*  Kinetic-segregation model of T cell activation - Wikipedia
... the immobilized conventional antibody poses less prominent spatial constraints than the immobilized superagonistic antibody. ... However, when these antibodies are immobilized (either by secondary antibody bound to plastic or by Fc receptors on other cells ... Immobilized superagonistic antibodies bound to CD28 exclude CD45 phosphatases completely and the signal leading to T-cell ... However, its authors suggest it might be also applied to CD28 triggering by superagonistic antibodies (mitogenic antibodies). ...
*  31st week of 2011 patent applcation highlights part 43
Superagonistic Anti-CD28 Antibodies - The present invention relates to one or more nucleic acid(s) encoding a binding molecule ... The electrode is then exposed to an antibody-enzyme liquid comprising an antibody-enzyme species, said antibody-enzyme species ... The present invention provides for the retention of catalysts and other immobilized entities within a reaction region. In one ... MONOCLONAL ANTIBODY STRO-4 - The present invention relates to a monoclonal antibody designated STRO-4 which specifically binds ...
*  Roquin differentiates the specialized functions of duplicated T cell costimulatory receptor genes CD28 and ICOS | Garvan...
During evolutionary adaptation in the immune system, host defense is traded off against autoreactivity. Signals through the costimulatory receptor CD28 enable T cells to respond specifically to pathogens, whereas those through the related costimulatory receptor, ICOS, which arose by gene duplication, are critical for affinity maturation and memory antibody responses. ICOS ligand, unlike the pathogen-inducible CD28 ligands, is widely and constitutively expressed in the immune system. Here, we show that crosstalk between these two pathways provides a mechanism for obviating the normal T cell dependence on CD28. Several CD28-mediated responses-generation of follicular helper T cells, germinal center formation, T helper 1 cell-dependent extrafollicular antibody responses to Salmonella and bacterial clearance, and regulatory T cell homeostasis-became independent of CD28 and dependent on ICOS when the E3 ubiquitin ligase Roquin was mutated. Mechanisms to functionally ...
*  Melanoma Missionary: Pinpointing when T cell costimulatory receptor CTLA-4 is Engaged!!!! Melanoma..Jim Breitfeller
Three major events must occur to induce CD8+ T cell-mediated, tumor-protective immunity against syngeneic melanoma. First, the T-cell receptor must be triggered by a (or multiple) self antigen-derived peptide MHC class I complex (7-13). Therefore, this event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells (14). Peripherally tolerant or "ignorant" self-reactive T-cell clones, once properly activated, may serve as tumor-specific effector T cells (15, 16). Second, simultaneously with T-cell receptor triggering, a distinct second costimulatory signal must be delivered, mediated by IL-2, B7-1, or B7-2, which engage IL-2 receptors and CD28 on the surface of the T cell, respectively (17). A source of these cofactors for effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts of IL-2, or by mature dendritic cells that display an increased level of B7-1/B7-2 costimulatory molecules on their cell ...
*  Modulation by IL-2 of CD70 and CD27 Expression on CD8+ T Cells: Importance for the Therapeutic Effectiveness of Cell Transfer...
Signaling mediated through the IL-2R, in conjunction with signals mediated through the T cell Ag receptor, promotes the proliferation and effector function of T cells (32). Some of the signals, such as up-regulation of the IL-2R α-chain, result from cooperative signals mediated both through the T cell Ag receptor as well as through the IL-2R itself; however, the relative role of signals delivered through these pathways has not been fully elucidated. Human tumor-reactive effector T cells have been shown to proliferate extensively in vitro in the presence of high-dose IL-2 alone (33). In addition, between 15 and 20% of melanoma and renal cancer patients treated with high-dose IL-2 alone respond to therapy (6), which may reflect the ability of IL-2 to maintain the proliferation of T cells that were activated by prior exposure to tumor Ags.. Interactions between the costimulatory receptor CD27 and its ligand, CD70, have also been found to play a key role in T lymphocyte activation, proliferation, ...
