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T-cell co-stimulatory pathways in autoimmunity
J?rg J Goronzy, Cornelia M Weyand
Arthritis Research & Therapy , 2008, DOI: 10.1186/ar2414
Abstract: Since its first introduction, the concept of co-stimulation has sparked the interest of autoimmunity researchers and immunologists interested in translational applications, because it holds the promise to influence immune responses without needing to define the antigen involved. The basic idea is that co-stimulatory signals decide whether an activation signal translates into an immune response or into tolerance. The concept goes back to the report by Cohn and Bretscher [1], who postulated in the 1970s that regulatory control of a system requiring high sensitivity and high specificity, such as the adaptive immune system, must rely on two independent signals.Lafferty [2] and Jenkins and Schwartz [3] introduced this concept into T-cell immunology in the 1980s. Signal 1 is delivered by the T-cell receptor (TCR) recognizing the antigenic peptide within the context of the major histocompatibility complex (MHC) molecule. However, stimulation of the TCR alone does not induce a productive T-cell response, but renders the T cells anergic. A second signal, generally provided by molecules expressed on the antigen-presenting cell (APC), is required to optimize a T-cell response. In this concept, the APC holds a central position because of its ability to provide a co-stimulatory signal. Dendritic cells (DCs) are of particular importance in T-cell priming, but B cells and macrophages can also function as APCs. Under normal conditions, other cell types, such as epithelial or stromal cells, cannot induce an immune response because they lack the co-stimulatory ligand. Subsequent studies have shown that APCs need activation signals to provide co-stimulatory ligands, for example through the activation of Toll-like receptors [4,5].The model has placed co-stimulation at the central decision point in the induction of an immune response; in fact, stimulation of a na?ve T-cell response is unlikely in the absence of co-stimulatory signals. It is therefore not surprising that this decision po
Canine Distemper Virus Infection Leads to an Inhibitory Phenotype of Monocyte-Derived Dendritic Cells In Vitro with Reduced Expression of Co-Stimulatory Molecules and Increased Interleukin-10 Transcription  [PDF]
Visar Qeska, Yvonne Barthel, Vanessa Herder, Veronika M. Stein, Andrea Tipold, Carola Urhausen, Anne-Rose Günzel-Apel, Karl Rohn, Wolfgang Baumg?rtner, Andreas Beineke
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096121
Abstract: Canine distemper virus (CDV) exhibits a profound lymphotropism that causes immunosuppression and increased susceptibility of affected dogs to opportunistic infections. Similar to human measles virus, CDV is supposed to inhibit terminal differentiation of dendritic cells (DCs), responsible for disturbed repopulation of lymphoid tissues and diminished antigen presenting function in dogs. In order to testify the hypothesis that CDV-infection leads to an impairment of professional antigen presenting cells, canine DCs have been generated from peripheral blood monocytes in vitro and infected with CDV. Virus infection was confirmed and quantified by transmission electron microscopy, CDV-specific immunofluorescence, and virus titration. Flow cytometric analyses revealed a significant down-regulation of the major histocompatibility complex class II and co-stimulatory molecules CD80 and CD86 in CDV-infected DCs, indicative of disturbed antigen presenting capacity. Molecular analyses revealed an increased expression of the immune inhibitory cytokine interleukin-10 in DCs following infection. Results of the present study demonstrate that CDV causes phenotypical changes and altered cytokine expression of DCs, which represent potential mechanisms to evade host immune responses and might contribute to immune dysfunction and virus persistence in canine distemper.
