Invariant natural killer T cells: bridging innate and adaptive immunity

Cells of the innate immune system interact with pathogens via conserved pattern-recognition receptors, whereas cells of the adaptive immune system recognize pathogens through diverse, antigen-specific receptors that are generated by somatic DNA rearrangement. Invariant natural killer T (iNKT) cells are a subset of lymphocytes that bridge the innate and adaptive immune systems. Although iNKT cells express T cell receptors that are generated by somatic DNA rearrangement, these receptors are semi-invariant and interact with a limited set of lipid and glycolipid antigens, thus resembling the pattern-recognition receptors of the innate immune system. Functionally, iNKT cells most closely resemble cells of the innate immune system, as they rapidly elicit their effector functions following activation, and fail to develop immunological memory. iNKT cells can become activated in response to a variety of stimuli and participate in the regulation of various immune responses. Activated iNKT cells produce several cytokines with the capacity to jump-start and modulate an adaptive immune response. A variety of glycolipid antigens that can differentially elicit distinct effector functions in iNKT cells have been identified. These reagents have been employed to test the hypothesis that iNKT cells can be harnessed for therapeutic purposes in human diseases. Here, we review the innate-like properties and functions of iNKT cells and discuss their interactions with other cell types of the immune system.     

Harnessing NK cells for cancer immunotherapy: immune checkpoint receptors and chimeric antigen receptors

Natural killer (NK) cells, key antitumor effectors of the innate immune system, are endowed with the unique ability to spontaneously eliminate cells undergoing a neoplastic transformation. Given their broad reactivity against diverse types of cancer and close association with cancer prognosis, NK cells have gained considerable attention as a promising therapeutic target for cancer immunotherapy. NK cell-based therapies have demonstrated favorable clinical efficacies in several hematological malignancies but limited success in solid tumors, thus highlighting the need to develop new therapeutic strategies to restore and optimize antitumor activity while preventing tumor immune escape. The current therapeutic modalities yielding encouraging results in clinical trials include the blockade of immune checkpoint receptors to overcome the immune-evasion mechanism used by tumors and the incorporation of tumor-directed chimeric antigen receptors to enhance NK cell antitumor specificity and activity. These observations, together with recent advances in the understanding of NK cell activation within the tumor microenvironment, will facilitate the optimal design of NK cell-based therapy against a broad range of cancers and, more desirably, refractory cancers.     

A formal model of an artificial immune system

The paper presents a mathematical model based on the features of antigen-antibody bindings in the immune system. In the natural immune system, local binding of immune cells and molecules to antigenic peptides is based generally on the behavior of surface proteins. In particular, immune cells contain proteins on their receptors, and apparently, these proteins play the key role both in immune response and recognition processes. In this work, we consider the immune cells in the form of formal B-cell and formal T-cell and develop a mathematical model of their interactions. We refer this model as the formal immune system (FIS). The paper provides an analysis of a network of bindings (or interactions) among the formal proteins of the FIS.     

Interleukin-1 inhibits follicle stimulating hormone-induced differentiation in rat granulosa cells in vitro

Increasing evidence suggests that factors secreted from cells of the immune system can affect endocrine function. In this report we show that the monokine, interleukin-1, inhibits follicle stimulating hormone-induced development of luteinizing hormone receptors and reduces progesterone secreted from cultured rat granulosa cells. These effects of interleukin-1 were observed in the physiological range of 10(-9) M. The ability of sex steroids to influence the immune response together with our results support the hypothesis that there is a bidirectional communication network which links the immune and reproductive endocrine systems.     

Decoding dangerous death: how cytotoxic chemotherapy invokes inflammation, immunity or nothing at all

Chemotherapy and immunotherapy can be either synergistic or antagonistic modalities in the treatment of cancer. Cytotoxic chemotherapy not only affects the tumor but also targets dividing lymphocytes, the very cells that are required to develop an immune response. For this reason, chemo- and immunotherapy have been seen as antagonistic. However, cell death can be immunogenic and the way in which chemotherapeutic drug kills a tumor cell is likely to be an important determinant of how that dying cell interacts with the immune system and whether the interaction will lead to an immune response. When a cell dies as the result of infection, the immune system responds rapidly and the system of Toll-like receptors (TLR) plays a key role in this process. In this review, we will briefly summarize the intracellular signaling pathways that link TLR ligation with immune activation and we will address the questions where and how TLRs recognize their targets.     

