Dendritic cells induce a subpopulation of IL-12Rβ2-expressing treg that specifically consumes IL-12 to control Th1 responses

Cytokines secreted from dendritic cells (DCs) play an important role in the regulation of T helper (Th) cell differentiation and activation into effector cells. Therefore, controlling cytokine secretion from DCs may potentially regulate Th differentiation/activation. DCs also induce de-novo generation of regulatory T cells (Treg) that modulate the immune response. In the current study we used the mixed leukocyte reaction (MLR) to investigate the effect of allospecific Treg on IL-12, TNFβ and IL-6 secretion by DCs. Treg cells were found to markedly down-regulate IL-12 secretion from DCs following stimulation with TLR7/8 agonist. This down-regulation of IL-12 was neither due to a direct suppression of its production by the DCs nor a result of marked DC death. We found that IL-12 was rather actively consumed by Treg cells. IL-12 consumption was mediated by a subpopulation of IL-12Rβ2-expressing Treg cells and was dependent on MHC class-II expressed on dendritic cells. Furthermore, IL-12 consumption by Tregs increased their suppressive effect on T cell proliferation and Th1 activation. These results provide a new pathway of Th1 response regulation where IL-12 secreted by DCs is consumed by a sub-population of IL-12Rβ2-expressing Treg cells. Consumption of IL-12 by Tregs not only reduces the availability of IL-12 to Th effector cells but also enhances the Treg immunosuppressive effect. This DC-induced IL-12Rβ2-expressing Treg subpopulation may have a therapeutic advantage in suppressing Th1 mediated autoimmunity

Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice

Foxp3 + regulatory T cells (T reg cells) effectively suppress immunity, but it is not determined if antigen-induced T reg cells (iT reg cells) are able to persist under conditions of inflammation and to stably express the transcription factor Foxp3. We used spleen cells to stimulate the mixed leukocyte reaction (MLR) in the presence of transforming growth factor β (TGF-β) and retinoic acid. We found that the CD11c high dendritic cell fraction was the most potent at inducing high numbers of alloreactive Foxp3 + cells. The induced CD4 +CD25 +Foxp3 + cells appeared after extensive proliferation. When purified from the MLR, iT reg cells suppressed both primary and secondary MLR in vitro in an antigen-specific manner. After transfer into allogeneic mice, iT reg cells persisted for 6 mo and prevented graft versus host disease (GVHD) caused by co-transferred CD45RB hi T cells. Similar findings were made when iT reg cells were transferred after onset of GVHD. The CNS2 intronic sequence of the Foxp3 gene in the persisting iT reg cells was as demethylated as the corresponding sequence of naturally occurring T reg cells. These results indicate that induced Foxp3 + T reg cells, after proliferating and differentiating into antigen-specific suppressive T cells, can persist for long periods while suppressing a powerful inflammatory disease

Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice

Regulatory T cells generated by allostimulation with dendritic cells, transforming growth factor β, and retinoic acid stably express Foxp3 and can suppress even ongoing GVHD in mice

A Scalable Heterogeneous Solution for Massive Data Collection and Database Loading

Abstract. Massive collection of data at high rates is critical for many industries. Typically, a massive stream of records is gathered from the business information network at a very high rate. Because of the complexity of the collection process, the classical database solution falls short. The high volume and rate of records involved requires a heterogeneous pipeline comprised of two major parts: a system that carries out massive collection and then uploads the information to a database, and a subsequent data analysis and management system consisting of an Extract Transform and Load component. We developed a massive collection and loading system, based on a highly scalable heterogeneous architecture solution. The solution has been applied successfully for Telco revenue assurance, and can be applied to other industrial areas. The solution was successful in scaling up a Telco client system to handle streams of records ten times larger than was previously possible.

C-C2-03: The Risk for Diabetes Mellitus Among Women with Gestational Diabetes: A Population-Based Study in Israel

Background and Aims: to determine the incidence of postpartum diabetes mellitus (DM) in the years following a diagnosis of gestational diabetes (GDM) and to determine whether severity of GDM is associated with developing diabetes

Strains of bacterial species induce a greatly varied acute adaptive immune response: The contribution of the accessory genome

<div><p>A fundamental question in human susceptibility to bacterial infections is to what extent variability is a function of differences in the pathogen species or in individual humans. To focus on the pathogen species, we compared in the same individual the human adaptive T and B cell immune response to multiple strains of two major human pathogens, <i>Staphylococcus aureus</i> and <i>Streptococcus pyogenes</i>. We found wide variability in the acute adaptive immune response induced by various strains of a species, with a unique combination of activation within the two arms of the adaptive response. Further, this was also accompanied by a dramatic difference in the intensity of the specific protective T helper (Th) response. Importantly, the same immune response differences induced by the individual strains were maintained across multiple healthy human donors. A comparison of isogenic phage KO strains, demonstrated that of the pangenome, prophages were the major contributor to inter-strain immune heterogeneity, as the T cell response to the remaining “core genome” was noticeably blunted. Therefore, these findings extend and modify the notion of an adaptive response to a pathogenic bacterium, by implying that the adaptive immune response signature of a bacterial species should be defined either per strain or alternatively to the species’ ‘core genome’, common to all of its strains. Further, our results demonstrate that the acquired immune response variation is as wide among different strains within a single pathogenic species as it is among different humans, and therefore may explain in part the clinical heterogeneity observed in patients infected with the same species.</p></div

Image_4_Quantifying how much host, pathogen, and other factors affect human protective adaptive immune responses.jpeg

Recognizing the “essential” factors that contribute to a clinical outcome is critical for designing appropriate therapies and prioritizing limited medical resources. Demonstrating a high correlation between a factor and an outcome does not necessarily imply an essential role of the factor to the outcome. Human protective adaptive immune responses to pathogens vary among (and perhaps within) pathogenic strains, human individual hosts, and in response to other factors. Which of these has an “essential” role? We offer three statistical approaches that predict the presence of newly contributing factor(s) and then quantify the influence of host, pathogen, and the new factors on immune responses. We illustrate these approaches using previous data from the protective adaptive immune response (cellular and humoral) by human hosts to various strains of the same pathogenic bacterial species. Taylor’s law predicts the existence of other factors potentially contributing to the human protective adaptive immune response in addition to inter-individual host and intra-bacterial species inter-strain variability. A mixed linear model measures the relative contribution of the known variables, individual human hosts and bacterial strains, and estimates the summed contributions of the newly predicted but unknown factors to the combined adaptive immune response. A principal component analysis predicts the presence of sub-variables (currently not defined) within bacterial strains and individuals that may contribute to the combined immune response. These observations have statistical, biological, clinical, and therapeutic implications.</p