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Lymphatic collecting vessels direct lymph into and from lymph nodes (LNs) and can become hyperpermeable as the result of a previous infection. Enhanced permeability has been implicated in compromised immunity due to reduced flow of lymph and immune cells to LNs, which are the primary site of antigen presentation to T cells. Presently, very little is known about the molecular signals that affect lymphatic collecting vessel permeability. Here, we have shown that lymphatic collecting vessel permeability is controlled by CCR7 and that the chronic hyperpermeability of collecting vessels observed in [Ccr7.sup.- /-] mice is followed by vessel fibrosis. Reexpression of CCR7 in DCs, however, was sufficient to reverse the development of such fibrosis. IFN regulatory factor 4-positive ([IRF4.sup.+]) DCs constitutively interacted with collecting lymphatics, and selective ablation of this DC subset in Cd11c-Cre [Irf4.sup.fl/fl] mice also rendered lymphatic collecting vessels hyperpermeable and fibrotic. Together, our data reveal that CCR7 plays multifaceted roles in regulating collecting vessel permeability and fibrosis, with one of the key players being IRF4-dependent DCs., Introduction DCs in the immune system are well characterized as potent antigen-presenting cells (APCs) for driving T cell-mediated host defense. Much of this activity takes place in lymph nodes (LNs), [...]

Diarrheal diseases represent a major health burden in developing countries. Parenteral immunization typically does not induce efficient protection against enteropathogens because it does not stimulate migration of immune cells to the gut. Retinoic acid (RA) is critical for gut immunity, inducing upregulation of gut-homing receptors on activated T cells. In this study, we have demonstrated that RA can redirect immune responses elicited by s.c. vaccination of mice from skin-draining inguinal LNs (ingLNs) to the gut. When present during priming, RA induced robust upregulation of gut-homing receptors in ingLNs, imprinting gut-homing capacity on T cells. Concurrently, RA triggered the generation of gut-tropic [IgA.sup.+] plasma cells in ingLNs and raised the levels of antigen-specific IgA in the intestinal lumen and blood. RA applied s.c. in vivo induced autonomous RA production in ingLN DCs, further driving efficient induction of gut-homing molecules on effector cells. Importantly, RA-supplemented s.c. immunization elicited a potent immune response in the small intestine that protected mice from cholera toxin-induced diarrhea and diminished bacterial loads in Peyer patches after oral infection with Salmonella. Thus, the use of RA as a gut-homing navigator represents a powerful tool to induce protective immunity in the intestine after s.c. immunization, offering what we believe to be a novel approach for vaccination against enteropathogens., Introduction Diarrheal diseases are among the major causes of death in developing countries, particularly in young children. Although many parenterally applied vaccines are highly efficient in preventing systemic infectious diseases, [...]

All metazoan cells carry transmembrane receptors of the integrin family, which couple the contractile force of the actomyosin cytoskeleton to the extracellular environment. In agreement with this principle, rapidly migrating leukocytes use integrin-mediated adhesion when moving over two-dimensional surfaces. As migration on two-dimensional substrates naturally overemphasizes the role of adhesion, the contribution of integrins during three-dimensional movement of leukocytes within tissues has remained controversial. We studied the interplay between adhesive, contractile and protrusive forces during interstitial leukocyte chemotaxis in vivo and in vitro. We ablated all integrin heterodimers from murine leukocytes, and show here that functional integrins do not contribute to migration in three-dimensional environments. Instead, these cells migrate by the sole force of actin-network expansion, which promotes protrusive flowing of the leading edge. Myosin II-dependent contraction is only required on passage through narrow gaps, where a squeezing contraction of the trailing edge propels the rigid nucleus., The current model of metazoan cell migration is frequently described as a multistep cycle: F-actin polymerization at the cell front pushes out a membrane protrusion that subsequently becomes anchored to [...]