The inhibitory receptor LILRB4 (ILT3) modulates antigen presenting cell phenotype and, along with LILRB2 (ILT4), is upregulated in response to Salmonella infection
Damien P Brown, Des C Jones, Katie J Anderson, Nicolas Lapaque, Robin A Buerki, John Trowsdale, Rachel L Allen
BMC Immunology , 2009, DOI: 10.1186/1471-2172-10-56
Abstract: We studied the effects of LILRB4 ligation on antigen presenting cell phenotype, and the expression of LILRB2 and LILRB4 on Salmonella-infected antigen presenting cells. Ligation of LILRB4 throughout in vitro culture of dendritic cells led to an upregulation of the co-stimulatory protein CD86. Alterations in the production of IL-8 and IL-10 by LILRB4-ligated macrophages were also observed. Infection with Salmonella typhimurium or TLR stimulation with Salmonella components led to an upregulation of LILRB2 and LILRB4.Our results indicate that the inhibitory effects of LILRB4 do not result from a failure to upregulate co-stimulatory proteins. In addition to the high level expression that can render antigen presenting cells tolerogenic, there may be a role for lower level expression and activity of LILRB2 and LILRB4 in response to TLR signalling during an immune response to bacterial infection.Leukocyte Ig-like receptors (LILR, also known as ILT and LIR) are a family of innate immune receptors that are predominantly expressed on cells of the myelomonocytic lineage [1]. The 11 members of the LILR protein family are divided into 'activating' (subfamily A) or 'inhibitory' (subfamily B) receptors on the basis of their transmembrane and cytoplasmic domains. There is a growing interest in LILR expression and/or function in situations of immune dysregulation and following transplantation [2-4], but as innate immune receptors they would also be predicted to play a role in an immune response to infection.LILRB4 was first identified as an inhibitory receptor expressed on myeloid antigen presenting cells which associates with the protein tyrosine phosphotase SHP-1 [5]. The importance of this particular receptor as an immune modulator was highlighted when it was shown that high level expression of LILRB4 with LILRB2 rendered antigen presenting cells tolerogenic [4,6,7]. LILRB4 and LILRB2 may differ in their mechanisms of immune regulation. In receptor ligation studies, the tolerogen
The Mucosal Adjuvant Cyclic di-AMP Exerts Immune Stimulatory Effects on Dendritic Cells and Macrophages  [PDF]
Ivana ?krnjug, Christine Rueckert, Rimma Libanova, Stefan Lienenklaus, Siegfried Weiss, Carlos A. Guzmán
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095728
Abstract: The cyclic di-nucleotide bis-(3′,5′)-cyclic dimeric adenosine monophosphate (c-di-AMP) is a candidate mucosal adjuvant with proven efficacy in preclinical models. It was shown to promote specific humoral and cellular immune responses following mucosal administration. To date, there is only fragmentary knowledge on the cellular and molecular mode of action of c-di-AMP. Here, we report on the identification of dendritic cells and macrophages as target cells of c-di-AMP. We show that c-di-AMP induces the cell surface up-regulation of T cell co-stimulatory molecules as well as the production of interferon-β. Those responses were characterized by in vitro experiments with murine and human immune cells and in vivo studies in mice. Analyses of dendritic cell subsets revealed conventional dendritic cells as principal responders to stimulation by c-di-AMP. We discuss the impact of the reported antigen presenting cell activation on the previously observed adjuvant effects of c-di-AMP in mouse immunization studies.
Effects of lactoferrin on elicitation of the antigen-specific cellular and humoral cutaneous response in mice  [PDF]
Micha? Zimecki,Jolanta Artym,Maja Koci?ba,Marian Kruzel
Post?py Higieny i Medycyny Do?wiadczalnej , 2012,
Abstract: Immune contact dermatitis is an inflammation of the skin resulting from exposure to allergens in the environment. The aim of this study was to compare the actions of lactoferrin (LF), a natural immunomodulator, on the elicitation phases of the cellular and humoral, cutaneous immune responses to oxazolone and toluene diisocyanate (TDI), respectively. LF was given i.v. in a 10 mg/mouse dose, together with the eliciting doses of the antigens. The ear edema and the number of lymphocytes in the draining lymph nodes were measured. In addition, the production of IL-2 in the cultures of lymph node cells and the content of IL-4 in lymph node cells were determined. LF had a profound inhibitory effect on the eliciting phase of the immune response to oxazolone as measured by the ear edema and lymph node cell number. The suppressive effect of LF on the effector phase of the immune response to TDI was moderate. LF had some stimulatory effect on the ex vivo content of IL-4 in lymphocytes in the immune response to TDI. On the other hand, it significantly inhibited IL-2 in vitro production in the immune response to oxazolone. The data strongly suggest that LF exerted differential actions on the activities of antigen-specific Th1 and Th2 cells involved in respective types of the cutaneous immune responses.
Targeting Co-Stimulatory Pathways in Gene Therapy  [PDF]
Yiping Yang
Frontiers in Microbiology , 2011, DOI: 10.3389/fmicb.2011.00202
Abstract: Gene therapy with recombinant viral vectors such as adenovirus and adenovirus-associated virus holds great promise in treating a wide range of diseases because of the high efficiency with which the viruses transfer their genomes into host cells in vivo. However, the activation of the host immune responses remains a major hurdle to successful gene therapy. Studies in the past two decades have elucidated the important role co-stimulation plays in the activation of both T and B cells. This review summarizes our current understanding of T cell co-stimulatory pathways, and strategies targeting these co-stimulatory pathways in gene therapy applications as well as potential future directions.
