Lateral compartmentalization of membrane proteins into microdomains regulates signal transduction; however, structural determinants are incompletely understood. Membrane glycoproteins bind galectins in proportion to the number (i.e. NX(S/T) sites) and degree of GlcNAc branching within attached N-glycans, forming a molecular lattice that negatively regulates T cell function and autoimmunity. We find that in resting T cells, partition of CD45 inside and T cell receptor (TCR)/CD4-Lck/Zap-70 outside microdomains is positively and negatively regulated by the galectin lattice and actin cytoskeleton, respectively. In the absence of TCR ligands, the galectin lattice counteracts F-actin to retain CD45 in microdomains while concurrently blocking TCR/CD4-Lck/Zap-70 partition to microdomains by preventing a conformational change in the TCR that recruits Nck/Wiscott Aldrich Syndrome (WASp)/ SLP76/F-actin/CD4 to TCR. The counterbalancing activities of the galectin lattice and actin cytoskeleton negatively and positively regulate Lck activity in resting cells and CD45 versus TCR clustering and signaling at the early immune synapse, respectively. Microdomain-localized CD45 inactivates Lck and inhibits TCR signaling at the early immune synapse. Thus, the galectin lattice and actin cytoskeleton interact on opposing sides of the plasma membrane to control microdomain structure and function, coupling basal growth signaling with thresholds to activation.Separation of plasma membrane proteins into microdomains enriched in cholesterol and glycosphingolipids has been implicated in cell signaling and activation (1-6). However, the hypothesis that their formation is determined solely by "phase separation" of cholesterol and saturated phospholipids from unsaturated phospholipids has been challenged (1-6). An emerging model suggests other factors, such as protein-protein binding and the actin cytoskeleton, play important roles in the stability, size, and retention of proteins in membrane microdomains (1-5). The clearest example of this is the immunological synapse, where agonist-induced T cell receptor (TCR) 2 signaling provokes actin cytoskeleton-dependent coalescence of membrane microdomains enriched in signaling molecules at the contact site between T cells and antigen presenting cells (7)(8)(9)(10)(11)(12).TCR clustering at the immune synapse is negatively regulated by multivalent cross-linking of cell surface glycoproteins with galectins, interactions that form a molecular lattice restricting glycoprotein movement in the plane of the membrane and endocytosis (13)(14)(15)(16)(17). Glycoproteins are differentially incorporated into the galectin lattice based on the number of associated N-glycan chains (i.e. NX(S/T) sites) as well as degree of GlcNAc branching (13,15,18). The latter is dynamically controlled by Golgi processing and metabolic production of 19), the sugar nucleotide donor for medial Golgi GlcNAc-branching enzymes Mgat1, -2, -4, and -5. In naïve T cells, genetic and metabolic control of GlcNAc branched N-glycans sets thresh...

Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-b, that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell (LPMC) Th1 cytokine generation in an IL-10-dependent manner in WT mice. Helminths also stimulate mucosal TGF-b release. As TGF-b exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-b signaling in helminthic modulation of intestinal immunity. T cell TGF-b signaling is interrupted in TGF-b receptor II dominant negative (TGF-bRII DN) mice by T-cellspecific over-expression of a TGF-bRII DN. We studied LPMC responses in WT and TGF-bRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-b signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-b-signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-bRII DN mice. Thus, T cell TGF-b signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal IFN-c generation and H. polygyrus-mediated suppression of chronic colitis. IntroductionHelminth exposure is associated with immune modulation in the human or murine host and decreased immune reactivity to antigens unrelated to the parasite [1]. This response may be useful in the treatment of autoimmune and immunological diseases, like inflammatory bowel disease [2,3]. Helminths stimulate the host to produce Th2 (IL-4, IL-5, IL-9, IL-13) or regulatory (IL-10, TGF-b) cytokines, while blocking Th1 cytokine responses [4,5].Helminthic parasites limit disease activity in various animal models of inflammatory bowel disease. For example, rectal trinitrobenzene sulfonic acid administration causes a T cell cytokinedriven colitis that is prevented by systemic administration of 1870Schistosoma mansoni eggs or duodenal colonization with Heligmosomoides polygyrus larvae [6,7]. H. polygyrus-mediated regulation of IFN-g, IL-12/23 (p40) production and protection from colitis is in part blocked by inhibiting IL-10 signaling in this trinitrobenzene sulfonic acid model. IL-10 is a major immune regulatory cytokine [8] that helps prevent intestinal inflammation. Accelerated, severe colitis is triggered in IL-10 deficient and not WT mice by Helicobacter hepaticus infection or treatment of the animals with non-steroidal antinflammatory drugs [9][10][11]. Although different cells can produce IL-10 and regulate immune responses, animal studies implicate CD4 T lymphocyte derived IL-10 as a non-redundant regulator of intestinal immune balance [12]. IL-10 is involved in helminthic regulation of mucosal Th1 cytokine responses where T cells constitute the major source of intestinal 14]. The mechanism of how helminths induce IL-10-producing T cells is unknown. ...

[reaction: see text] The diphenylamino group is an effective handle for electropolymerization to give electron donor-acceptor conjugated polymers. In addition, interesting electrochromic and photoresponsive behavior of 13 has been investigated.

To our knowledge, this is the first study to show that the dose and intensity of longitudinal use of GC were both associated with risk of AE among a nationwide Asian SLE cohort.