Showing papers by "Jason G. Cyster published in 2010"

B cell follicles and antigen encounters of the third kind

Abstract: Defining where and in what form lymphocytes encounter antigen is fundamental to understanding how immune responses occur. Although knowledge of the recognition of antigen by CD4(+) and CD8(+) T cells has advanced greatly, understanding of the dynamics of B cell-antigen encounters has lagged. With the application of advanced imaging approaches, encounters of this third kind are now being brought into focus. Multiple processes facilitate these encounters, from the filtering functions of lymphoid tissues and migration paths of B cells to the antigen-presenting properties of macrophages and follicular dendritic cells. This Review will discuss how these factors work together in the lymph node to ensure efficient and persistent exposure of B cells to diverse forms of antigen and thus effective triggering of the humoral response.

A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

Abstract: Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 × 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.

Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice

Abstract: Tregs play an important role in protecting the skin from autoimmune attack. However, the extent of Treg trafficking between the skin and draining lymph nodes (DLNs) is unknown. We set out to investigate this using mice engineered to express the photoconvertible fluorescence protein Kaede, which changes from green to red when exposed to violet light. By exposing the skin of Kaede-transgenic mice to violet light, we were able to label T cells in the periphery under physiological conditions with Kaede-red and demonstrated that both memory phenotype CD4+Foxp3– non-Tregs and CD4+Foxp3+ Tregs migrated from the skin to DLNs in the steady state. During cutaneous immune responses, Tregs constituted the major emigrants and inhibited immune responses more robustly than did LN-resident Tregs. We consistently observed that cutaneous immune responses were prolonged by depletion of endogenous Tregs in vivo. In addition, the circulating Tregs specifically included activated CD25hi Tregs that demonstrated a strong inhibitory function. Together, our results suggest that Tregs in circulation infiltrate the periphery, traffic to DLNs, and then recirculate back to the skin, contributing to the downregulation of cutaneous immune responses.

Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses.

Abstract: Humoral immune responses depend on B cells encountering antigen, interacting with helper T cells, proliferating and differentiating into low-affinity plasma cells or, after organizing into a germinal center (GC), high-affinity plasma cells and memory B cells. Remarkably, each of these events occurs in association with distinct stromal cells in separate subcompartments of the lymphoid tissue. B cells must migrate from niche to niche in a rapid and highly regulated manner to successfully mount a response. The chemokine, CXCL13, plays a central role in guiding B cells to follicles whereas T-zone chemokines guide activated B cells to the T zone. Sphingosine-1-phosphate (S1P) promotes cell egress from the tissue, as well as marginal-zone B-cell positioning in the spleen. Recent studies have identified a role for the orphan receptor, EBV-induced molecule 2 (EBI2; GPR183), in guiding activated B cells to inter and outer follicular niche(s) and down-regulation of this receptor is essential for organizing cells into GCs. In this review, we discuss current understanding of the roles played by chemokines, S1P and EBI2 in the migration events that underlie humoral immune responses.

Neural Crest–Derived Pericytes Promote Egress of Mature Thymocytes at the Corticomedullary Junction

Abstract: T cell egress from the thymus is essential for adaptive immunity, yet the requirements for and sites of egress are incompletely understood. We have shown that transgenic expression of sphingosine-1-phosphate receptor-1 (S1P1) in immature thymocytes leads to their perivascular accumulation and premature release into circulation. Using an intravascular procedure to label emigrating cells, we found that mature thymocytes exit via blood vessels at the corticomedullary junction. By deleting sphingosine kinases in neural crest-derived pericytes, we provide evidence that these specialized vessel-ensheathing cells contribute to the S1P that promotes thymic egress. Lymphatic endothelial cell-derived S1P was not required. These studies identify the major thymic egress route and suggest a role for pericytes in promoting reverse transmigration of cells across blood vessel endothelium.

