a strong potentiation of the MalE100–114 CD4+ T cell epitope presentation is observed as compared with the MalE protein, which depends on CyaA interaction with its CD11b receptor and its subsequent clathrin-mediated endocytosis. In vivo, CyaA induces strong and specific Th1 CD4+ and CD8+ T cell responses against, respectively, the MalE100–114 and OVA257–264 epitopes. These results underscore the potency of CyaA for design of new vaccines.
Augmentation of T Cell Levels and Responses Induced by Androgen Deprivation
Authors: Roden Anja C. , Moser Michael T. , Tri Samuel D. , Mercader Maria , Kuntz Susan M. , Dong Haidong , Hurwitz Arthur A. , McKean David J. , Celis Esteban , Leibovich Bradley C. , Allison James P. , Kwon Eugene D. 
Published: April 2014

Abstract
Androgen has been implicated as a negative regulator of host immune function and a factor contributing to the gender dimorphism of autoimmunity. Conversely, androgen deprivation has been suggested to potentiate male host immunity. Studies have shown that removal of androgen in postpubertal male mice produces an increase in size and cellularity of primary and peripheral lymphoid organs, and enhances a variety of immune responses. Yet, few details are known about the effect of androgen removal on T cell-mediated immunity. In this study, we demonstrate two pronounced and independent alterations in T cell immunity that occur in response to androgen deprivation, provided by castration, in postpubertal male mice. First, we show that levels of T cells in peripheral lymphoid tissues of mice are increased by androgen deprivation. Second, T cells from these mice transiently proliferate more vigorously to TCR- and CD28-mediated costimulation as well as to Ag-specific activation. In addition, androgen deprivation accelerates normalization of host T and B cell levels following chemotherapy-induced lymphocyte depletion. Such alterations induced by androgen deprivation may have implications for enhancing immune responses to immunotherapy and for accelerating the recovery of the immune system following chemotherapy.
A General Survey of Thymocyte Differentiation by Transcriptional Analysis of Knockout Mouse Models
Authors: Puthier Denis , Joly Florence , Irla Magali , Saade Murielle , Victorero Geneviève , Loriod Béatrice , Nguyen Catherine 
Published: April 2014

Abstract
The thymus is the primary site of T cell lymphopoiesis. To undergo proper differentiation, developing T cells follow a well-ordered genetic program that strictly depends on the heterogeneous and highly specialized thymic microenvironment. In this study, we used microarray technology to extensively describe transcriptional events regulating αβ T cell fate. To get an integrated view of these processes, both whole thymi from genetically engineered mice together with purified thymocytes were analyzed. Using mice exhibiting various transcriptional perturbations and developmental blockades, we performed a transcriptional microdissection of the organ. Multiple signatures covering both cortical and medullary stroma as well as various thymocyte maturation intermediates were clearly defined. Beyond the definition of histological and functional signatures (proliferation, rearrangement), we provide the first evidence that such an approach may also highlight the complex cross-talk events that occur between maturing T cells and stroma. Our data constitute a useful integrated resource describing the main gene networks set up during thymocyte development and a first step toward a more systematic transcriptional analysis of genetically modified mice.
B Cells Expressing Bcl-2 and a Signaling-Impaired BAFF-Specific Receptor Fail to Mature and Are Deficient in the Formation of Lymphoid Follicles and Germinal Centers
Authors: Rahman Ziaur S. M. , Manser Tim 
Published: April 2014

AbstractThe TNF family cytokine B cell-activating factor belonging to the TNF family (BAFF) (BLyS) plays a fundamental role in regulating peripheral B cell survival and homeostasis. A BAFF-specific receptor (BAFF-R; BR3) appears to mediate these functions via activation of the NF-κB2 pathway. Signaling by the BAFF-R is also required to sustain the germinal center (GC) reaction. Engagement of this receptor results in the induction of Bcl-2, suggesting that this antiapoptotic factor acts downstream of the BAFF-R and NF-κB2 pathway to promote peripheral B cell survival during primary and Ag-driven development. To test this idea, we created lines of mice coexpressing a Bcl-2 transgene and a signaling-deficient form of the BAFF-R derived from the B lymphopenic A/WySnJ strain. Surprisingly, although dramatically elevated numbers of B cells accumulate in the periphery of these mice, these B cells exhibit extremely perturbed primary development, formation of lymphoid microenvironments, and GC and IgG responses. Moreover, mice expressing the bcl-2 transgene alone display a loss of marginal zone B cells, an expansion of follicular B cells that appear immature, and alterations of the GC reaction. These results suggest that the BAFF-R and Bcl-2 regulate key and nonoverlapping aspects of peripheral B cell survival and development.
Long Distance Control of MHC Class II Expression by Multiple Distal Enhancers Regulated by Regulatory Factor X Complex and CIITA
Authors: Krawczyk Michal , Peyraud Nicolas , Rybtsova Natalia , Masternak Krzysztof , Bucher Philipp , Barras Emmanuèle , Reith Walter 
Published: April 2014

Abstract
MHC class II (MHC-II) genes are regulated by an enhanceosome complex containing two gene-specific transcription factors, regulatory factor X complex (RFX) and CIITA. These factors assemble on a strictly conserved regulatory module (S-X-X2-Y) found immediately upstream of the promoters of all classical and nonclassical MHC-II genes as well as the invariant chain (Ii) gene. To identify new targets of RFX and CIITA, we developed a computational approach based on the unique and highly constrained architecture of the composite S-Y motif. We identified six novel S′-Y′ modules situated far away from the promoters of known human RFX- and CIITA-controlled genes. Four are situated at strategic positions within the MHC-II locus, and two are found within the Ii gene. These S′-Y′ modules function as transcriptional enhancers, are bona fide targets of RFX and CIITA in B cells and IFN-γ-induced cells, and induce broad domains of histone hyperacetylation. These results reveal a hitherto unexpected level of complexity involving long distance control of MHC-II expression by multiple distal regulatory elements.