Modulation of Innate Antigen-Presenting Cell Function by Pre-patent Schistosome Infection  [PDF]
Christine E. Ferragine,Colleen D. Walls,Stephen J. Davies
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002136
Abstract: Schistosomes are intravascular helminths that infect over 200 million people worldwide. Deposition of eggs by adult schistosomes stimulates Th2 responses to egg antigens and induces granulomatous pathology that is a hallmark of schistosome infection. Paradoxically, schistosomes require host immune function for their development and reproduction and for egress of parasite eggs from the host. To identify potential mechanisms by which immune cells might influence parasite development prior to the onset of egg production, we assessed immune function in mice infected with developing schistosomes. We found that pre-patent schistosome infection is associated with a loss of T cell responsiveness to other antigens and is due to a diminution in the ability of innate antigen-presenting cells to stimulate T cells. Diminution of stimulatory capacity by schistosome worms specifically affected CD11b+ cells and did not require concomitant adaptive responses. We could not find evidence for production of a diffusible inhibitor of T cells by innate cells from infected mice. Rather, inhibition of T cell responsiveness by accessory cells required cell contact and only occurred when cells from infected mice outnumbered competent APCs by more than 3:1. Finally, we show that loss of T cell stimulatory capacity may in part be due to suppression of IL-12 expression during pre-patent schistosome infection. Modulation of CD4+ T cell and APC function may be an aspect of host immune exploitation by schistosomes, as both cell types influence parasite development during pre-patent schistosome infection.
Probably Intersecting Families are Not Nested  [PDF]
Paul A. Russell,Mark Walters
Mathematics , 2011,
Abstract: It is well known that an intersecting family of subsets of an n-element set can contain at most 2^(n-1) sets. It is natural to wonder how `close' to intersecting a family of size greater than 2^(n-1) can be. Katona, Katona and Katona introduced the idea of a `most probably intersecting family.' Suppose that X is a family and that 0
Most Probably Intersecting Hypergraphs  [PDF]
Shagnik Das,Benny Sudakov
Mathematics , 2013,
Abstract: The celebrated Erd\H{o}s-Ko-Rado theorem shows that for $n \ge 2k$ the largest intersecting $k$-uniform set family on $[n]$ has size $\binom{n-1}{k-1}$. It is natural to ask how far from intersecting larger set families must be. Katona, Katona and Katona introduced the notion of most probably intersecting families, which maximise the probability of random subfamilies being intersecting. We study the most probably intersecting problem for $k$-uniform set families. We provide a rough structural characterisation of the most probably intersecting families and, for families of particular sizes, show that the initial segment of the lexicographic order is optimal.
Enhanced Dendritic Cell-Mediated Antigen-Specific CD4+ T Cell Responses: IFN-Gamma Aids TLR Stimulation  [PDF]
Kuo-Ching Sheng,Stephanie Day,Mark D. Wright,Lily Stojanovska,Vasso Apostolopoulos
Journal of Drug Delivery , 2013, DOI: 10.1155/2013/516749
Abstract: Phenotypic maturation and T cell stimulation are two functional attributes of DCs critical for immune induction. The combination of antigens, including those from cancer, with Toll-like receptor (TLR) ligands induces far superior cellular immune responses compared to antigen alone. In this study, IFN-gamma treatment of bone marrow-derived DC, followed by incubation with the TLR2, TLR4, or TLR9 agonists, enhanced DC activation compared to TLR ligation alone. Most notably, the upregulation of CD40 with LPS stimulation and CD86 with CpG stimulation was observed in in vitro cultures. Similarly, IFN-gamma coinjected with TLR ligands was able to promote DC activation in vivo, with DCs migrating from the site of immunization to the popliteal lymph nodes demonstrating increased expression of CD80 and CD86. The heightened DC activation translated to a drastic increase in T cell stimulatory capacity in both antigen independent and antigen dependent fashions. This is the first time that IFN-gamma has been shown to have a combined effect with TLR ligation to enhance DC activation and function. The results demonstrate the novel use of IFN-gamma together with TLR agonists to enhance antigen-specific T cell responses, for applications in the development of enhanced vaccines and drug targets against diseases including cancer. 1. Introduction Vaccination requires highly purified proteins or synthetic peptides usually in combination with immune stimulating adjuvants or danger signals, to successfully prime T cells. In the last 10 years, there has been an upsurge of data suggesting that dendritic cells (DCs) are the most important cells to stimulate immune responses against antigens [1]. DCs link the innate and adaptive immune responses by (i) binding a vast array of pathogens through their cell surface receptors, including C-type lectins, Toll-like receptors (TLRs), and scavenger receptors and inducing inflammatory responses for their elimination and (ii) are able to stimulate CD4+ T cell responses and cross present antigens for CD8+ T cell stimulation against antigens. Numerous strategies have been utilized to target antigens to DCs, following the abundance of information becoming available regarding cell surface expression of receptors and their role in stimulating immune responses [2]. The mannose receptor, DC-SIGN, scavenger receptor, DEC-205, and Toll-like receptors (TLRs) are amongst the most thoroughly studied DC receptors [2]. Targeting of these receptors is becoming an effective strategy of delivering antigens in DC-based anticancer immunotherapy studies. TLRs
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