*  Interleukin-10-producing CD5+ B cells inhibit mast cells during immunoglobulin E-mediated allergic responses | Science Signaling
Subsets of B cells inhibit various immune responses through their production of the cytokine interleukin-10 (IL-10). We found that IL-10-producing CD5+ B cells suppressed the immunoglobulin E (IgE)- and antigen-mediated activation of mast cells in vitro as well as allergic responses in mice in an IL-10-dependent manner. Furthermore, the suppressive effect of these B cells on mast cells in vitro and in vivo depended on direct cell-to-cell contact through the costimulatory receptor CD40 on CD5+ B cells and the CD40 ligand on mast cells. This contact enhanced the production of IL-10 by the CD5+ B cells. Through activation of the Janus-activated kinase-signal transducer and activator of transcription 3 pathway, IL-10 decreased the abundance of the kinases Fyn and Fgr and inhibited the activation of the downstream kinase Syk in mast cells. Together, these findings suggest that an important function of IL-10-producing CD5+ B cells is inhibiting mast cells and IgE-mediated allergic responses.. ...
*  Frontiers | Five layers of receptor signalling in γδ T cell differentiation and activation | Immunology
The contributions of gamma-delta T cells to immunity to infection or tumours critically depend on their activation and differentiation into effectors capable of secreting cytokines and killing infected or transformed cells. These processes are molecularly controlled by surface receptors that capture key extracellular cues and convey downstream intracellular signals that regulate gamma-delta T cell physiology. The understanding of how environmental signals are integrated by gamma-delta T cells is critical for their manipulation in clinical settings. Here we discuss how different classes of surface receptors impact on human and murine gamma-delta T cell differentiation, activation and expansion. In particular, we review the role of five receptor types: the T cell receptor (TCR), costimulatory receptors, cytokine receptors, NK receptors and inhibitory receptors. Some of the key players are the costimulatory receptors CD27 and CD28, which differentially impact on pro-inflammatory subsets of gamma-delta T
*  Efficiency of T-cell costimulation by CD80 and CD86 cross-linking correlates with calcium entry - Zurich Open Repository and...
Costimulation is a fundamental principle of T-cell activation. In addition to T-cell receptor engagement, the interaction between CD80 and/or CD86 with CD28 and/or cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptors is required to regulate T-cell activation and tolerance. While the importance of costimulation is clearly established, the exact molecular mechanism is unknown. We demonstrate that T-cell proliferation and the ability of CD8(+) T-effector cells to kill were enhanced slightly by CD80 but dramatically by CD86 costimulation. To further analyse the cellular process of costimulation, we developed a single-cell assay to analyse Ca(2+) signals following costimulation with bi-specific antibodies. We found that this stimulation method worked in every human T-cell that was analysed, making it one of the most efficient T-cell activation methods to date for primary human T cells. The enhanced proliferation and killing by costimulation was paralleled by an increase of Ca(2+) influx following ...
*  The role of the cytoplasmic tail of antigen-presenting cell surface molecule CD80 in delivery of T cell costimulation
CD80 is a highly glycosylated surface protein of 45-60 kDa found on activated B cells, T cells, monocytes, and dendritic cells. Based upon the CD80 cDNA sequence, the molecular weight of the protein core is 30 kDa. The remaining 15-30 kDa of the molecular weight is N-linked carbohydrate attached at eight possible sites in the extracellular region. CD80, and its structural and functional homolog CD86, both bind to the T cell molecules CD28 and CTLA-4. CD28 is found on resting and activated T cells, and is a major costimulatory molecule in the immune response. Ligation of CD28 increases both cytokine gene transcription and mRNA stability, and up-regulates cytokine receptor expression. CTLA-4 is expressed on T cells and B cells only after activation. Its role in T cell immunity is less clear than that of CD28. Initially, antibodies to CTLA-4 were shown to enhance CD3-and CD28-mediated T cell proliferation, but it has become clear recently that CTLA-4 is a major negative regulatory protein, ...
