B and Th cell response to Ag in vivo: Implications for vaccine development and diseases

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156140/2/imr12899_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156140/1/imr12899.pd

Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells.

The cellular dynamics of the egress of lymphocytes from lymph nodes are poorly defined. Here we visualized the branched organization of lymph node cortical sinuses and found that after entry, some T cells were retained, whereas others returned to the parenchyma. T cells deficient in sphingosine 1-phosphate receptor type 1 probed the sinus surface but failed to enter the sinuses. In some sinuses, T cells became rounded and moved unidirectionally. T cells traveled from cortical sinuses into macrophage-rich sinus areas. Many T cells flowed from medullary sinuses into the subcapsular space. We propose a multistep model of lymph node egress in which cortical sinus probing is followed by entry dependent on sphingosine 1-phosphate receptor type 1, capture of cells in a sinus region with flow, and transport to medullary sinuses and the efferent lymph

Module-Based Analysis of Robustness Tradeoffs in the Heat Shock Response System

Biological systems have evolved complex regulatory mechanisms, even in situations where much simpler designs seem to be sufficient for generating nominal functionality. Using module-based analysis coupled with rigorous mathematical comparisons, we propose that in analogy to control engineering architectures, the complexity of cellular systems and the presence of hierarchical modular structures can be attributed to the necessity of achieving robustness. We employ the Escherichia coli heat shock response system, a strongly conserved cellular mechanism, as an example to explore the design principles of such modular architectures. In the heat shock response system, the sigma-factor σ(32) is a central regulator that integrates multiple feedforward and feedback modules. Each of these modules provides a different type of robustness with its inherent tradeoffs in terms of transient response and efficiency. We demonstrate how the overall architecture of the system balances such tradeoffs. An extensive mathematical exploration nevertheless points to the existence of an array of alternative strategies for the existing heat shock response that could exhibit similar behavior. We therefore deduce that the evolutionary constraints facing the system might have steered its architecture toward one of many robustly functional solutions

Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning

Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P is not defined. We generated mice that expressed Cre from the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and that showed efficient recombination of loxP-flanked genes in lymphatic endothelium. We report that mice with Lyve-1 CRE-mediated ablation of sphingosine kinase (Sphk) 1 and lacking Sphk2 have a loss of S1P in lymph while maintaining normal plasma S1P. In Lyve-1 Cre+ Sphk-deficient mice, lymphocyte egress from LNs and Peyer's patches is blocked. Treatment with pertussis toxin to overcome Gαi-mediated retention signals restores lymphocyte egress. Furthermore, in the absence of lymphatic Sphks, the initial lymphatic vessels in nonlymphoid tissues show an irregular morphology and a less organized vascular endothelial cadherin distribution at cell–cell junctions. Our data provide evidence that lymphatic endothelial cells are an in vivo source of S1P required for lymphocyte egress from LNs and Peyer's patches, and suggest a role for S1P in lymphatic vessel maturation

CCL3 Promotes Germinal Center B Cells Sampling by Follicular Regulatory T Cells in Murine Lymph Nodes

Previous studies and our findings suggest upregulated expression of proinflammatory chemokines CCL3/4 in germinal center (GC) centrocytes. However, the role of CCL3/4 for centrocyte interactions with follicular T cells and regulation of humoral immunity is poorly understood. We found that CCL3 promotes chemotaxis of Tfr cells ex vivo. Two-photon imaging revealed that B cells-intrinsic production of CCL3 promotes their probing by follicular regulatory T cells (Tfr) within GCs of murine lymph nodes. Overall this study suggests that CCL3 facilitates direct interactions of foreign antigen-specific GC B cells and their negative regulation with Tfr cells in vivo

Visualizing B cell capture of cognate antigen from follicular dendritic cells

The prominent display of opsonized antigen by follicular dendritic cells (FDCs) has long favored the view that they serve as antigen-presenting cells for B cells. Surprisingly, however, although B cell capture of antigen from macrophages and dendritic cells has been visualized, acquisition from FDCs has not been directly observed. Using two-photon microscopy, we visualized B cell capture of cognate antigen from FDCs. B cell CXCR5 expression was required, and encounter with FDC-associated antigen could be detected for >1 wk after immunization. B cell–FDC contact times were often brief but occasionally persisted for >30 min, and B cells sometimes acquired antigen together with FDC surface proteins. These observations establish that FDCs can serve as sites of B cell antigen capture, with their prolonged display time ensuring that even rare B cells have the chance of antigen encounter, and they suggest possible information transfer from antigen-presenting cell to B cell

PESFOR-W: Improving the design and environmental effectiveness of woodlands for water Payments for Ecosystem Services

ABSTRACT: The EU Water Framework Directive aims to ensure restoration of Europe?s water bodies to ?good ecological status? by 2027. Many Member States will struggle to meet this target, with around half of EU river catchments currently reporting below standard water quality. Diffuse pollution from agriculture represents a major pressure, affecting over 90% of river basins. Accumulating evidence shows that recent improvements to agricultural practices are benefiting water quality but in many cases will be insufficient to achieve WFD objectives. There is growing support for land use change to help bridge the gap, with a particular focus on targeted tree planting to intercept and reduce the delivery of diffuse pollutants to water. This form of integrated catchment management offers multiple benefits to society but a significant cost to landowners and managers. New economic instruments, in combination with spatial targeting, need to be developed to ensure cost effective solutions - including tree planting for water benefits - are realised. Payments for Ecosystem Services (PES) are flexible, incentive-based mechanisms that could play an important role in promoting land use change to deliver water quality targets. The PESFOR-W COST Action will consolidate learning from existing woodlands for water PES schemes in Europe and help standardize approaches to evaluating the environmental effectiveness and cost-effectiveness of woodland measures. It will also create a European network through which PES schemes can be facilitated, extended and improved, for example by incorporating other ecosystem services linking with aims of the wider forestscarbon policy nexus

Wandering cells: dissecting spatio-temporal regulation of B cell responses

Non UBCUnreviewedAuthor affiliation: University of MichiganResearche