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Medawar''s hypotheses for explaining maternal immune tolerance of the semi-allogeneic fetus are now proven incorrect or insufficient. The mother''s immune response is not passive, suppressed, indolent or physically constrained in pregnancy. Instead, her immune system is centrally engaged with all steps of the reproductive process from conception to embryo implantation and placental development. Emerging studies show that immune cells are positioned and equipped to sense antigens and other signals originating in seminal fluid, the embryo and placental trophoblast. The immune response appears competent to utilise this information to discriminate the reproductive fitness and compatibility of the male partner and the integrity and developmental competence of the conceptus tissue. Since the immune response is modulated by the individual''s infectious, inflammatory, stress, nutritional and metabolic status, immune influence on progression or disruption of pregnancy may be further influenced by environmental stressors and resource availability. This opinion paper advances the view that the immune system operates in pregnancy to integrate these signals and to exert executive quality control to either accommodate or reject the conceptus. It is argued that ‘immune-mediated quality control’ would facilitate optimal female reproductive investment and maximise offspring fitness, and thereby explain the evolutionary advantage of maternal immune awareness of the conceptus tissue. [Copyright &y& Elsevier]

Abstract: Unc119 is an adapter signaling molecule, which regulates activation of tyrosine kinases in T cells, eosinophils and fibroblasts. It plays an important role in the photoreceptor synapses of the retina. Recently, we have shown that it inhibits bacterial uptake through macropinocytosis. In this paper we demonstrate a role for Unc119 in clathrin- and caveolae-based endocytosis as well as macropinocytosis. Depletion of Unc119 in fibroblasts increases, whereas overexpression inhibits uptake of transferrin, FM4-64, albumin, viruses, and ligand-coated beads. Physiological stimuli that upregulate the expression of Unc119 also inhibits endocytosis. Unc119 has the opposite effect on cholera toxin B uptake, which represents a clathrin- and dynamin-independent endocytic process. Unc119 interacts with dynamin, a key effector molecule of many endocytic processes. More importantly, Unc119 inhibits the GTPase activity of dynamin. Binding of Unc119 to dynamin decreases the association with its binding partner amphiphysin, a known regulator of dynamin activation. Thus, Unc119 regulates various endocytic pathways through dynamin and sets a threshold point for vesicular trafficking. [Copyright &y& Elsevier]

Abstract: A viral infection model with immune circadian rhythms is investigated in this paper. By employing the persistence theory, we establish a threshold between the extinction and the uniform persistence of the disease. These results can be used to explain the oscillation behaviors of virus population, which were observed in chronic HBV or HCV carriers. Further, numerical simulations indicate that the dynamics of the lytic component of cytotoxicity T cells (CTLs) is crucial to the outcome of a viral infection. [Copyright &y& Elsevier]

Cortical F-actin plays important roles during HIV-1 infection. A recent paper in Cell highlights the involvement of F-actin in enhancing dendritic cell (DC)-mediated HIV-1 infection of T cells. Such a critical mechanism of HIV-1 trans -enhancement between human DCs and T cells had not been analyzed in molecular detail before this work. [ABSTRACT FROM AUTHOR]

Two recent papers published in Immunity and Cell Host & Microbe underline the great importance of B cells and of antibodies (Abs) in orchestrating crucial T helper cell type 2 (Th2) protective immune responses to gastrointestinal nematodes. The findings in animal models now raise major questions as to how B cells and Abs carry out these functions in humans. Here we discuss recent technological advances in humanizing animal models at the level of both Abs and their Fc-receptors, that might provide some answers. [Copyright &y& Elsevier]

Abstract: The development of specific therapies for organ-specific autoimmune diseases requires the identification of relevant immunogenic epitopes, recognized by both pathogenic T cells and autoantibodies. Here, we review the most relevant studies focused in the identification of peptides in multiple sclerosis (MS) and the distinct T cell reactivity induced in patients compared to controls. Only a few studies reported significant differences in terms of T cell reactivity to them. The current knowledge on this issue, and the diagnostic and therapeutic possibilities opened by the identification of pathogenic MS epitopes are discussed in this paper. [Copyright &y& Elsevier]

Abstract: Antigen presenting molecules play an important role in both innate and adoptive immune responses by priming and activating T cells. Among them, CD1 molecules have been identified to present both exogenous and endogenous lipid antigens to CD1-restricted T cells. The involvement of CD1-restricted T cells in autoimmune diseases and in defense against infectious diseases, however, remains largely unknown. Identifying novel antigenic lipids that bind to CD1 molecules and understanding the role of CD1-restricted T cells should lead to the successful development of vaccines, because the lipids can be used as antigens and also as adjuvants. In this paper, we have constructed functional recombinant human CD1 dimeric proteins and established a competitive ELISA assay to measure the lipid binding to CD1 molecules using the CD1 dimers. By using the competitive ELISA assay, we were able to show that the lipid extracts from murine malaria parasites can actually be loaded onto CD1 molecules. In addition, we have demonstrated that artificial antigen-presenting cells, which consist of magnetic beads coated with CD1d dimer and anti-CD28 antibody, stimulated and expanded human invariant NKT cells as efficiently as autologous immature DCs. A set of the tools presented in the current study should be valuable for screening various CD1 molecule-binding lipid antigens and for isolating CD1-restricted T cells. [Copyright &y& Elsevier]

Abstract: Gene therapy mediated by nonviral vectors provides great advantages over conventional drug therapy in inducing immunosuppression after organ transplantation, yet it was rarely reported because T cells are normally difficult to transfect. In this paper, a nonviral vector that effectively transports genes into T cells is developed by attaching a T cell specific ligand, the CD3 single chain antibody (scAbCD3), to the distal ends of poly(ethylene glycol)-grafted polyethylenimine (scAbCD3-PEG-g-PEI). This polymer was first complexed with superparamagnetic iron oxide nanoparticles (SPIONs) and was then used to condense plasmid DNA into nanoparticles with an ideally small size and low cytotoxicity. Based on a reporter gene assay, targeting ligand functionalization of the delivery agent leads to 16 fold of enhancement in the gene transfection level in HB8521 cells, a rat T lymphocyte line. This targeting event in cell culture was successfully imaged by MRI scan. Inspiringly, delivery of a therapeutic gene DGKα with our MRI-visible delivery agent was likewise efficient, resulting in a 43% inhibition in the stimulated proliferation of HB8521 cells as well as a 38% inhibition in the expression of a major functional cytokine interleukin-2 (IL-2), indicating the effective T cell anergy induced by gene therapy. [Copyright &y& Elsevier]