History,applications, and challenges of immune repertoire research

The diversity of T and B cells in terms of their receptor sequences is huge in the vertebrate’s immune system and provides broad protection against the vast diversity of pathogens. Immune repertoire is defined as the sum of T cell receptors and B cell receptors (also named immunoglobulin) that makes the organism’s adaptive immune system. Before the emergence of high-throughput sequencing, the studies on immune repertoire were limited by the underdeveloped methodologies, since it was impossible to capture the whole picture by the low-throughput tools. The massive paralleled sequencing technology suits perfectly the researches on immune repertoire. In this article, we review the history of immune repertoire studies, in terms of technologies and research applications. Particularly, we discuss several aspects of challenges in this field and highlight the efforts to develop potential solutions, in the era of high-throughput sequencing of the immune repertoire.     

Continuing education of the immune system--dendritic cells, immune regulation and tolerance

T cells, as they develop in the thymus come to express antigen receptors. The specificity of these receptors cannot be predicted and must include many with potential anti-self reactivity. Those that encounter self-antigens, in association with self-MHC (major histocompatibility complex), with high affinity are inactivated and do not leave the thymus. Not all self-antigens however are expressed in the thymus and thus many potentially self-reactive T cells enter the periphery. It poses therefore a fundamental immunological question: how peripheral self-tolerance is maintained in health? Dendritic cells (DC) play a central role in the activation of T cells, especially na?ve T cells. Their importance in initiating immune responses against pathogens has been well established. However, DC represent complex populations of cells. Recent advances in our knowledge including molecular understanding of DC/T cell interactions have begun to reveal another important dimension of DC functions in the periphery, being not only initiators but also regulators of the immune system. This review summarises recent findings on the roles of DC in the regulation of immune responses and the maintenance of peripheral tolerance, in an attempt to explain how break down of this may lead to immunopathologies and autoimmunity. The concept of a regulatory DC and its possible role in the generation of T regulatory cells in health and in diseases are also discussed. Based on these, the need for a "continuing education" of the immune system throughout one's life, in which DC are again the "tutors", is postulated.     

Immune regulation by SLAM family receptors and SAP-related adaptors

The signalling lymphocytic activation molecule (SLAM) family of receptors is expressed by a wide range of immune cells. Through their cytoplasmic domain, SLAM family receptors associate with SLAM-associated protein (SAP)-related molecules, a group of cytoplasmic adaptors composed almost exclusively of an SRC homology 2 domain. SAP, the prototype of the SAP family, is mutated in a human immunodeficiency named X-linked lymphoproliferative (XLP) disease. Recent observations indicate that SLAM family receptors, in association with SAP family adaptors, have crucial roles during normal immune reactions in innate and adaptive immune cells. The latest progress in this field is reviewed here.     

Contribution of D2 dopamine receptors of the rat dorsolateral caudate nucleus to immunomodulation

The analysis of the immune response changes in Wistar rats under activation or blockade of D2 DA receptors has shown that electrolytic lesion of the dorsolateral caudate nucleus characterized by a high density of D2 DA receptors resulted in a decrease of the immune response to SRBC. At the same time, in rats with similar lesion stimulation of the immune reactions caused by a selective D2 agonist guinpirol (1.0 mg/kg) did not develop completely. Administration of haloperidol (2.0 mg/kg), the immune-inhibitory effect of which is associated with increasing serotoninergic system activity, to rats with impaired dorso-lateral caudate nucleus did not produce more expressed immunosuppression. However, the level of the immune response in sham-operated rats receiving haloperidol was significantly lower than that of animal with the destructed nucleus caudatus. Considering that qunmpirol-induced immunostimulation is related to the selective activation of the DA-ergic brain system, it is concluded that D2 DA receptors of the nucleus caudatus are involved in the mechanisms of immunostimulation, although D2 DA receptors of other brain structures may also impact this process.     

