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New strategies for immune modulation have shown real promise in regenerative medicine as well as the fight against autoimmune diseases, allergies, and cancer. Dendritic cells (DCs) are gatekeepers of the immune system and their ability in shaping the adaptive immune responses makes DCs ideal targets for immune modulation. Carbohydrates are abundant in different biological systems and are known to modulate DC phenotype and function. However, how simple monosaccharides instruct DC function is less well understood. In this study, we used a combinatorial array of immobilized monosaccharides to investigate how they modulate DC phenotype and function and crucially the impact of such changes on downstream adaptive immune responses. Our data show that a selection of monosaccharides significantly suppress lipopolysaccharide-induced DC activation as evidenced by a reduction in CD40 expression, IL-12 production, and indoleamine 2,3-dioxygenase activity, while inducing a significant increase in IL-10 production. These changes are indicative of the induction of an anti-inflammatory or regulatory phenotype in DCs, which was further confirmed in DC–T cell co-cultures where DCs cultured on the ‘regulatory’ monosaccharide-coated surfaces were shown to induce naïve T cell polarization toward regulatory phenotype. Our data also highlighted a selection of monosaccharides that are able to promote mixed Treg and Th17 cell differentiation, a T cell phenotype expected to be highly immune suppressive. These data show the potential immunomodulatory effects of immobilized monosaccharides in priming DCs and skewing T cell differentiation toward an immune-regulatory phenotype. The ability to fine-tune immune responses using these simple carbohydrate combinations (e.g. as coatings for existing materials) can be utilized as novel tools for immune modulation with potential applications in regenerative medicine, implantable medical devices, and wound healing where reduction of inflammatory responses and maintaining immune homeostasis are desirable., Graphical abstract Image 1

SUMMARY T cells compete with malignant cells for limited nutrients within the solid tumor microenvironment. We found that effector memory CD4 T cells respond distinctly from other T cell subsets to limiting glucose and can maintain high levels of interferon-γ (IFN-γ) production in a nutrient-poor environment. Unlike naive (TN) or central memory T (TCM) cells, effector memory T (TEM) cells fail to upregulate fatty acid synthesis, oxidative phosphorylation, and reductive glutaminolysis in limiting glucose. Interference of fatty acid synthesis in naive T cells dramatically upregulates IFN-γ, while increasing exogenous lipids in media inhibits production of IFN-γ by all subsets, suggesting that relative ratio of fatty acid metabolism to glycolysis is a direct predictor of T cell effector activity. Together, these data suggest that effector memory T cells are programmed to have limited ability to synthesize and metabolize fatty acids, which allows them to maintain T cell function in nutrient-depleted microenvironments., In Brief Ecker et al. distinguish unique metabolic and functional properties of naive and memory T cell subsets during glucose limitation. During glucose starvation, T cells begin to differentially rely on fatty acid synthesis and glutamine utilization to survive. Unexpectedly, reliance on fatty acid synthesis alters the ability to produce IFN-γ.

Allergies are a global issue. However, medical intervention for allergy treatment is limited. Recent studies have focused on allergy prevention with food components. Both the lactic acid bacteria Enterococcus faecalis IC-1 (IC-1) and the flavonoid luteolin have been shown to have an anti-allergic effect. Following the concept of diet diversity and synergistic effects, the purpose of this study was to explore the anti-allergic activity of a combination of IC-1 and luteolin. A combination of IC-1 and luteolin had anti-allergic effects with the passive cutaneous anaphylaxis reaction and strongly inhibited mast cell degranulation in a Caco-2/RBL-2H3 cells co-culture system. Oral administration with a combination of IC-1 and luteolin significantly decreased blood IgE content in ovalbumin (OVA)-induced allergic mice and alleviated symptoms of an allergy attack. These might have been done through correcting Th2 shifting with the allergy state since a combination of IC-1 and luteolin increased the IFN-γ content in blood. Furthermore, in vitro differentiation of the Th2 subset confirmed that a combination of IC-1 and luteolin inhibited naive T cell from differentiating into a Th2 subset through inhibition of Th2 transcription factor GATA-3 expression. The combination also promoted the gene expression level of IFN-γ in mice bone marrow-derived dendritic cells. These results suggested a synergistic anti-allergic effect using a combination of IC-1 and luteolin both in reducing IgE content and in inhibiting mast cell degranulation during the allergy state.