Abstract: Short synthetic peptides are important tools in biomedical research permitting to generate hapten specific polyclonal sera for analytical purposes or functional studies. In this paper we provide proof of principle that a peptide located in a highly conserved portion of the Gag protein of the caprine arthritis encephalitis virus and carrying an immunodominant T helper cell epitope functions as an efficient carrier peptide, mediating a strong antibody response to a peptidic hapten encompassing a well-characterized B cell epitope of Env. The carrier and hapten peptides were collinearly synthesized permutating their molecular arrangement. While the antibody response to the hapten was similar for both constructs, the antibody response to a B cell epitope overlapping the T helper cell epitope of the Gag carrier peptide was considerably different. This permits a modular use of the carrier peptide to generate antibody directed exclusively to the hapten peptide or a strong humoral response to both carrier- and hapten-peptide. Finally, we have mapped the epitopes involved in this polarized antibody response and discussed the potential immunological implications. [Copyright &y& Elsevier]

Abstract: This paper presents some initial experimental results obtained with a dual-head prototype single photon emission microscope system (SPEM) that is dedicated to mouse brain studies using I-125 labeled radiotracers. In particular, this system will be used for in vivo tacking of radiolabeled T cells in mouse brain. This system is based on the use of the intensified electron multiplying charge-coupled device (I-EMCCD) camera that offers the combination of an excellent intrinsic spatial resolution, a good signal-to-noise ratio, a large active area and a reasonable detection efficiency over an energy range between 27–140keV. In this study, the dual-head SPEM system was evaluated using both resolution phantoms and a mouse with locally injected T cells labeled with I-125. It was demonstrated that for a relatively concentrated source object, the current dual-head SPEM system is capable of visualizing the tiny amount of radioactivity (∼12nCi) carried by a very small number (<1000) of T cells. The current SPEM system design allows four or six camera heads to be installed in a stationary system configuration that offers a doubled or tripled sensitivity at a spatial resolution similar to that obtained with the dual-head system. This development would provide a powerful tool for in vivo and non-invasive tracking of radiolabeled T cells in mouse brain and potentially for other rodent brain imaging studies. [Copyright &y& Elsevier]

Abstract: This paper describes the use of a novel flow cell, the T-cell, adapted to the flow-through cell apparatus, for the study of ibuprofen release from implantable loaded pellets and its performance in comparison to the compendial tablet cell. In fact, the drug targeting with a local delivery system becomes increasingly used to achieve therapeutic doses directly on the implantation site while maintaining a low systemic drug level. Due to the long and expensive in vivo studies necessary to evaluate the efficacy of such delivery systems, in vitro dissolution techniques are performed despite there being no standard method in the biomaterial field. In this work, dissolution profiles obtained with the T-cell configuration clearly indicate a prolonged release of ibuprofen. Dissolution data fitted to Higuchi, Hixson–Crowell, Ritger–Peppas and Kopcha equations indicate the coexistence of diffusion and erosion mechanisms governing ibuprofen release. T-cell adapted to the standard flow-through dissolution apparatus is shown to better simulate in vivo conditions than the tablet cell. This is relevant for in vivo/in vitro correlations. [Copyright &y& Elsevier]

Abstract: Many previous studies have described differential responses to mutagens among human lymphocyte subpopulations. However, there are some confusing data about the sensitivity to mutagens among lymphocyte subpopulations. In this paper we review the studies published to date reporting differential responses among CD4+ T-cells, CD8+ T-cells, B-cells and NK-cells exposed to different mutagens, using different assay methods, such as micronuclei (MN), sister chromatid exchanges (SCEs), single cell gel electrophoresis (SCGE), and fluorescence-activated cell sorting (FACS). These methods are mostly used for genetic biomonitoring of human populations exposed to potential mutagens. Thus, this review may provide a reference of target cells sensitive to mutagens that will be useful for genetic biomonitoring of human populations. [Copyright &y& Elsevier]

Abstract: This paper describes studies performed with ERA-63 a low molecular weight pharmaceutical with intended immunomodulatory effects. Since this compound was also known to have estrogenic activity a non-conventional approach was taken in order to differentiate between estrogenic and non-estrogenic-induced immunomodulatory effects. EE was included not only for qualitative comparison (hazard identification) between immunomodulatory effects but also, in case of similar effects, to facilitate the extrapolation of the findings in the rat to anticipated effects in humans. After 28 days of treatment with dosages ranging from pharmacological up to clearly toxic levels for both compounds the immunotoxic potential was assessed by performing a T cell-dependent antibody response and a host resistance assay in rats. Selected ERA-63 dose levels (0.167–0.2, 1.67–2 and 16.7–20mg/kg) were expected to have comparable estrogenic activity to respective EE dose levels (0.05, 0.5 and 5mg/kg). General toxicity parameters reflecting estrogenic activity (i.e. decreased body- and organ weights of thymus and testis, and increased bilirubin and GGT levels) confirmed the comparable estrogenic activity for both compounds at the dose levels tested. Together with the comparable estrogen-related immune suppression (i.e. decreases in specific antibody responses and an increased susceptibility for Listeria monocytogenes infects) for both compounds, this indicates that available clinical data for EE facilitates the human risk assessment of ERA-63. [Copyright &y& Elsevier]

Summary: Hypoxia-inducible factor–1α (HIF-1α) is critical not only in the regulation of oxygen homeostasis but also in the regulation of innate and adaptive immune systems. We previously reported that T-cell receptor–mediated activation of T cells in mice leads to the expression of an alternative isoform of HIF-1α that inhibits activated T cells in a delayed negative feed-back manner. In this paper, we describe a novel mRNA isoform of human HIF-1α that is upregulated in peripheral T lymphocytes after T-cell receptor stimulation. This activation- inducible isoform is expressed using the alternative first exon I.3, and it encodes a protein that is 24 amino acids longer than the ubiquitous HIF-1α isoform. This mRNA isoform I.3 of HIF-1α is expressed in a tissue-specific manner with the highest expression found in peripheral blood leukocytes and the thymus. [Copyright &y& Elsevier]