Receptor-Mediated Interaction Between the Sympathetic Nervous System and Immune System in Inflammation

The sympathetic nervous system plays a central role in establishing communication between the central nervous system and the immune system during inflammation. Inflammation activates the sympathetic nervous system, which causes release of the transmitters of the sympathetic nerv-ous system in the periphery. The transmitters of the sympathetic nervous system are the cate-cholamines noradrenaline and adrenaline and the purines ATP, adenosine, and inosine. Once these transmitters are released, they stimulate both presynaptic receptors on nerve terminals and post-synaptic receptors on immune cells. The receptors that are sensitive to catecholamines are termed adrenoceptors, whereas the receptors that bind purines are called purinoceptors. Stimulation of the presynaptic receptors exerts an autoregulatory effect on the release of transmitters. Ligation of the postsynaptic receptors on inflammatory cells modulates the inflammatory ac-tivities of these cells. The present review summarizes some of the most important aspects of the current state of knowledge about the interactions between the sympathetic nervous system and the immune system during inflammation with a special emphasis on the role of adreno and purinoceptors.     

Natural killer cells: detectors of stress

Natural killer (NK) cells are a key component of the innate immune system, as they are able to detect microbe-infected cells, tumors as well as allogeneic cells, without specific sensitization. NK cell effector functions (cytotoxicity, cytokine secretion) are regulated by a wide array of inhibitory and activating receptors. MHC class I molecules are the ligands of most inhibitory receptors, while activating receptors recognize either pathogen-encoded molecules, or self-proteins whose expression is up-regulated upon microbial infection or tumor development. Upon integration of these negative and positive signals, Natural Killer cells can discriminate between healthy "self" (tolerance) and autologous cells undergoing different types of cellular stress or allogeneic cells (immunosurveillance). The knowledge of the different mechanisms of target cell recognition is thus crucial to dissect NK cell involvement in homeostatic and disease conditions as well as to develop novel alternative therapeutic approaches based on NK cell manipulation.     

Human NK cells: From development to effector functions

NK cells are the major lymphocyte subset of the innate immune system that mediates antiviral and anti-tumor responses. It is well established that they develop mechanisms to distinguish self from non-self during the process of NK cell education. Unlike T and B cells, natural killer cells lack clonotypic receptors and are activated after recognizing their target via germline-encoded receptors through natural cytotoxicity, cytokine stimulation, and Ab-dependent cellular cytotoxicity. Subsequently, they utilize cytotoxic granules, death receptor ligands, and cytokines to perform their effector functions. In this review, we provide a general overview of human NK cells, as opposed to murine NK cells, discussing their ontogeny, maturation, receptor diversity, types of responses, and effector functions. Furthermore, we also describe recent advances in human NK cell biology, including tissue-resident NK cell populations, NK cell memory, and novel approaches used to target NK cells in cancer immunotherapy.     

Developments in lupus 2006

Published reports in 2006 on systemic lupus erythematosus are reviewed with regard to preclinical and clinical studies on disturbances of the immune system including co-stimulation, cytokines and recent insights into new therapeutic approaches. Increasing knowledge of components of the innate immune system, such as certain receptors (Toll-like receptors, Fc receptors and complement receptors) and cytokines as well as immune cells (dendritic cells, plasmacytoid cells and neutrophils) supports their immunopathogenic relevance and enhance our understanding of the pathogenic complexity of lupus. Although it remains to be shown which of those could be targets for therapy or biomarkers, lymphocyte-directed therapy is currently under promising clinical investigation.     

Pathogen recognition and innate immunity

Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.     

Role of natriuretic peptide signaling in modulating asthma and inflammation

Atrial natriuretic peptide (ANP), the C-terminal peptide comprising residues 99-126 of the pro-ANP hormone, has been studied for 3 decades for its cardiovascular effects. Recent reports suggest that it plays a significant role in modulation of the immune system. Immune cells, including macrophages, dendritic cells, and T lymphocytes, express receptors for ANP. ANP plays a significant role in shaping the early immune response to environmental antigens and may play a critical role in the interaction between cells of the innate and adaptive immune systems; it also appears to be involved in polarizing the immune response to allergens. Thus, ability to alter the magnitude of natriuretic peptide receptor A (NPRA) signaling could be exploited to develop therapeutics for several allergic diseases, including asthma. This report will review and critically evaluate the role of the ANP pathway in asthma and inflammation.     