Conventional HIV T cell vaccine strategies have not been successful in containing acute peak viremia, nor in providing long-term control. We immunized rhesus macaques intramuscularly and rectally using a heterologous adenovirus vectored SIV vaccine regimen encoding normally weakly immunogenic tat, vif, rev and vpr antigens fused to the MHC class II associated invariant chain. Immunizations induced broad T cell responses in all vaccinees. Following up to 10 repeated low-dose intrarectal challenges, vaccinees suppressed early viral replication (P=0.01) and prevented the peak viremia in 5/6 animals. Despite consistently undetectable viremia in 2 out of 6 vaccinees, all animals showed evidence of infection induced immune responses indicating that infection had taken place. Vaccinees, with and without detectable viremia better preserved their rectal CD4+ T cell population and had reduced immune hyperactivation as measured by naive T cell depletion, Ki-67 and PD-1 expression on T cells. These results indicate that vaccination towards SIV accessory antigens vaccine can provide a level of acute control of SIV replication with a suggestion of beneficial immunological consequences in infected animals of unknown long-term significance. In conclusion, our studies demonstrate that a vaccine encoding subdominant antigens not normally associated with virus control can exert a significant impact on acute peak viremia.

CD8+ T cells clear primary infections with intracellular pathogens and provide long-term immunity against reinfection. Two different types of CD8+ T cells are responsible for these functions: short-lived effector T cells and memory T cells. The cellular relationship between these two types of CD8+ T cells has been subject to much investigation. Both cell types can derive from a single naive CD8+ T cell precursor. Their generation requires a fate choice early during a T cell response. As a result, two populations of T cells emerge. One of these consists of terminally differentiated short-lived effector T cells. The other contains cells able to develop into long-lived memory T cells. A foundation for development of these two populations may be laid during the first division of an activated naive T cell precursor, as a consequence of asymmetric segregation of fate-determining factors into the daughter cells. Nonetheless, the binary choice between the two lineages is strongly influenced by signals, which ensure that the differentiation process is matched with the needs posed by the infection. Here, we will discuss the genetic and metabolic programs governing differentiation of these two lineages as well as the processes leading to their induction and consolidation to create bistability. These processes involve extensive lateral inhibition between the programs as well as positive feedback between the genetic programs and the signaling pathways responsible for their induction. These features will be highlighted by discussing the role of the Notch signaling pathway in guiding the decision between the two lineages.

On antigen encounter, naive CD8+ and CD4+ T cells differentiate into a large number of effector cells that migrate to inflamed tissues to fight infections or tumors. Following elimination of the target, a few cells remain in the long-term, the so-called memory T cells that are capable to reexpand and respond more vigorously on a second encounter with the cognate antigen. While the naive T cell compartment is fairly homogenous, effector and memory T cells are largely diverse, comprising dozens of subsets with diverse functions, molecular characteristics, and localization in the body. In addition, CD4+ and, to some extent, also CD8+ T cells can differentiate into several effector subsets according to their pattern of cytokine expression, including the T helper 1 (Th1), Th2, and Th17 cells. It has become clear that specific subsets of T cells dominate different types of infections and pathological conditions and have different capacities to infiltrate and reject tumors. Their correct phenotypic identification is therefore of foremost importance for their live purification by magnetic or fluorescence-activated cell sorting and subsequent molecular characterization. Here, we present a comprehensive list of the main T cell subpopulations with a major focus on human cells along with their surface phenotypic properties.

Hepatitis B surface antigen (HBsAg)-specific T cells were analysed in 16 healthy individuals vaccinated against hepatitis B, using optimised protocols. HBsAg-specific IFN-gamma producing CD4(+) T cells were found at a similar low frequency (0.01%) within the naive T cell subset, the central and the effector memory T cell subset. Overall, HBsAg-specific total CD4(+) T cells were detected in approximately 81% of the HBV vaccinees. The use of dendritic cells substantially increased the otherwise low proliferative responses but not the percentage of IFN-gamma producing cells. The analysis of readily detectable CMV-specific CD4(+) T cell responses was used as a positive control and confirmed the adequacy of our assays. T cell responses associated with (in-) adequate hepatitis B vaccination can now be analysed in more detail. (C) 2007 Elsevier B.V. All rights reserved.

Once alerted by the innate immune system to the presence of a pathogen or a cellular abnormality, the adaptive immune system responds by activating and expanding antigen-specific B and T lymphocytes. This chapter focuses specifically on the activation and activities of T lymphocytes, which coordinate the adaptive immune response. We open with a description of where and how naive T cells first encounter antigen. We then examine what factors influence the differentiation of helper CD4+ T lymphocytes into one of several effector subsets, each of which secretes a distinct subset of cytokines. We follow with a discussion of the origin and function of cytotoxic CD8+ T cells, the lymphocyte with the capacity to directly kill tumor cells. We close with a brief summary of the unique challenges that face the adaptive immune system when it tried to mount a response to a tumor.