Abstract: CD40L is a type II membrane protein comprised of 261 amino acids. CD40L plays a crucial role in the immune system where it is primarily expressed on activated T cells and triggers immunoglobulin class switching. The genetic disease X-linked hypergammaglobulinemia (HIGM1, XHIGM or XHIM) is caused by mutations in the CD40L gene. Individuals with HIGM1 are susceptible to recurrent infections to pathogens and a relationship has been shown to exist with malaria [Sabeti, P., Usen, S., Farhadian, S., Jallow, M., Doherty, T., Newport, M., Pinder, M., Ward, R., Kwiatkowski, D., 2002a. CD40L association with protection from severe malaria. Genes Immun. 3, 286–291]. In this paper, we phylogenetically examine the promoter region of CD40L in primates and other mammals via phylogenetic shadowing. This analysis revealed several regions of the CD40L promoter that were highly constrained and thereby inferred to be functional. These constrained regions confirmed many known regulatory sites. In addition, a novel, highly constrained upstream region was also identified which had an NF-AT recognition motif. These analyses also showed that the different mammal groups do not share an exactly similar set of promoter binding sites and taxon-specific promoters have evolved. [Copyright &y& Elsevier]

Abstract: Although techniques that permit analysis of the clonal composition of T cell populations have been used extensively to provide a better understanding of the mechanisms that influence efficacy of T cell responses in humans and mice, such methods are lacking for other animal species. In this paper we report the establishment and validation of a panel of Vβ subfamily-specific semi-nested PCR assays, and a CDR3β heteroduplex technique for analysing the clonal diversity of bovine αβ T cell responses. Development of these methods was based on available sequence data for 48 functional Vβ genes classified within 17 subfamilies. These techniques were used to determine the clonal composition of parasite-reactive CD8+ T cells obtained from two animals immunised with the protozoan parasite Theileria parva. Analyses of uncloned T cell lines as well as large panels of cloned T cells derived from each of these lines confirmed the specificity and sensitivity of the assays. Specific PCR products were obtained from 96% of the T cell clones examined, indicating that the currently identified Vβ genes represent most of the functional Vβ subfamilies in cattle. Heteroduplex analyses, coupled with sequencing of PCR products, identified over 20 clonal expansions within each of the T cell lines, distributed over a large number of Vβ subfamilies, although a limited number of clonotypes numerically dominated the response in both animals. The development and validation of these methods provides for the first time a generic set of molecular tools that can be used to perform detailed analysis of the TCR diversity and clonal composition of bovine T cell responses. [Copyright &y& Elsevier]

Abstract: In this paper, an immune-inspired model, named innate and adaptive artificial immune system (IA-AIS) is proposed and applied to the problem of identification of unsolicited bulk e-mail messages (SPAM). It integrates entities analogous to macrophages, B and T lymphocytes, modeling both the innate and the adaptive immune systems. An implementation of the algorithm was capable of identifying more than 99% of legitimate or SPAM messages in particular parameter configurations. It was compared to an optimized version of the naïve Bayes classifier, which has been attained extremely high correct classification rates. It has been concluded that IA-AIS has a greater ability to identify SPAM messages, although the identification of legitimate messages is not as high as that of the implemented naïve Bayes classifier. [Copyright &y& Elsevier]

Abstract: Increasing susceptibility of the elderly to many infectious diseases is highly associated with the loss or delay in the generation of antigen-specific CD4+ T cells. For Mycobacterium tuberculosis infection, where antigen-specific CD4+ T cell derived IFN-γ is essential, such a loss can lead to a significant failure to control infection. The present paper develops a mathematical model of infection with M. tuberculosis in old mice. The model includes an early resistance to infection which is mediated by CD8+ T cells. A subsequent reversal of this phenotype results from the slow generation of CD4+ T cell mediated immunity in old age. The model simulations corroborate experimental data and hence, the model was used to test whether immunity to infection could be improved in old mice, if CD4+ T cell responses were enhanced. Our simulations indicate that boosting antigen presentation and T cell proliferation can decrease the M. tuberculosis burden in the lung. [Copyright &y& Elsevier]

Abstract: In this paper, an improved design of a capacitive micromachined ultrasonic transducer (CMUT) is presented. The design improvement aims to address the reliability issues of a CMUT and to extend the device operation beyond the contact (collapse) voltage. The major design novelty is the isolation posts in the vacuum cavities of the CMUT cells instead of full-coverage insulation layers in conventional CMUTs. This eliminates the contact voltage drifting due to charging caused by the insulation layer, and enables repeatable CMUT operation in the post-contact regime. Ultrasonic tests of the CMUTs with isolation posts (PostCMUTs) in air (electrical input impedance and capacitance vs. bias voltage) and immersion (transmission and reception) indicate acoustic performance similar to that obtained from conventional CMUTs while no undesired side effects of this new design is observed. [Copyright &y& Elsevier]

Since influenza A viruses of the H5N1 subtype continue to circulate in wild and domestic birds and cause an ever increasing number of human cases, it is feared that H5N1 viruses may cause the next influenza pandemic. Therefore, there is considerable interest in the development of vaccines that confer protection against infections with these viruses or ideally, protection against influenza viruses of different subtypes. For the development of broad-protective vaccines the induction of virus-specific cytotoxic T lymphocytes (CTL) may be an important target, since it has been demonstrated that CTL contribute to protective immunity and are largely directed to epitopes shared by influenza viruses of various subtypes. In the present paper, the possibility to develop (cross-reactive) CTL-inducing vaccines is discussed. [Copyright &y& Elsevier]

Abstract: This paper describes the histopathological features and cellular distribution of T lymphocytes (CD3), B cells (CD79), follicular dendritic cells (FDC) and macrophages (alpha-1-antitrypsin, lysozyme) in lymphoid aggregates (Kisselev nodules) found in the lung, kidney and liver of wild boar (Sus scrofa L.). The distribution of immunoreactive cells, tested for antibodies, was similar to that found in the cortex of lymph nodes: lymphoid follicles with germinal centers mainly consisting of CD79+ B cells with sparse interfollicular tissue (CD3+ T lymphocytes). This finding and the association of these structures with helminthic infections suggests that local humoral immunity is central to the organism’s response to parasitic challenge. The presence of follicular dendritic cells confirms the high degree of organization of these lymphoid-like structures. The role of other pathogenic factors and the induction of chronic inflammatory reaction in these ectopic lymphoid sites is also discussed. [Copyright &y& Elsevier]