Functional Switching and Stability of Regulatory T Cells

It is widely accepted that the primary immune system contains a subpopulation of cells, known as regulatory T cells whose function is to regulate the immune response. There is conflicting biological evidence regarding the ability of regulatory cells to lose their regulatory capabilities and turn into immune promoting cells. In this paper, we develop mathematical models to investigate the effects of regulatory T cell switching on the immune response. Depending on environmental conditions, regulatory T cells may transition, becoming effector T cells that are immunostimulatory rather than immunoregulatory. We consider this mechanism both in the context of a simple, ordinary differential equation (ODE) model and in the context of a more biologically detailed, delay differential equation (DDE) model of the primary immune response. It is shown that models that incorporate such a mechanism express the usual characteristics of an immune response (expansion, contraction, and memory phases), while being more robust with respect to T cell precursor frequencies. We characterize the affects of regulatory T cell switching on the peak magnitude of the immune response and identify a biologically testable range for the switching parameter. We conclude that regulatory T cell switching may play a key role in controlling immune contraction.     

Not always the bad guys: B cells as regulators of autoimmune pathology

When B cells react aggressively against self, the potential for pathology is extreme. It is therefore not surprising that B-cell depletion is seen as an attractive therapy in autoimmune diseases. However, B cells can also be essential for restraining unwanted autoaggressive T-cell responses. Recent advances have pointed to interleukin-10 (IL-10) production as a key component in B-cell-mediated immune regulation. In this Opinion article, we develop a hypothesis that triggering of Toll-like receptors controls the propensity of B cells for IL-10 production and immune suppression. According to this model, B cells can translate exposure to certain microbial infections into protection from chronic inflammatory diseases.     

Co-expression of two LTB4 receptors in human mononuclear cells

Leukotriene B4 (LTB4) is one of the most potent chemoattractants and activators of leukocytes, and is involved in inflammatory diseases. Two G-protein-coupled-receptors for LTB4, BLT1 and BLT2, have been isolated, and shown to be a high- and low-affinity receptor, respectively. The tissue distributions of these receptors are different, and distinct roles of each receptor remain elusive. We compared the expression of these two receptors using semi-quantitative PCR analyses, and show that these two receptors are expressed in various subsets of human lymphocytes in different quantities. BLT1 expression is highest in CD14+ monocytes, while BLT2 expression is high in CD8+ cytotoxic T-, CD4+ helper T-, and CD19+ B-cells. Moreover, BLT2 expression in these lymphocytes decreased upon activation of the cells. We also established CHO cells stably expressing both receptors, and found that these cells could migrate toward LTB4 with a broad range of LTB4. These findings suggest novel roles of LTB4 in immune system, and the biological significance of high- and low- affinity LTB4 receptors in chemotaxis.     

Innate immunity: structure and function of TLRs

The innate immune system provides the first line of defence against infection. Through a limited number of germline-encoded receptors called pattern recognition receptors (PRRs), innate cells recognize and are activated by highly conserved structures expressed by large group of microorganisms called pathogen-associated molecular patterns (PAMPs). PRRs are involved either in recognition (scavenger receptors, C-type lectins) or in cell activation (Toll-like receptors or TLR, helicases and NOD molecules). TLRs play a pivotal role in cell activation in response to PAMPs. TLR are type I transmembrane proteins characterized by an intracellular Toll/IL 1 receptor homology domain that are expressed by innate immune cells (dendritic cells, macrophages, NK cells), cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, fibroblasts). In all the cell types analyzed, TLR agonists, alone or in combination with costimulatory molecules, induce cell activation. The crucial role played by TLR in immune cell activation has been detailed in dendritic cells. A TLR-dependent activation of dendritic cells is required to induce their maturation and migration to regional lymph nodes and to activate na?ve T cells. The ability of different cell types to respond to TLR agonists is related to the pattern of expression of the TLRs and its regulation as well as their intracellular localization. Recent studies suggest that the nature of the endocytic and signaling receptors engaged by PAMPs may determine the nature of the immune response generated against the microbial molecules, highlighting the role of TLRs as molecular interfaces between innate and adaptive immunity. In this review are summarized the main biological properties of the TLR molecules.