15 research outputs found
Signaling through CD5 Activates a Pathway Involving Phosphatidylinositol 3-Kinase, Vav, and Rac1 in Human Mature T Lymphocytes
CD5 acts as a coreceptor on T lymphocytes and plays an important role in T-cell signaling and T-cell-B-cell
interactions. Costimulation of T lymphocytes with anti-CD5 antibodies results in an increase of the intracellular
Ca21 levels, and subsequently in the activation of Ca21/calmodulin-dependent (CaM) kinase type IV. In
the present study, we have characterized the initial signaling pathway induced by anti-CD5 costimulation. The
activation of phosphatidylinositol (PI) 3-kinase through tyrosine phosphorylation of its p85 subunit is a
proximal event in the CD5-signaling pathway and leads to the activation of the lipid kinase activity of the p110
subunit. The PI 3-kinase inhibitors wortmannin and LY294002 inhibit the CD5-induced response as assessed
in interleukin-2 (IL-2) secretion experiments. The expression of an inactivated Rac1 mutant (Rac1 z N17) in
T lymphocytes transfected with an IL-2 promoter-driven reporter construct also abrogates the response to CD5
costimulation, while the expression of a constitutively active Rac1 mutant (Rac1-V12) completely replaces the
CD5 costimulatory signal. The Rac1-specific guanine nucleotide exchange factor Vav is heavily phosphorylated
on tyrosine residues upon CD5 costimulation, which is a prerequisite for its activation. A role for Vav in the
CD5-induced signaling pathway is further supported by the findings that the expression of a dominant negative
Vav mutant (Vav-C) completely abolishes the response to CD5 costimulation while the expression of a
constitutively active Vav mutant [Vav(D1-65)] makes the CD5 costimulation signal superfluous. Wortmannin
is unable to block the Vav(D1-65)- or Rac1 z V12-induced signals, indicating that both Vav and Rac1 function
downstream from PI 3-kinase. Vav and Rac1 both act upstream from the CD5-induced activation of CaM
kinase IV, since KN-62, an inhibitor of CaM kinases, and a dominant negative CaM kinase IV mutant block
the Vav(D1-65)-and Rac1 z V12-mediated signals. We propose a model for the CD5-induced signaling pathway
in which the PI 3-kinase lipid products, together with tyrosine phosphorylation, activate Vav, resulting in the
activation of Rac1 by the Vav-mediated exchange of GDP for GTP
Production and glyco-engineering of immunomodulatory helminth glycoproteins in plants
Host-parasite interactio
Dusting the sugar fingerprint: C-type lectin signaling in adaptive immunity
Pathogen recognition by dendritic cells (DCs) is central to the induction of adaptive immunity. Pattern recognition receptors (PRRs) on DCs interact with pathogens, leading to signaling events that dictate adaptive immune responses. It is becoming clear that C-type lectins are important PRRs that recognize carbohydrate structures. Most pathogens express carbohydrate structures on their surface and these function as a so-called sugar fingerprint that are recognized by specific C-type lectins. Triggering of C-type lectin induces signaling cascades that initiate or modulate specific cytokine responses and therefore tailor T cell polarization to the pathogens. Here we will discuss our current understanding of the innate signaling pathways induced by C-type lectins DC-SIGN and dectin-1 in humans and how these pathways shape adaptive immunit
Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling.
Contains fulltext :
52765.pdf (publisher's version ) (Closed access)The blood-brain barrier (BBB) prevents the entrance of circulating molecules and immune cells into the central nervous system. The barrier is formed by specialized brain endothelial cells that are interconnected by tight junctions (TJ). A defective function of the BBB has been described for a variety of neuroinflammatory diseases, indicating that proper regulation is essential for maintaining brain homeostasis. Under pathological conditions, reactive oxygen species (ROS) significantly contribute to BBB dysfunction and inflammation in the brain by enhancing cellular migration. However, a detailed study about the molecular mechanism by which ROS alter BBB integrity has been lacking. Here we demonstrate that ROS alter BBB integrity, which is paralleled by cytoskeleton rearrangements and redistribution and disappearance of TJ proteins claudin-5 and occludin. Specific signaling pathways, including RhoA and PI3 kinase, mediated observed processes and specific inhibitors of these pathways prevented ROS-induced monocyte migration across an in vitro model of the BBB. Interestingly, these processes were also mediated by protein kinase B (PKB/Akt), a previously unknown player in cytoskeleton and TJ dynamics that acted downstream of RhoA and PI3 kinase. Our study reveals new insights into molecular mechanisms underlying BBB regulation and provides novel opportunities for the treatment of neuroinflammatory diseases