Abstract: It is well-known that the mathematical models provide very important information for the research of human immunodeficiency virus-type 1 and hepatitis C virus (HCV). However, the infection rate of almost all mathematical models is linear. The linearity shows the simple interaction between the T cells and the viral particles. In this paper, we consider the classical mathematical model with non-linear infection rate. The global dynamics of this model is rigorously established. We prove that, if the basic reproduction number , the HIV infection is cleared from the T-cells population; if , the HIV infection persists. Further, the existence of a non-trivial periodic solution is also studied by means of numerical simulation. [Copyright &y& Elsevier]

Dietary fish oil has immunomodulatory effects that are partly mediated by its effects on cytokine secretion. In this paper, we examine whether dietary fish oil has different effects on cytokine secretion by T cells and macrophages. Female BalbC mice were fed diets supplemented with 18% fish oil + 2% corn oil or 20% corn oil. Concanavalin A (ConA)- and LPS-induced TNF-alpha and IL-10 secretion by splenocytes was examined using ELISA. Dietary fish oil decreased ConA induced-, but increased LPS-induced, TNF-alpha and IL-10 secretion by total murine splenocytes. Dietary fish oil increased the number of splenocytes secreting TNF-alpha and IL-10, following stimulation with LPS, by 123 and 38%, respectively, but did not affect cytokine secretion by each cell, as determined using enzyme-linked immunospot. Spleens from mice fed the fish oil diet had over 2-fold higher proportion of macrophages with high expression of CD11b than spleens from mice fed the corn oil diet. In addition, fish oil increased the proportion of total and CD11b(+) splenocytes that expressed the LPS receptor complex molecules, CD14 and toll-like receptor (TLR)4/myeloid differentiation factor-2 (MD-2), by 85 and 28%, respectively. The increased proportion of macrophages expressing the LPS receptor complex molecules, CD14 and TLR4/MD-2, in spleens from mice fed the fish oil diet may explain the increased number of cells that secreted the cytokines after LPS stimulation. [ABSTRACT FROM AUTHOR]

To gain transplantation tolerance between donor organs and hosts is the ultimate goal of all sorts of organ transplantations. Induction of regulatory T cells has been demonstrated to lead to transplantation tolerance. This paper will review subsets of regulatory T cells, the role and mechanisms of CD4+CD25+ regulatory T cells (Tregs) in graft rejection and tolerance, pathway used by Tregs to recognized alloantigens, pathways of Tregs homing into the graft and effects of immunosuppression on Tregs. It was well known that Tregs play a pivotal role in transplantation tolerance. The mechanisms by which Tregs exert their regulatory effect in the induction and maintenance of transplantation tolerance, anthropogenicly, consist of physical cell-to-cell contact with potential target cells, autocrine and paracrine properties. ICAM-1, TGF-beta, CTLA-4, GITR and OX40 (CD134), etc. are involved in the regulatory function of Tregs through cell-to-cell contact mechanism. 1L-10 and TGF-13are two important soluble mediators involved in the autocrine mechanism by which Tregs exert their regulatory function. Paracrine properties refer to reeducate potentially destructive alloresponsive T cells to gain regulatory function. All that discussed above could illustrate, at least partially, how naturally occurring Tregs exert their regulatory function in vivo as they constitute only 5–10% of peripheral CD4+ T cells. [ABSTRACT FROM AUTHOR]

Abstract: In the past years, research on immune regulation has exploded thanks to the re-emergence of T suppressor cells (Ts), now coined as regulatory T cells (Tregs). It has been established that different populations of Tregs exist in the immune system, and the generation, mechanism of suppression and the cellular and molecular targets of Tregs are being unraveled. This will lead to new opportunities for immune intervention to treat autoimmune disease and to achieve clinical transplantation tolerance. The scientific progress in the field of translational medicine was presented at the 7th International Conference on New Trends in Immunosuppression and Immunotherapy in Berlin in February 2006. In this special issue of International Immunopharmacology, several papers submitted to this congress will highlight some of the advances in this burgeoning field of translational medicine. [Copyright &y& Elsevier]

Abstract: α-Galactosyl-ceramide (1) has been identified as a powerful modulator of immunological processes through its capacity to bind CD1d molecules and specifically activate invariant natural killer (NK)-like T cells (iNKT cells). This paper describes the synthesis of 1, the analogous α-galactosyl-ceramide 3, and its short chain analogue ‘OCH’ (2), by use of the 4,6-di-O-tert-butylsilylene (DTBS) protecting group to produce a powerful α-galactosylating agent. In vivo experiments confirmed these compounds to be potent and selective activators of iNKT cells in a CD1d-dependent manner, each inducing a unique profile of cytokine release. This synthesis strategy will permit the generation of novel derivatives for use in the study of the mechanism of iNKT cell activation. [Copyright &y& Elsevier]

Abstract: The vasoactive intestinal peptide (VIP)-VPAC1 and VPAC2 G protein-coupled receptor (GPCR) systems are autocrine and paracrine regulators of diverse T cell functions. It has been recognized that VIP evokes two types of T cell responses. The first are rapid in onset and brief in duration, such as altered traffic in blood, lymphoid corridors, and tissues. The second are slow in onset and sustained in duration, such as enhanced helper T cell (Th) differentiation in the thymus and increased survival in lymphoid tissues with biases favoring the Th2-type effector and memory subsets. Investigations of some other sets of GPCRs for peptide and lipid mediators have demonstrated expression both in nuclear membranes and plasma membranes with respective linkages to responses that are slow in onset and sustained, and those that are rapid in onset and brief in duration. The hypothesis presented in this paper suggests that plasma membrane VPAC receptors transduce short-term effects of exogenous VIP on T cell effector functions, whereas nuclear VPAC receptors mediate endogenous VIP alterations in differentiation, proliferation, and survival. The types of substantial additional proof needed to support this hypothesis are described, as are its advantages for more selective VIP-directed therapies. [Copyright &y& Elsevier]