Publisher Summary This chapter focuses on the Th17 and T regulatory (Treg) signaling pathways in autoimmunity. Treg cells are distinguished from conventional naive T cells by their constitutive expression of the transcription factor Forkhead box, winged-helix protein 3 (Foxp3). Current paradigms suggest that the balance between conventional naive T cell activation and Treg-mediated immune suppression controls whether immune responses are ultimately protective, ineffective, or pathogenic. Early clinical results utilizing Treg cellular therapy support the notion that increasing Treg numbers in autoimmune patients can support tolerance. Evidence from both autoimmune mouse models and human patients reveals that Treg cells are necessary to prevent spontaneous autoimmunity throughout life, thereby indicating that Treg cells can also regulate immune responses to pathogens and developing tumors. T cell–driven autoimmune disorders continue to present a significant unmet clinical need. Advances in the understanding of T cell activation, differentiation, and regulation have yielded novel approaches to specifically dampen pathogenic immune reactions without creating potentially dangerous states of general immune suppression. Specific modulation of Th17 and Treg cells affords broad therapeutic promise for the treatment of autoimmune and chronic inflammatory conditions.

Publisher Summary This chapter focuses on the association that exists between the SNS and the immune system. The sympathetic nervous system (SNS) plays a role in modulating the magnitude of a primary antibody response, suggesting one possible mechanism by which behavior might influence the level of immunity. Antigen exposure caused a change in the firing rate of neurons within the hypothalamus, which allowed activation of the SNS. The brain communicates with cells in the periphery through two well-characterized mechanisms: namely, the SNS and the neuroendocrine system. Radioligand binding analysis and pharmacological approaches confirmed that adrenergic receptors that bind norepinephrine (NE) are expressed on immune cells. These findings and many others set the stage for the establishment of an entirely new field of study focused on the role played by the SNS in modulating the immune response. Most immune cells express b2AR for NE, but that the Th2 cell represses expression as it differentiates from a naive T cell. Engagement of b2AR on immune cells activates a cascade of distinct signaling intermediates that affect gene expression for certain antibody isotypes. And finally, b2AR-induced changes in CD86 gene expression on a B cell are associated with changes in CD86 function in the B cell, which is responsible for changes in immune-cell activity and function.

7 páginas, 3 figuras, 1 tabla., Current techniques to peripherally assess thymic function are: the signal-joint T-cell receptor excision circle (sj-TREC) level measurement and the naive T cell and CD31+ TREC-rich subset determination. However, all of them are indirect approaches and none could be considered a direct recent thymic emigrant (RTE) marker. To overcome their limitations, Dion et al. (2004) described the sj/β-TREC ratio that allows the peripheral quantification of the double negative to double positive intrathymic proliferation step. Nevertheless, the protocol described is expensive, sample and time-consuming, thus, limiting its usefulness. In this study, we describe a simplified protocol that reduces from 33 to 9 the amount of PCR reaction needed but maintaining the sensitivity and reproducibility of the original technique. In addition, we corroborated the effectiveness of our technique as an accurate thymic output-related marker by correlating the peripheral sj/β-TREC ratio with a direct measurement of thymic function as the percentage of double positive thymocytes (r = 0.601, p < 0.001)., SFM and ERM have grants from the Fondo de Investigaciones Sanitarias (FIS06/00176 and CP08/00172 respectively). This study is supported by the Fundación la para la Investigación y la Prevención del SIDA en España (FIPSE, 12481/05, 36624/06), Redes Temáticas de Investigación en SIDA (ISCIII RETIC RD06/0006/0021), Redes Temáticas de Cardiovascular (ISCIII RECAVA RD06/0014), Proyecto de Excelencia, Consejería de Innovación, Ciencia y Empresa (P06-CTS-01579) and Consejería de Salud, Servicio Andaluz de Salud (156/2006 and PI0366/07).

Identification of macrophages as host cells for the mammalian stage of Leishmania spp. traces back to about 40 years ago, but many questions concerning the ways these parasites establish themselves in these cells, which are endowed with potent innate microbicidal mechanisms, are still unanswered. It is known that microbicidal activities of macrophages can be enhanced or induced by effector T lymphocytes following the presentation of antigens via MHC class I or class II molecules expressed at the macrophage plasma membrane. However, Leishmania spp. have evolved mechanisms to evade or to interfere with antigen presentation processes, allowing parasites to partially resist these T cell-mediated immune responses. Recently, the presence of Leishmania amastigotes within dendritic cells has been reported suggesting that they could also be host cells for these parasites. Dendritic cells have been described as the only cells able to induce the activation of naive T lymphocytes. However, certain Leishmania species infect dendritic cells without inducing their maturation and impair the migration of these cells, which could delay the onset of the adaptive immune responses as both processes are required for naive T cell activation. This review examines how Leishmania spp. interact with these two cell types, macrophages and dendritic cells, and describes some of the strategies used by Leishmania spp. to survive in these inducible or constitutive antigen-presenting cells.