*  Plus it
Therapeutic tumor immunity requires the presence and appropriate activation of tumor antigen specific CD8+ T cells and migration of activated tumor-antigen specific CD8+ T cells into a tumor microenvironment where immunosuppressive barriers have been eliminated. Antibody mediated blockade of CTLA-4 and PD-1 is a clinically effective strategy to dampen tumor mediated immunosuppression in a minority of patients with advanced cancer, and this approach may be potentiated through vaccination to prime additional CTL clones and through direct stimulation of T cell costimulatory molecules of the TNF superfamily. Here we provide a systematic comparison of anti-tumor vaccination with either heat shock protein gp96-Ig or traditional peptide/adjuvant vaccines given alone or in combination with CTLA-4 or PD-1 blockade and direct T cell costimulation via OX40, 4-1BB and TNFRSF25. Through the tracking of tumor-antigen specific CD4+ and CD8+ T cell responses, these studies demonstrate that both TNFRSF4 and ...
*  Protein Kinase B Regulates T Lymphocyte Survival, Nuclear Factor κb Activation, and Bcl-XL Levels in Vivo | JEM
The induction of survival versus apoptosis is a central issue during T cell development and activation. The differential regulation of thymocyte survival versus death through TCR-mediated selection signals plays a key role in establishing a functional mature T cell repertoire (1). In mature T cells, several studies have demonstrated that signals from MHC molecules are required for the survival of resting T cells (2)(3)(4). In addition, the induction of apoptosis is strictly regulated after antigenic triggering (5). However, during T cell activation, the T cell costimulatory molecule CD28 is believed to contribute to survival signals (6)(7)(8).. Several molecules have been identified that play key roles in regulating apoptosis in T cells (9). Important advances in understanding T cell apoptosis have come through the study of Bcl-2 family members. Bcl-2-related proteins function to promote either cell survival (such as Bcl-2 and Bcl-XL) or cell death (such as Bax and BAD). Several studies have ...
*  Rabbit Polyclonal to ME1. - BET-bromodomain inhibition research
A population of individual T cells expressing an invariant V24JQ T cell antigen receptor (TCR) chain and high levels of CD161 (NKR-P1A) appears to play an immunoregulatory role through production of both T helper (Th) type 1 and Th2 cytokines. and cytokine secretion in response to CD1d+ target cells, demonstrating a physiological accessory molecule function for CD161. However, CD1d-restricted target cell lysis by activated V24invt T cells, which involved a granule-mediated exocytotic mechanism, was CD161-impartial. In further contrast to the mouse, the signaling pathway involved in V24invt T cell costimulation through CD161 did not appear to involve stable association with tyrosine kinase p56Lck. These results demonstrate a role for CD161 as a novel costimulatory molecule for TCR-mediated acknowledgement of CD1d by human V24invt T cells. (Camarillo, CA). Functional Analysis of T Cells. For activation of T cells (105/ well), anti-CD3 mAb OKT3 was bound overnight in PBS (50 l/well) to 96-well ...
*  Costimulation of Effector CD8+ T Cells: Which Receptor is Optimal for Immunotherapy? | MedCrave
The NKG2D costimulatory receptor is currently a focus of anti-tumor, anti-viral, and auto-immunity studies. NKG2D is an activating receptor expressed on NK cells, all human CD8+ T cells, activated murine CD8+ T cells, γδ T cells, and some CD4+ T cells [5,6]. In T cells, NKG2D associates with an adaptor protein, DAP10, and provides a costimulation signal by activating intracellular signaling pathways [7-9]. The cytoplasmic domain of DAP10 has one known signaling motif, a YINM-sequence, that is also found in the CD28 costimulatory receptor [8,9]. After receptor stimulation, the tyrosine is phosphorylated and phosphatidylinositol-3 kinase (PI3K) and a Grb2-Vav1 complex are subsequently activated, leading to downstream Akt activation and mitogen-activated protein kinases (MAPKs) respectively [9]. Akt activation by either of these two receptors initiates a plethora of downstream signaling pathways including NF-κB, mTORc1, NFAT, GSK-3β, and many others depending on what other proteins are being ...