Abstract: Collagen induced arthritis (CIA) is the most studied animal model for rheumatoid arthritis and is associated with the MHC class II molecule Aq. T-cell recognition of a peptide from type II collagen, CII256–270, bound to Aq is a requirement for development of CIA. Lysine 264 is the major T-cell recognition site of CII256–270 and CIA is in particular associated with recognition of lysine 264 after posttranslational hydroxylation and subsequent attachment of a β-d-galactopyranosyl moiety. In this paper we have studied the structural requirements of collagenous glycopeptides required for T-cell stimulation, as an extension of earlier studies of the recognition of the galactose moiety. Synthesis and evaluation of alanine substituted glycopeptides revealed that there are T-cells that only recognise the galactosylated hydroxylysine 264, and no other amino acid side chains in the peptide. Other T-cells also require glutamic acid 266 as a T-cell contact point. Introduction of a methylene ether isostere instead of the amide bond between residues 260 and 261 allowed weaker recognition by some, but not all, of the T-cells. Altogether, these results allowed us to propose a model for glycopeptide recognition by the T-cells, where recognition from one or the other side of the galactose moiety could explain the different binding patterns of the T-cells. [Copyright &y& Elsevier]

Abstract: Human T-cell lymphotropic virus I (HTLV-I) infection is linked to the development of adult T-cell leukemia/lymphoma (ATL), among many illness. The healthy CD4+ T cells infect HTLV-I through cell-to-cell contact with infected T-cells. The infected T cells can remain latent and harbor virus for several years before virus production occurs. Actively infected T cells can infect other T cells and can convert to ATL cells, whose growth is assumed to follow a classical logistic growth function. In this paper, we consider the classical mathematical model with saturation response of the infection rate. By stability analysis we obtained the condition for the infected T cells die out and the condition for HTLV-I infection becomes chronic. At the same time, we also obtained the condition for a unique endemic equilibrium is globally stable in the interior of the feasible region. [Copyright &y& Elsevier]

Abstract: Invading pathogens are controlled by the innate and adaptive arms of the immune system. Adaptive immunity, mediated by B and T lymphocytes, recognises pathogens via high affinity receptors. However, the establishment of a primary adaptive immune response is not rapid enough to eradicate invading microorganisms as it involves cell proliferation, gene activation and protein synthesis. More rapid defence mechanisms are provided by innate immunity, which recognises invading pathogens by germ-line-encoded pattern recognition receptors. Recent evidence shows that this recognition can mainly be attributed to the family of TOLL-like receptors (TLR). Binding of pathogen-associated molecular patterns to TLR induces the production of reactive oxygen and nitrogen intermediates, pro-inflammatory cytokines, and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. In this paper, we will discuss the current knowledge with regards to the TLR, and in particular the bovine family of TLR. In addition, we will show the expression of TLR mRNA in bovine antigen-presenting cell subsets, summarise the discovery and the critical roles of TLR2 in host defence against Mycobacteria, and provide evidence for a mycobacteria species-specific response of bovine macrophages. [Copyright &y& Elsevier]

Abstract: Withanolide, coagulin-H (1), was evaluated for its effect on various cellular functions related to immune response including lymphocyte proliferation, and expression of interleukin-2 (IL-2) cytokine, and results were compared with prednisolone (2), a commonly used immune modulating drug. Coagulin-H (1) was found to have a powerful inhibitory effect on lymphocyte proliferation and Th-1 cytokine production. Inhibition of the phytohaemagglutinin (PHA)-activated T-cell proliferation by coagulin-H (1) was observed in a concentration dependant manner. A complete suppression of PHA-activated T-cell was observed at ≥2.5μg/mL concentrations of compound (1) and this suppression activity was similar to that of prednisolone (2). Coagulin-H (1) also significantly inhibited IL-2 production by 80%. The interactions of coagulin-H (1) (a natural inhibitor) and prednisolone (2) (a drug) to IL-2 were also investigated in order to understand the differences in their effects on T-cell responses. This paper also describes the results of molecular docking study on IL-2 inhibition. Docking studies predicted that coagulin-H (1) binds to receptor binding site of IL-2 more effectively than prednisolone (2). Based on the computational and the experimental results, coagulin-H (1) was identified as a potential immunosuppressive candidate. [Copyright &y& Elsevier]

G2A is a G protein-coupled receptor that is predominantly expressed in lymphoid tissues and macrophages. G2A can be induced by diverse stimuli to cause cell cycle arrest in the G2/M phase in pro-B and T cells. G2A is also expressed in macrophages within atherosclerotic lesions, suggesting G2A involvement in atherosclerosis. Recently, G2A was discovered to possess proton-sensing ability. In this paper, we report another function of G2A, that is, as a receptor for 9-hydroxyoctadecadienoic acid (9-HODE) and other oxidized free fatty acids. G2A, expressed in CHO-K1 or HEK293 cells, showed 9-HODE-induced intracellular calcium mobilization, inositol phosphate accumulation, inhibition of cAMP accumulation, [35S]guanosine 5′-3-O-(thio)triphosphate binding, and MAP kinase activation. Furthermore, G2A was activated by various oxidized derivatives of linoleic and arachidonic acids, but it was weakly activated by cholesteryl-9-HODE. Oxidized phosphatidylcholine (1-palmitoyl-2-linoleoyl) when hydrolyzed with phospholipase A2 also evoked intracellular calcium mobilization in G2A-expressing cells. These results indicate that G2A is activated by oxidized free fatty acids produced by oxidation and subsequent hydrolysis of phosphatidylcholine or cholesteryl linoleate. Thus, G2A might have a biological role in diverse pathological conditions including atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: The T-cell antigen-activated signaling pathway is a highly regulated intracellular biochemical system that is crucial for initiating an appropriate adaptive immune response. To improve the understanding of the complex regulatory mechanisms controlling the early events in T-cell signaling, a detailed mathematical model was developed that utilizes ordinary differential equations to describe chemical reactions of the signaling pathway. The model parameter values were constrained by experimental data on the activation of a specific signaling intermediate and indicated an initial rapid cascade of phosphorylation events followed by a comparatively slow signal downregulation. Nonlinear analysis of the model suggested that thresholding and bistability occur as a result of the embedded positive and negative feedback loops within the model. These nonlinear system properties may enhance the T-cell receptor specificity and provide sub-threshold noise filtering with switch-like behavior to ensure proper cell response. Additional analysis using a reduced second-order model led to further understanding of the observed system behavior. Moreover, the interactions between the positive and negative feedback loops enabled the model to exhibit, among a variety of other feasible dynamics, a sustained oscillation that corresponds to a stable limit cycle in the two-dimensional phase plane. Quantitative analysis in this paper has helped identify potential regulatory mechanisms in the early T-cell signaling events. This integrated approach provides a framework to quantify and discover the ensemble of interconnected T-cell antigen-activated signaling pathways from limited experimental data. [Copyright &y& Elsevier]

