IntroductionTo ensure rapid encounters between Ag and rare lymphocytes, strategically positioned secondary lymphoid organs (SLOs) filter, retain, and present Ag to passing lymphocytes. 1 In case lymphocytes do not encounter their specific Ag on antigen-presenting cells (APCs), they exit SLOs after approximately 8 to 12 hours and reenter the blood stream via efferent lymphatics. 2 As an adaptation to their motile lifestyle, lymphocytes undergo transient adhesive interactions with other hematopoietic and stromal cells. Lymphocytes interact mainly with 2 types of stromal cells: First, bloodborne lymphocytes adhere to endothelial cells, in particular those composing the high endothelial venules (HEVs) of peripheral lymph nodes (PLNs) and other lymphoid tissues. 2,3 Second, T and B cells move along fibroblast-like cells forming the stromal network underlying the 3-dimensional matrix of lymphoid microenvironments, that is, the follicular dendritic cells (FDCs) of B-cell follicles, the T-cell zone fibroblastic reticular cells (TRCs) and marginal reticular cells (MRCs) in the cortex of B-cell follicles and interfollicular areas. [4][5][6] These transient stroma-lymphocyte interactions are central to immunosurveillance and have thus been examined in previous studies, in particular using genetically modified or inhibitortreated lymphocytes. The molecular mechanisms governing the rapid firm adhesion of blood-borne lymphocytes within PLN HEVs follow a multistep adhesion sequence, where CD62L-mediated tethering and rolling on peripheral lymph node addressin (PNAd) expressed on HEVs is followed by activation of the chemokine receptor CCR7 on rolling lymphocytes. This is because HEVs present the CCR7 ligands CCL19 and, in particular, CCL21 on their luminal surface. 7,8 CCR7 activation and shear forces from the continuous blood flow lead to a rapid conformational activation of LFA-1 leading to increased affinity for adhesion receptors of the intercellular adhesion molecule (ICAM) superfamily, in particular ICAM-1 and ICAM-2. 9 Furthermore, chemokine-activated ␣4 integrins can bind vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Rapid integrin activation results in a sudden stop of lymphocytes rolling in HEVs. 10,11 The molecular mechanisms involved in the subsequent transendothelial migration (TEM) of firmly adherent lymphocytes across HEVs into the surrounding lymphoid tissue are less well understood, although in vitro studies suggest the formation of specialized docking/capping structures between endothelial cells and lymphocytes. In particular, ICAM-1 and VCAM-1 form circular structures surrounding adherent lymphocytes, which are thought to facilitate adhesion and trans-or paracellular lymphocyte crossing of the endothelial lining. 12-14 After transmigration, twophoton microscopy (2PM) experiments have shown that T cells move along TRCs, which express ICAM-1. 6,15 Lack of ICAM-1 on stromal cells resulted in a minor decrease in T-cell motility, in line with a migration mod...

Considerable efforts have been invested in the development of small synthetic metallonucleases for the cleavage of RNA, or more ambitiously DNA, as a result of their potential application as therapeutic agents and robust, versatile replacements for nucleases as laboratory tools.[1] Currently, these complexes are still very inefficient relative to enzymes and this behavior limits their practical applications. More fundamentally, the development of artificial systems both tests and expands our understanding of how catalysis works under biological conditions.

This feature article presents an overview of the types of hydrogen bonding interactions involving metal complexes and their functional effects. It shows with recent examples why hydrogen bonds have become a crucial functional and structural element in modern inorganic chemistry. The relevance of this combination in tackling current chemistry challenges such as energy production and the development of new materials and more effective catalysts, sensors and medicines is illustrated.

