34 research outputs found
Endophilin A2 regulates B‐cell endocytosis and is required for germinal center and humoral responses
Get PDFAbstract: Antigen‐specific B‐cell responses require endosomal trafficking to regulate antigen uptake and presentation to helper T cells, and to control expression and signaling of immune receptors. However, the molecular composition of B‐cell endosomal trafficking pathways and their specific roles in B‐cell responses have not been systematically investigated. Here, we report high‐throughput identification of genes regulating B‐cell receptor (BCR)‐mediated antigen internalization using genome‐wide functional screens. We show that antigen internalization depends both on constitutive, clathrin‐mediated endocytosis and on antigen‐induced, clathrin‐independent endocytosis mediated by endophilin A2. Although endophilin A2‐mediated endocytosis is dispensable for antigen presentation, it is selectively required for metabolic support of B‐cell proliferation, in part through regulation of iron uptake. Consequently, endophilin A2‐deficient mice show defects in GC B‐cell responses and production of high‐affinity IgG. The requirement for endophilin A2 highlights a unique importance of clathrin‐independent intracellular trafficking in GC B‐cell clonal expansion and antibody responses
Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse
No full textThis project contains data associated with Manuscript 14493 at Wellcome Open Research/F1000. The authors are: Chiara Beilina, Kaushik Choudhuri, Gerben Bouma, Dessislava Malinova, Jaime Llodra, David L. Stokes, Motomu Shimaoka, Timothy A. Springer, Michael L. Dustin, Adrian J. Thrasher, Siobhan O. Burn
Meaning-making as a critical process in educational reform implementation: insights from the development of standards-based student growth objectives
No full textThis case study focused on the process through which educators make meaning of the purpose of developing student growth objectives (SGOs) as measures of teaching effectiveness in the first year (2013-2014) of the statewide rollout of the policy in New Jersey. During the same year, two other components of the comprehensive educational reform were launched - the teacher evaluation initiative (part of which is the development of SGOs) and the statewide implementation of the Common Core State Standards (CCSS). As educational reform implementation depends on educators’ meaning-making process, the study used a cognitive approach to the study of reform implementation, based on work by Spillane and colleagues (2000, 2002), and explored assumptions of a proposed theory of change, built around the policy’s officially stated outcomes. Data were collected in three separate rounds of interviews with seven 3rd grade teachers and three administrators. Questions addressed multiple aspects of the policy’s mandates, including the nature of collaborative practices, selection of appropriate assessments, and perceptions of the policy’s adequacy in providing valid measures to be used for teacher evaluation purposes. The findings show that teachers and administrators developed distinctly different implementation goals based on their interpretation of the policy’s purpose. Teachers approached the implementation process with the goal of showcasing their teaching talent and obtain high evaluation ratings. Administrators saw the SGO policy as means to boost students’ overall academic performance, and more specifically to improve outcomes on the state’s year-end test. Consistent with findings in other studies of policy implementation, educators adopted mostly form-based interpretations (Spillane and Callahan, 2000, Coburn, 2004) of needed changes. Although teachers and administrators used common language to describe implementation, the meanings they derived differed significantly. Educators also developed rudimentary function-based understandings of the policy’s intent which were suppressed by strong regulatory pressuresPh.D.Includes bibliographical referencesby Dessislava Gradinarova-Kirov
The Ins and Outs of Antigen Uptake in B cells
No full textA review of our current knowledge of B cell antigen uptake mechanisms, the relevance of these processes to pathology, and outstanding questions in the field. Specific antigens induce B cell activation through the B cell receptor (BCR) which initiates downstream signaling and undergoes endocytosis. While extensive research has shed light on the signaling pathways in health and disease, the endocytic mechanisms remain largely uncharacterized. Given the importance of BCR-antigen internalization for antigen presentation in initiating adaptive immune responses and its role in autoimmunity and malignancy, understanding the molecular mechanisms represents critical, and largely untapped, potential therapeutics. In this review, we discuss recent advancements in our understanding of BCR endocytic mechanisms and the role of the actin cytoskeleton and post-translational modifications in regulating BCR uptake. We discuss dysregulated BCR endocytosis in the context of B cell malignancies and autoimmune disorders. Finally, we pose several outstanding mechanistic questions which will critically advance our understanding of the coordination between BCR endocytosis and B cell activation
Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse [version 2; referees: 2 approved]
Get PDFBACKGROUND:
Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses. Here we examine the importance of γc for myeloid dendritic cell (DC) function.
METHODS:
We utilize a combination of in vitro DC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction.
RESULTS:
We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecular cis associations or cytoskeletal reorganization following MHCII ligation.
CONCLUSION:
These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition
Adaptive E-learning Content Design and Delivery Based on Learning Styles and Knowledge Level
Get PDFACM Computing Classification System (1998): K.3.1, K.3.2.The possibility of adaptive learning content delivery in e-learning systems is one of the important factors for highly improving their
quality. Therefore, the application field of adaptive e-learning is relevant and significant. This article presents the main results of a PhD thesis examining various aspects of this area. The aim of the dissertation is to propose a model and a platform architecture of an adaptive e-learning system and a corresponding prototype to be designed, implemented and tested in experimental conditions. On one hand, the developed prototype will assist a learner in accessing and using learning resources which are adapted according to his/her personal characteristics (in this case his/her learning style and level of knowledge). On the other hand, it will facilitate the author of the learning content and course instructor in the creation of appropriate learning objects and applying them to the suitable pedagogical strategies.The work reported in this paper is supported by the ADOPTA project funded by the
Bulgarian National Science Fund under agreement no. D002/155
Actin cytoskeletal defects in immunodeficiency
Get PDFThe importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott-Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency
Weak commutativity and finiteness properties of groups
No full textWe consider the group X(G) obtained from G*G by forcing each element g in the first free factor to commute with the copy of g in the second free factor. Deceptively complicated finitely presented groups arise from this construction: X(G) is finitely presented if and only if G is finitely presented, but if F is a non-abelian free group of finite rank then X(F) has a subgroup of finite index whose third homology is not finitely generated511168180CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP303350/2013-02016/05678-3The first author was supported in part by a Wolfson Research Merit Award from the Royal Society. The second author was supported in part by regular grant 2016/05678‐3 from FAPESP and ‘bolsa de produtividade em pesquisa’ 303350/2013‐0 CNPq, Brazi
B cells extract antigens at arp2/3-generated actin foci interspersed with linear filaments
Get PDFAntibody production depends on B cell internalization and presentation of antigens to helper T cells. To acquire antigens displayed by antigen-presenting cells, B cells form immune synapses and extract antigens by the mechanical activity of the acto-myosin cytoskeleton. While cytoskeleton organization driving the initial formation of the B cell synapse has been studied, how the cytoskeleton supports antigen extraction remains poorly understood. Here we show that after initial cell spreading, F-actin in synapses of primary mouse B cells and human B cell lines forms a highly dynamic pattern composed of actin foci interspersed with linear filaments and myosin IIa. The foci are generated by Arp2/3-mediated branched-actin polymerization and stochastically associate with antigen clusters to mediate internalization. However, antigen extraction also requires the activity of formins, which reside near the foci and produce the interspersed filaments. Thus, a cooperation of branched-actin foci supported by linear filaments underlies B cell mechanics during antigen extraction.</p