Abstract: There is a fundamental difference in complexity between signaling initiated by ligands on the surface of one cell binding to receptors on the surface of another cell and ligands in solution binding to these receptors. The fact that two cells must approach each other and form a number of intercellular bonds of different types, all within the restricted geometry of the intercellular contact region, introduces the possibility of complex spatio-temporal dynamics of surface receptors that is not present otherwise. Mathematical modelling of these dynamics is in its early stages. However, useful tools have emerged. The purpose of this paper is to describe some of these mathematical tools, indicating their strengths and shortcomings, and suggest some directions for future theoretical studies. [Copyright &y& Elsevier]

Abstract: Contamination of water with arsenic is a problem affecting several regions of the world. Peripheral blood mononuclear cells (PBMC) from chronically exposed individuals show a lower replicating activity than non-exposed individuals when stimulated with phytohemagglutinin (PHA). We have previously reported that PBMC from healthy donors treated in vitro with 1 μM sodium arsenite (NaAsO2) and stimulated with PHA showed a reduction in proliferation by a delay in cell cycle entry and a decrease in the rounds of cell division. In this paper we tested the effect of 1–5 μM NaAsO2 on the proliferation, viability, blast transformation, expression of the CD4 and CD8 molecules, and during the activation and proliferation of both CD4+ and CD8+ T lymphocytes. We found a reduction in cell proliferation and an increase in non-dividing cells with higher concentrations of NaAsO2 (2–5 μM) when proliferation was studied by 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution. The use of 7-aminoactinomycin D (7-AAD) in CFSE-labeled cells allowed us to detect an increase in percentage of non-dividing cells, and an increase in apoptotic/dead cells mainly in non-proliferating cells. Analysis of the expression of CD4 and CD8 molecules on these cells showed that concentrations ≥2 μM NaAsO2 reduced the expression of the CD8 molecule and induced apoptosis/death in CD4+ cells. Analysis of blast transformation by flow cytometry showed an accumulation of CD8+ resting cells in the presence of NaAsO2. Analysis of CD25 and CD69 expression in kinetics experiments in both subtypes showed a delay in the expression of CD25 and a delay in the downregulation of the CD69 molecule, in both CD4+ and CD8+ cells. However, in the case of CD8+ cells, we detected an accumulation of a CD25−CD69− population in the presence of increasing concentrations of NaAsO2. Altogether, our results show that NaAsO2 alters the expression kinetics of the early activation molecules CD25 and CD69 similarly in both subtypes. In addition, activated and non-activated CD4+ cells die by apoptotic mechanisms and although a percentage of CD8+ cells also die by apoptosis, a subpopulation of these cells is unable to activate and thus accumulates as resting cells. [Copyright &y& Elsevier]

Two recently published papers highlight the importance of insulin as a major autoantigenic target of the T cell autoimmune attack in the non-obese diabetic mouse model of diabetes and in type 1 diabetes in humans. Knowledge of the major targets of the autoimmune attack will enable us specifically to focus on these to develop treatments that could alter the ability of pathogenic T cells to cause diabetes. Targeting these T cells could be a strategy for the prevention and cure of the diabetes in the future. [Copyright &y& Elsevier]

To effectively direct targeted repression, the class I histone deacetylases (HDACs) associate with many important regulatory proteins. In this paper we describe the molecular characterization of a member of the Jumonji domain 2 (JMJD2) family of proteins, and demonstrate its binding to both class I HDACs and the retinoblastoma protein (pRb). JMJD2 proteins are characterized by the presence of two leukemia-associated protein/plant homeodomain (LAP/PHD) zinc fingers, one JmjN, one JmjC (containing an internal retinoblastoma-binding protein 2 (RBBP2)-like sequence), and two Tudor domains. The first member of this group, JMJD2A, is widely expressed in human tissues and cell lines, and high endogenous expression of JMJD2A mRNA was found in several cell types, including human T-cell lymphotropic virus 1 (HTLV-1)-infected cell lines. JMJD2A and JMJD2B exhibit cell type-specific responses to the HDAC inhibitor trichostatin A. We show that the JMJD2A protein associates in vivo with pRb and class I HDACs, and mediates repression of E2F-regulated promoters. In HTLV-1 virus-infected cells, we find that JMJD2A binds to the viral Tax protein. Antibodies to JMJD2A recognize the native protein but also a half-sized protein fragment, the latter up-regulated in THP-1 cells during the G2/M phase of the cell cycle. The ability of JMJD2A to associate with pRb and HDACs and potentiate pRb-mediated repression of E2F-regulated promoters implies an important role for this protein in cell proliferation and oncogenesis. [ABSTRACT FROM AUTHOR]

Abstract: The CFSE dye dilution assay is widely used to determine the number of divisions a given CFSE labelled cell has undergone in vitro and in vivo. In this paper, we consider how the data obtained with the use of CFSE (CFSE data) can be used to estimate the parameters determining cell division and death. For a homogeneous cell population (i.e., a population with the parameters for cell division and death being independent of time and the number of divisions cells have undergone), we consider a specific biologically based “Smith–Martin” model of cell turnover and analyze three different techniques for estimation of its parameters: direct fitting, indirect fitting and rescaling method. We find that using only CFSE data, the duration of the division phase (i.e., approximately the S+G2 +M phase of the cell cycle) can be estimated with the use of either technique. In some cases, the average division or cell cycle time can be estimated using the direct fitting of the model solution to the data or by using the Gett–Hodgkin method [Gett A. and Hodgkin, P. 2000. A cellular calculus for signal integration by T cells. Nat. Immunol. 1:239-244]. Estimation of the death rates during commitment to division (i.e., approximately the G1 phase of the cell cycle) and during the division phase may not be feasible with the use of only CFSE data. We propose that measuring an additional parameter, the fraction of cells in division, may allow estimation of all model parameters including the death rates during different stages of the cell cycle. [Copyright &y& Elsevier]