*  LICOS, a primordial costimulatory ligand? - Radcliffe Department of Medicine
In mammals, the classical B7 molecules expressed on antigen-presenting cells, B7-1 (CD80) and B7-2 (CD86), bind the structurally related glycoproteins CD28 and CTLA-4 (CD152), generating costimulatory signals that regulate the activation state of T cells. A recently identified human CD28-like protein, ICOS, also induces costimulatory signals in T cells when crosslinked with antibodies, but it is unclear whether ICOS is part of a B7-mediated regulatory pathway of previously unsuspected complexity, or whether it functions independently and in parallel. Here, we report that, rather than binding B7-1 or B7-2, ICOS binds a new B7-related molecule of previously unknown function that we call LICOS (for ligand of ICOS). At 37 degrees C, LICOS binds only to ICOS but, at lower, non-physiological temperatures, it also binds weakly to CD28 and CTLA-4. Sequence comparisons suggest that LICOS is the homologue of a molecule expressed by avian macrophages and of a murine protein whose expression is induced ...
*  A conserved polylysine motif in CD86 cytoplasmic tail is necessary for cytoskeletal association and effective co-stimulation. -...
T cell activation requires both antigen specific and co-stimulatory signals that include the interaction of CD28 with its ligands CD80 and CD86. These signals are delivered by antigen presenting cells (APC) in the context of the immunological synapse (IS). Reorganization of the cytoskeleton is required for the formation and maintenance of the IS. Our results show that a highly conserved polylysine motif in CD86 cytoplasmic tail, herein referred to as the K4 motif, is responsible for the constitutive association of CD86 to the cytoskeleton in primary human APC as well as in a murine APC model. This motif is not involved in initial APC:T cell conjugate formation but mutation of the K4 motif affects CD86 reorientation at the IS. Importantly, APCs expressing CD86 with mutated K4 motif are severely compromised in their capacity to trigger complete T cell activation upon peptide presentation as measured by IL-2 secretion. Altogether, our results reveal the critical importance of the cytoskeleton-dependent
*  TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-theta signaling and promote...
TLR ligands act directly upon T cells to restore proliferation in the absence of protein kinase C-theta signaling and promote autoimmune ...
*  Differential engagement of Tim-1 during activation can positively or negatively...
T cell activation is a tightly regulated event involving complex receptor-ligand interaction, ultimately leading to downstream signaling events. Optimal T cell activation requires at least two signals, antigen recognition and costimulation (29-31). The TCR-CD3 complex, which recognizes antigens presented by MHC molecules, is critical in maintaining the specificity of T cell responses. Signal two, or costimulation, is an antigen-independent signal required for sustained T cell activation, proliferation, and survival. Although several costimulatory molecules have been identified that can either enhance (e.g., CD28 and ICOS) or inhibit (e.g., CTLA4 and PD-1) T cell responses in terms of T cell activation, none of these molecules has been found to both activate and inhibit T cell proliferation/cytokine responses. With the specific anti-Tim-1 antibodies described here, we provide evidence that engagement of Tim-1 can both activate and inhibit T cell responses. We have shown that two mAbs that are ...
*  IL-15 Superagonist Technology
Altor is building on our IL-15 technology to create a next-generation targeted IL-15 scaffold platform to recognize and target specific antigens found in various cancers and viral infections. We have adapted the IL-15 superagonist complex to create a functional scaffold for the design of multi-specific fusion protein complexes. Using an antibody or single-chain T cell receptors (STARTM) as recognition domains linked to the IL-15 scaffold, we have generated both bivalent and bispecific product candidates (TxM).. Extensive characterization of these product candidates consisting of therapeutic antibodies and this scaffold indicates that such a targeted immunotherapeutic can potentiate the anti-tumor activities of the therapeutic antibody as well as potently facilitate immune responses. Thus, we are utilizing this IL-15 scaffold platform to generate multiple targeted IL-15 product candidates that can simultaneously promote killing of target cells and retain ...