BackgroundMultiple myeloma (MM) is a plasma cell malignancy with a multifaceted immune dysfunction. Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan into kynurenine (KYN), which inhibits effector T cells and promote regulatory T-cell (Treg) differentiation. It is presently unknown whether MM cells express IDO1 and whether IDO1 activity correlates with immune system impairment.MethodsWe investigated IDO1 expression in 25 consecutive patients with symptomatic MM and in 7 patients with either monoclonal gammopathy of unknown significance (MGUS; n=3) or smoldering MM (SMM; n=4). IDO1-driven tryptophan breakdown was correlated with the release of hepatocyte growth factor (HGF) and with the frequency of Treg cells and NY-ESO-1-specific CD8+ T cells.ResultsKYN was increased in 75% of patients with symptomatic MM and correlated with the expansion of CD4+CD25+FoxP3+ Treg cells and the contraction of NY-ESO-1-specific CD8+ T cells. In vitro, primary MM cells promoted the differentiation of allogeneic CD4+ T cells into bona fide CD4+CD25hiFoxP3hi Treg cells and suppressed IFN-γ/IL-2 secretion, while preserving IL-4 and IL-10 production. Both Treg expansion and inhibition of Th1 differentiation by MM cells were reverted, at least in part, by d,l-1-methyl-tryptophan, a chemical inhibitor of IDO. Notably, HGF levels were higher within the BM microenvironment of patients with IDO+ myeloma disease compared with patients having IDO- MM. Mechanistically, the antagonism of MET receptor for HGF with SU11274, a MET inhibitor, prevented HGF-induced AKT phosphorylation in MM cells and translated into reduced IDO protein levels and functional activity.ConclusionsThese data suggest that IDO1 expression may contribute to immune suppression in patients with MM and possibly other HGF-producing cancers.

Key Points• CXCR5, but not CXCR4 or CCR7, acts with LFA-1 to mediate random B-cell migration in the T-cell area and B-cell follicles.• In contrast, stromal guidance during B-cell migration is LFA-1 independent and CXCR5 independent.It is not known how naive B cells compute divergent chemoattractant signals of the T-cell area and B-cell follicles during in vivo migration. Here, we used two-photon microscopy of peripheral lymph nodes (PLNs) to analyze the prototype G-protein-coupled receptors (GPCRs) CXCR4, CXCR5, and CCR7 during B-cell migration, as well as the integrin LFA-1 for stromal guidance. CXCR4 and CCR7 did not influence parenchymal B-cell motility and distribution, despite their role during B-cell arrest in venules. In contrast, CXCR5 played a nonredundant role in B-cell motility in follicles and in the T-cell area. B-cell migration in the T-cell area followed a random guided walk model, arguing against directed migration in vivo. LFA-1, but not a4 integrins, contributed to B-cell motility in PLNs. However, stromal network guidance was LFA-1 independent, uncoupling integrin-dependent migration from stromal attachment. Finally, we observed that despite a 20-fold reduction of chemokine expression in virus-challenged PLNs, CXCR5 remained essential for B-cell screening of antigen-presenting cells. Our data provide an overview of the contribution of prototype GPCRs and integrins during naive B-cell migration and shed light on the local chemokine availability that these cells compute. (Blood. 2013;121(20):4101-4109)

The effectiveness of grape seed extract (GSE) encapsulated in liposomes to inhibit the formation of heterocyclic aromatic amines (HAA) during frying of beef patties was assessed. All liposomal systems were prepared by high pressure homogenization at 22 500 psi. A total of six samples (rapeseed oil (control), GSE at 0.1% and 0.2%, and GSE-containing liposomes with 1%, 2%, and 5% soy lecithin) were investigated. MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline), PhIP (2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine), Norharman, and Harman were found after the marinade application and frying. PhIP concentrations decreased upon marination with GSE (0.1%) and GSE-containing liposomes (1% and 5%) (p < 0.05). MeIQx contents decreased in all samples compared to the oil control (p < 0.01) while no effect on β-carboline formation was observed. Results are in contrast to previous studies that had shown that liposomal encapsulation may enhance effectiveness of polyphenols to inhibit radical reactions. A mechanistic model was proposed to explain the observed differences.

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Considerable efforts have been invested in the development of small synthetic metallonucleases for the cleavage of RNA, or more ambitiously DNA, as a result of their potential application as therapeutic agents and robust, versatile replacements for nucleases as laboratory tools.[1] Currently, these complexes are still very inefficient relative to enzymes and this behavior limits their practical applications. More fundamentally, the development of artificial systems both tests and expands our understanding of how catalysis works under biological conditions.