Abstract: LFA-1 (leukocyte function-associated antigen-1), is a member of the β2-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold. [Copyright &y& Elsevier]

Abstract: In the present paper, the effect of the aqueous extract from aerial parts of Artemisia vestita (AV-ext), a traditional Tibetan medicine, on ear contact sensitivity was examined. AV-ext significantly reduced the ear swelling when administered during the induction phase of picryl-chloride (PCl)-induced ear contact sensitivity in mice. The extract also showed a dose-dependent inhibition on lymphocyte proliferation and IL-2 production in Con A-activated spleen cells. The proliferation inhibition was confirmed in the mixed lymphocytes reaction. Furthermore, the adhesion of the isolated spleen cells from PCl-sensitized mice to type IV collagen was significantly decreased in a dose-dependent manner by AV-ext. Such decrease was also seen in AV-ext-treated Jurkat T cells and the T cells purified from above spleen cells. The purified spleen T cells from PCl-sensitized mice produced more matrix metalloproteinase-9 (MMP-9) than naive T cells, and AV-ext remarkably reduced MMP-9 production both in vivo and in vitro. These results suggest that AV-ext may alleviate contact sensitivity through blocking the activation of T lymphocytes and decreasing their localization to the inflammatory sites via down-regulating the potential of cell adhesion and metalloproteinase production. [Copyright &y& Elsevier]

Abstract: Induction of CTL responses against protein antigens is an important aim in vaccine development. In this paper we present fusion-active virosomes as a vaccine delivery system capable of efficient induction of CTL responses in vivo. Virosomes are reconstituted viral membranes, which do not contain the genetic material of the virus they are derived from. Foreign macromolecules, including protein antigens, can be encapsulated in virosomes during the reconstitution process. Functionally reconstituted virosomes retain the cell binding and fusion characteristics of the native virus. Thus, upon uptake by cells through receptor-mediated endocytosis, virosomes will deliver their content to the cell cytosol. In a previous study, we demonstrated that protein antigens delivered in this manner to dendritic cells are efficiently processed for both MHC class I and class II presentation. Here, we studied in vivo induction of cellular immune responses against virosome-encapsulated ovalbumin (OVA) in mice. As little as 0.75μg OVA delivered by fusion-active virosomes was sufficient to induce a powerful class I MHC-restricted CTL response. All immunization routes that were used (i.m., i.p. and s.c.) resulted in efficient induction of CTL activity. The CTLs induced were cytotoxic in a standard 51Cr-release assay and produced IFNγ in response to OVA peptide. Thus, virosomes represent an ideal antigen delivery system for induction of cellular immunity against encapsulated protein antigens. [Copyright &y& Elsevier]

Ghrelin, a novel gut–brain peptide predominantly produced by the stomach, displays strong growth hormone (GH)-releasing activity mediated by the hypothalamus–pituitary GH secretagogue receptor (GHS-R). Recently, the ghrelin receptor has also been detected in peripheral systems including immune tissues, suggesting that ghrelin may play an important role in the regulation of immune function. In this paper, we assessed the presence and function of the ghrelin receptor in murine splenic T cells. The enriched T cells express the mRNA of ghrelin and ghrelin receptor mRNA, and there is a significantly positive correlation between them. Moreover, we showed that ghrelin dose-dependently inhibits proliferation of splenic T cells when they are costimulated by anti-CD3. In addition, ghrelin suppressed Th1 (IL-2 and IFN-γ) and Th2 (IL-4 and IL-10) cytokines mRNA expression. These results demonstrate the presence of the ghrelin receptor in murine spleen T lymphocytes and a functional role of ghrelin as a modulator of lymphocyte function. This function of ghrelin may have some relevance to the pathophysiology of immunologic alterations related to metabolism. [Copyright &y& Elsevier]

Gamma/delta T lymphocytes cells recognize the antigen in a non-classical way and are considered the third branch of the immune system devoted to defend the integrity of the body. Ageing is characterized by an impairment of the main way of protection (the adaptive branch) but, successfully aged people show compensatory mechanisms of defense such as proneness to inflammation. Moreover, very old subjects show an increased number of NK cells. We have previously demonstrated that γδT lymphocytes are reduced in elderly. In the present paper we have studied some characteristics of these cells to evaluate the possibility that these cells might balance the decreased action of the adaptive branch in successfully aged people. Cytofluorimetric analysis of cells collected from young, old and centenarian subjects has been used to evaluate the ability of these cells to expand in vitro. Here we demonstrate that γδT cells are impaired in the ability to proliferate to different stimuli such as isopentenyl pyrophoshate, that select γδT lymphocytes bearing δ2 chain, other than to phytohemagglutinin and anti-CD3 that are polyclonal activators. Moreover, we demonstrate that γδT cells in aged and centenarians show an enhanced sensitivity to undergo apoptosis induced both by α-Fas and TNF-α. All together these data suggest that γδT lymphocytes are impaired in elderly and suggest that the reduced ability to proliferate and the reduced number of circulating γδT lymphocytes is due to the proneness to apoptosis. Finally on the basis of these data, we conclude that γδT lymphocytes, do not participate in the remodeling of the immune system due to the reduction of classical T cell response and replacement by NK cells in elderly. [Copyright &y& Elsevier]

The status of ‘partial’ tolerance to organ allografts versus the status of complete tolerance is the main topic of this paper. Progress made in immunosuppression, particularly by use of various lymphocyte depleting agents for ‘induction therapy’, seems to favor the subsequent development of T cells with suppressor/regulatory properties. The effective deletion of alloreactive T helper and cytotoxic cells in conjunction with the expansion of antigen-specific suppressor (CD8 + CD28 - F0XP3+) and regulatory (CD4 + CD25+ F0XP3+) T cells creates a milieu in which the graft is well tolerated under an ‘umbrella’ of low dosage immunosuppression. The most elective induction treatment is Campath-1H, although ATGAM at high dosage is also widely used. Total lymphoid irradiation (TL1) is another very effective pretreatment strategy in spite of the risks which are associated with it. The induction of ‘partial’ tolerance is a step in the right direction for exploring strategies that may lead to the induction of complete tolerance. It is safe for the patients and can prolong significantly the function of the graft, preventing the onset of chronic rejection. [ABSTRACT FROM AUTHOR]