*  Modulating co-stimulation | SpringerLink
The modulation of co-stimulatory pathways represents a novel therapeutic strategy to regulate autoimmune diseases. Auto-reactive CD4+ T cells play a critical role in initiating the immune response leading to inflammation and autoimmune diseases. Blocking co-stimulatory signals prevents T-cell activation, thus diminishing autoimmune responses and possibly preventing the progression of autoimmune disease. Blockade of several co-stimulatory pathways has been investigated in animal models and has led to clinical trials testing specific blocking agents in humans. In this review we will describe the role of co-stimulatory pathways, primarily the CD28-B7 pathway, in autoimmune diseases, and we will present in vivo and in vitro studies supporting the efficacy of co-stimulation blockade in animal models of autoimmune disease. Finally, we will discuss the clinical therapeutic efficacy of blocking monoclonal antibodies in preventing or reducing auto-antigen driven T-cell activation in humans with ...
*  DC-expanded CD25+ CD4+ T cells suppress proliferation b | Open-i
DC-expanded CD25+ CD4+ T cells suppress proliferation better than unexpanded CD25+ CD4+ T cells. (A) CD25+ CD4+ T cells from NOD.BDC2.5 mice were expanded for 7
*  Plus it
The present results verify the previously suggested, but not definitively proven, mechanism that α-GalCer-activated iNKT-cells at least partly protect NOD mice from type 1 diabetes by driving the maturation of tolerogenic DCs. In contrast, iNKT-conditioned DCs in B6.H2g7 mice mature to an alternative immunogenic state that supports rather than inhibits AI4 T-cell-induced type 1 diabetes. The downstream maturation of iNKT-conditioned DCs in NOD and B6.H2g7 mice to a tolerogenic versus an immunogenic state is due to the induction of quantitatively different expression levels of T-cell costimulatory and inhibitory molecules.. A series of T-cell costimulatory molecules were upregulated to a much greater extent on iNKT-conditioned DCs from B6.H2g7 than NOD mice. In particular, CD70 and OX40L expression levels were unchanged or strongly upregulated on iNKT-conditioned DCs from NOD and B6.H2g7 mice, respectively. This could be significant given a report that iNKT-cells promote CD8+ cytotoxic T-cell ...
*  B7-DC costimulates PD1−/− CD4+ T cells. (a) Purifie | Open-i
B7-DC costimulates PD1−/− CD4+ T cells. (a) Purified CD4+ T cells from wt (open bars) or PD-1 KO mice (filled bars) were stimulated with 30 ng/well of preco
*  Film developing plus CD
Photography forums to discuss digital photography, film photography, photographers, techniques and cameras and equipment, along with advice on buying and using cameras.
*  TIDCs are not activated by LPS plus IFN-γ plus anti-CD | Open-i
TIDCs are not activated by LPS plus IFN-γ plus anti-CD40 stimulation. (A) Control BM-DCs or enriched C26-6CK TIDCs were cultured overnight with medium alone
*  2B4/CD244/SLAMF4 Proteins: Novus Biologicals
2B4/CD244/SLAMF4 Proteins available through Novus Biologicals. Browse our 2B4/CD244/SLAMF4 Protein catalog backed by our Guarantee+.
*  CD8+ T cells have an important role in mediating protec | Open-i
CD8+ T cells have an important role in mediating protection induced by LACK DNA vaccination. Mice (n = 10/group) receiving LACK or control DNA vaccination wer
*  Changes of CD8/HLADR+ T cells during a period of seven | Open-i
Changes of CD8/HLADR+ T cells during a period of seven years HAART ( ± SD,/ μL). Patient numbers: Effective group (A) (n = 25), Ineffective group (B) (n = 18)