Small intestine plasmacytoid dendritic cells (pDC) are poorly characterized. Here, we demonstrate that intestinal pDC show the characteristic plasma cell-like morphology, and are recognized by antibodies against B220, Ly6c, 120G8, and PDCA-1, markers that are typically expressed by pDC. Furthermore, intestinal pDC carry high levels of CCR9 and are largely absent in the intestine, but not in lung, liver, or secondary lymphoid organs of CCR9-deficient animals. Competitive adoptive transfers reveal that CCR9-deficient pDC are impaired in homing to the small intestine after i.v. transfer. In a model of cholera toxin-induced gut inflammation, pDC are recruited to the intestine in WT but not CCR9-deficient animals. Furthermore, after oral application of a Toll-like receptor (TLR) 7/8 ligand, myeloid DC of the lamina propria are rapidly mobilized in WT but not in CCR9-deficient animals. Mobilization of myeloid DC can be completely rescued by adoptively transferred WT pDC to CCR9-deficient mice before oral challenge. Together, our data reveal an essential role for CCR9 in the homing of pDC to the intestine under homeostatic and inflammatory conditions and demonstrate an important role for intestinal pDC for the rapid mobilization of lamina propria DC. chemokine receptor | gut | dendritic cell migration | Toll-like receptor 7 | cell mobilization

Author(s): Karin Reif [1, 2]; Eric H. Ekland [1, 2]; Lars Ohl [3]; Hideki Nakano [4]; Martin Lipp [5]; Reinhold Förster [3]; Jason G. Cyster (corresponding author) [1] B lymphocytes [...]

Author(s): Patrick Champagne [1, 2, 3]; Graham S. Ogg [3, 4]; Abigail S. King [4]; Christian Knabenhans [1]; Kim Ellefsen [1]; Massimo Nobile [1]; Victor Appay [4]; G. Paolo Rizzardi [...]

Author(s): K. Mark Ansel [1, 2]; Vu N. Ngo [1, 2]; Paul L. Hyman [1]; Sanjiv A. Luther [1]; Reinhold Förster [3]; Jonathon D. Sedgwick [4]; Jeffrey L. Browning [5]; [...]

It has been established that immunological memory is displayed by distinct T-cell subsets: tissue-homing cells with various effector functions and lymph-node-homing cells with no inflammatory or cytotoxic function. These two subsets permit a division of labour among memory cells. This research suggests a precursor-product relationship between the two memory subsets. In vitro stimulation of naive T cells leads to the production of both Tcm and Tem cells, while stimulation of Tcm cells leads to their efficient differentiation to Tem cells.

The primary immune response, coordinated by CCR7 by establishment of functional microenvironments in secondary lymphoid organs, is discussed. Mice with a disrupted CCR7 locus have been generated to test the function of CCR7, which was shown to be a major homing receptor and regulator for setting up an antigen-specific immune response.

Flow cytometry was used to analyze human platelets for CD40L expression on the cell surface. It could be detected on unstimulated platelets, although activation of platelets by thrombin, an agonist, led to maximal expression within a minute. Levels gradually declined, and CD40L was also released when collagen or ADP plus adrenaline were present as agonists. This shows that preformed CD40L is stored in platelets, and its translocation to the cell surface is part of a basic platelet reaction.

The role of the BLR1 G protein-coupled receptor in the migration of B and T lymphocytes into splenic follicles was analyzed in mice with mutated blr1 genes. The mutant mice exhibited defective inguinal lymph nodes and Payer's patches including the aberrant formation of primary follicles in the spleen and germinal centers (GC). Furthermore, the B cells of the mutants did not migrate into the splenic follicles due to the absence of functional GC and BLR1.

The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification that is mainly known to control the developmental plasticity of the nervous system. Here we show that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for the recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking is abrogated in polysialyltransferase-deficient mice, manifesting as disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions reveals that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, we describe a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis. [ABSTRACT FROM AUTHOR]