More than a contact surface, the immunological synapse is a specific arrangement of proteins in the contact area. Many different patterns of the immunological synapse have been discovered, and it is suggested that these patterns are related to the biological outcome of T-cell activation. Although exactly what determines the morphology of the immunological synapse remains unknown, it almost certainly is due to differences in the antigen-presenting cell as well as differences in the particular T cell studied. It will be important as this field grows to analyze this phenomenon in greater detail. Although the immunological synapse was first proposed to function to initiate T-cell signaling, it is clear now that T-cell receptor (TCR) signaling can occur in the absence of organized synapse formation. Rather, the formation of the immunological synapse appears to be a consequence of activation rather than a requirement for activation. The jury is still out on whether the synapse functions to sustain TCR signaling, but it seems very likely that the synapse is required for several hours to commit the naive T cell to enter cell cycle. Although much remains to be learned, all can agree that the immunological synapse does represent the polarization of the T cell, a process that is required to allow T-cell effector functions to be accomplished—be that cytolysis or cytokine release. It seems likely, given the rapid progress in this field, that much more will be known about immunological synapses in the very near future.

Publisher Summary This chapter describes the biology of HIV and its abundant genetic variations. Point mutation classifies viruses into two classes depending on whether replication errors are corrected (DNA viruses) or not (retroviruses and RNA viruses). Mutation rates are expressed as the probability of making a point mutation per base and per round of replication. The fixation rate refers to the number of amino acid changed, accumulated, or fixed per year. There are considerable qualitative and quantitative differences between HIV and influenza A with respect to their mutation and recombination rates. HIV replicates in CD4+ T lymphocytes, dendritic cells, and macrophages, but cross-sectional quantitative analyses show that T lymphocytes carry the greatest viral burden. HIV is more abundant in memory cells as opposed to naive T cell compartments. The chapter focuses principally on these memory cells. Two complementary approaches are applied to the study of viral dynamics in vivo. The first and most widely used approach is an experimental classic system in which the HIV plasma viraemia is remarkably stable over time, varying little from one day to another, and the decay of viraemia can be measured and modeled using multiple anti-HIV drugs. The second approach involves the rates of fixation of mutations of viruses.

With the increasing use of bone marrow transplantation, (BMT) in cancer and in the advent of AIDS, it has been realized that successful reconstitution of the immune system of the adult is of paramount concern. Naive T cell production in the host requires T cell development in the thymus of the adult. Due to the impairment of thymus function with age, there has been renewed interest in utilizing neuroendocrine hormones (i.e. growth hormone or GH) to restore thymopoietic function. GH has been previously demonstrated to improve T cell function and affect thymopoiesis in mice. Recent studies indicate that GH is not an obligate growth factor for thymopoiesis but instead acts to counteract the effects of stress on the thymus. Thus, GH may be of potential use to enhance thymus function and T cell repopulation, particularly after myeloablative procedures such as BMT or where peripheral T cell pools are depleted as in AIDS.

Publisher Summary The T lymphocytes develop from extra thymic stem cells that migrate from hematopoietic tissues and settle in the thymus. T lymphocyte development in the thymus depends on a functional microenvironment. Cross interactions between the various thymocyte subsets and stromal components determine the outcome of the structural changes in the microenvironment and eventual T cell development. The embryonic thymic microenvironment derives from neural crest cells, and extirpation of this region results in impaired thymic development. The thymic microenvironment is characterized by its distinct architecture of cortex and medulla that are composed of different cell types, including epithelial cells, macrophages, dendritic and antigen-presenting cells that manifest different properties in the cortex and medulla. The decrease in T cell development in the thymus could be due to aging effects at the stage of commitment to lymphocytes. The naive T cell compartment in aging is a mosaic of potentially active, as well as anergic cells. Anergy is related, at least in part, to the altered patterns of signal transduction.

The sites affected by allergic disease typically lie at the interface between the body and its external environment, and are exposed to the daily bombardment of allergens, pollutants, and pathogens. For an allergen to induce a primary response it must gain access to naive T cells within the lymphoid tissues. The dendritic cell (DC) is uniquely adapted to induce the primary response of a naive T cell to an antigen encountered in the periphery. DCs instilled into the airways are able to traffic to local draining lymph nodes, where they can drive T-cell priming. Following priming, the progeny of naive T cells enter the circulation and then they can enter peripheral tissues under the control of sets of adhesion molecules and in response to chemotactic gradients. The DC plays a continued role in the local stimulation of memory T cells at the sites of allergic inflammation following allergic sensitization.