Lymph node cortical sinus organization and relationship to lymphocyte egress dynamics and antigen exposure

Abstract: Recent studies have identified cortical sinuses as sites of sphingosine-1-phosphate receptor-1 (S1P1)-dependent T- and B-cell egress from the lymph node (LN) parenchyma. However, the distribution of cortical sinuses in the entire LN and the extent of lymph flow within them has been unclear. Using 3D reconstruction and intravital two-photon microscopy we describe the branched organization of the cortical sinus network within the inguinal LN and show that lymphocyte flow begins within blunt-ended sinuses. Many cortical sinuses are situated adjacent to high endothelial venules, and some lymphocytes access these sinuses within minutes of entering a LN. However, upon entry to inflamed LNs, lymphocytes rapidly up-regulate CD69 and are prevented from accessing cortical sinuses. Using the LN reconstruction data and knowledge of lymphocyte migration and cortical sinus entry dynamics, we developed a mathematical model of T-cell egress from LNs. The model suggests that random walk encounters with lymphatic sinuses are the major factor contributing to LN transit times. A slight discrepancy between predictions of the model and the measured transit times may be explained by lymphocytes undergoing a few rounds of migration between the parenchyma and sinuses before departing from the LN. Because large soluble antigens gain rapid access to cortical sinuses, such parenchyma–sinus shuttling may facilitate antibody responses.

A Role for S1P and S1P1 in Immature-B Cell Egress from Mouse Bone Marrow

Abstract: B lymphocyte egress from secondary lymphoid organs requires sphingosine-1-phosphate (S1P) and S1P receptor-1 (S1P1). However, whether S1P contributes to immature-B cell egress from the bone marrow (BM) has not been fully assessed. Here we report that in S1P- and S1P1-conditionally deficient mice, the number of immature-B cells in the BM parenchyma increased, while it decreased in the blood. Moreover, a slower rate of bromodeoxyuridine incorporation suggested immature-B cells spent longer in the BM of mice in which S1P1-S1P signaling was genetically or pharmacologically impaired. Transgenic expression of S1P1 in developing B cells was sufficient to mobilize pro- and pre-B cells from the BM. We conclude that the S1P1-S1P pathway contributes to egress of immature-B cells from BM, and that this mechanism is partially redundant with other undefined pathways.

Correction: A Role for S1P and S1P1 in Immature-B Cell Egress from Mouse Bone Marrow

Abstract: The order of the second and third authors was reversed. Ying Xu should be the second author and Jason G. Cyster should be the third author. The correct citation is: Pereira JP, Xu Y, Cyster JG (2010) A Role for S1P and S1P1 in Immature-B Cell Egress from Mouse Bone Marrow. PLoS ONE 5(2): e9277. doi:10.1371/journal.pone.0009277

Visualizing influenza virus capture in the lymph node following vaccination.

Abstract: cells in PE (Figure 1). The differentiation of Th17 cells from progenitor cells or Treg cells requires IL-1b and IL-6. Monocytes from PE cases secrete more IL-1b and IL-6 than those from normal pregnant women;15 therefore, Th17 cells might increase in PE. Th17 cells produce proinflammatory cytokines, such as IL-17A, IL-17F and IL-22. The chronic inflammation theory,16 endothelial dysfunction theory,17 poor angiogenesis theory,14 and immunomaladaptation theory1,2 in the pathophysiology of PE might be linked by imbalanced differentiation of Treg cells and Th17 cells (Figure 1). In normal pregnancy, Treg cells expand to reach an adequate level for induction of paternal antigen tolerance, but in PE cases, soluble endoglin produced by endothelial cells and syncytiotrophoblasts may disturb the Treg cell differentiation and angiogenesis. Furthermore, IL-1b and IL-6 produced by dendritic cells and monocytes may promote differentiation of naive T cells into Th17 cells and even the conversion of Treg cells into Th17 cells. Increased Th17 cells will then induce chronic inflammation, resulting in endothelial dysfunction. In summary, an imbalance between Treg cell and Th17 cell differentiation may explain PE pathogenesis bringing to an end the chaos in the numerous theories proposed until now.

Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production (vol 10, pg 1283, 2009)

Abstract: Corrigendum: Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production