Interaction of B7 with CD28 and CTLA4 plays an important function in T-cell activation and homeostasis. Disruption of CD28, CTLA4, or both has shown impact on T-cell biology. This paper examined the consequences of overexpressing a tailless mutant form of CTLA4 on T-cell activation and in vivo expansion.Retroviral gene transfer was used to infect bone marrow progenitor cells with either a control vector or a cytoplasmic domain-deleted mutant of CTLA-4 (ΔCTLA4). The cells were subsequently adoptively transferred to RAG-/- mice and allowed to repopulate. The T cells derived from the reconstituted RAG-/- mice were analyzed functionally in vitro and in vivo.The T cells were defective in their ability for IL-2 secretion, survival, and proliferation in response to Ag/APC stimulation in vitro. Addition of exogenous IL-2 or normal T cells was able to rescue the survival defect and allow cell-cycle progression. In adoptive transfer studies, the naïve T cells expressing ΔCTLA4 exhibited compromised capability to expand in RAG-/- mice. Memory ΔCTLA4T cells, however, were capable of proliferating in lymphopenic hosts to a similar extent as control memory T cells, but showed reduced survival.Surface ΔCTLA4 has similar tolerogenic/regulatory activity as CTLA4-Ig. In contrast to CTLA4-Ig, the effect of ΔCTLA-4 is autonomous. The inhibition of in vivo expansion by ΔCTLA4 indicates developmental and/or activation stage dependency of costimulation in T cells. [Copyright &y& Elsevier]

Abstract: We develop and analyze a model for the interactions of T-cells, antigen presenting cells (APCs), and HIV-1. Our model consists of five components: APCs, resting helper T-cells, activated uninfected helper T-cells, activated and infected helper T-cells, and the free virus. We emphasize the impact of APCs during HIV infection and the cell-to-cell contact manner in the transference of HIV-1 in vivo. The existence and stability of the uninfected steady state and those of the infected steady states are discussed. The uniform persistence of the system is also obtained. As a novel approach, multiple exposures of HIV-1 are illustrated and discussed in the paper. Through numerical stimulations, we check the sensitivity of APCs and helper T-cells in impacting the infection outcome and obtain some relevant results. We also give the lowest infectioe dose for certain individuals. [Copyright &y& Elsevier]

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Most evidence supports the autoimmune pathogenesis of the disease. According to this hypothesis, the activation of autoreactive T-cells is a central event in the development of autoimmune response in MS. We examined molecular events involved in the initiation of autoimmune response in MS. Recent studies in our laboratory have reported an unexpectedly high degree of T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon that might play a role in the initiation of autoimmune response in MS. This paper provides insights into the physiologic and pathologic role of autoreactive T-cells, and characterizes structurally and functionally the specific targets for new therapies of MS. [Copyright &y& Elsevier]

Protection of influenza virus infection is mainly mediated by neutralizing immunoglobulins that bind to the virus strain-specific haemagglutinin. The IgG antibody is known to contribute mostly to virus neutralization. Age-related decline in immune responsiveness is characterized by a decrease in antibody production and a reduced ability of T lymphocytes. Our primary objective is to enhance IgG antibody production in aged mice. In this paper, we demonstrate that Mao–Bushi–Saishin-To (MBST, Ma-Huang-Fu-Zi-Xin-Tang) activates IgG antibody production and the T cell helper activity concerning IgG antibody production in aged mice. These results indicate that the use of MBST has important benefits to protect against influenza virus infection in elderly people. [Copyright &y& Elsevier]

Effector T lymphocyte responses are considered critical for controlling human immunodeficiency virus type-1 (HIV-1) infection. The enzyme-linked immunospot (ELISpot) assay has emerged as a primary means of assessing HIV-specific T cell responses, and the development of objective methods that distinguish positive and negative ELISpot responses while properly controlling the rate of false positives is critical. In this paper, we consider several statistical methods that are helpful in defining such a positive criterion. Simulation results under a variety of scenarios suggest that a permutation-based criterion using a resampling adjustment for multiple comparisons yields the desired false positive rate while remaining competitive with other potential criteria in terms of sensitivity. These results also provide guidance on the effect of the number of experimental and negative control replicate wells on assay sensitivity. Application of different potential positive criteria using ELISpot assay results from IFN-γ-secreting T cells of HIV-1 seropositive and seronegative donors confirmed several of the results obtained under simulation. Our findings support the application of statistically-based positive criteria such as the permutation-based resampling approach in assessing HIV vaccine-induced T cell responses. Moreover, the proposed methods have potential utility in related HIV immunopathogenesis studies and in non-HIV clinical vaccine trials. [Copyright &y& Elsevier]

Different single-cell analyses for the detection of antigen-specific T cells based on antigen-triggered induction of cytokine production (elispot, intracellular cytokine staining, cytokine secretion assay, etc.) have been analyzed. In this paper we present the data of a thorough validation of the IFNγ Secretion Assay (ISA, Miltenyi Biotec, Bergisch Gladbach, Germany). In this assay the secreted IFNγ is bound to the cell surface and is then stained as an artificial surface molecule and analyzed by flow-cytometry. The introduction of five quality criteria markedly improved the reproducibility of this assay and made it very reliable (intra-assay variability<5%; inter-assay variability<20%). Recovery experiments further demonstrated that almost 100% of IFNγ+ labeled cells could be detected by this technology. In order to analyze which cell subsets contribute to IFNγ-production, we compared the results obtained in different individuals after VZAg-stimulation. Three different IFNγ-secretion patterns could be discerned. In Pattern 1 there is a predominant and almost equal contribution of T cells and NK cells with a minor contribution of CD3+CD56+ and B cells. Pattern 2, which is most abundant, is characterized by a predominance of NK cells (60–70%). Pattern 3 differs from the previous one in its minor contribution of NK cells. Here T cells predominate the IFNγ secretion. These results clearly demonstrate that the IFNγ+ subset distribution after VZAg-stimulation is not uniform and differs individually. Furthermore, the ISA-technology proves to be very useful in vaccine research. This was demonstrated by testing the IFNγ+ secretion pattern after HBsAg-stimulation in PBMC from HBsAg-vaccinated individuals. [Copyright &y& Elsevier]