Mast cells as modulators of T-cell responses

Summary:  Although mast cells have long been considered the integral effector cell in allergy and atopic disease, the paradigm of mast cell function is now evolving to incorporate data showing that mast cells make innumerable contributions to both protective and pathologic immune responses. Mast cells express cell surface molecules with costimulatory or co-inhibitory activity and produce a multitude of mediators that can direct dendritic cell (DC) or T-cell differentiation and function. In addition, mast cells exhibit a widespread distribution and are in close proximity to DCs and T cells at several critical sites. While there has been amazing progress in characterizing mast cell populations in vitro , only recently has the ability to monitor their in vivo effects become a reality. In this review, we discuss the evolution of our understanding of mast cell biology with an emphasis on their established and hypothesized roles in influencing T-cell differentiation and function. The fact that T-cell and mast cell interactions exist and are a normal component of most adaptive immune responses is one of the best illustrations of the now established concept that innate and adaptive immunity are not completely independent entities.     

Mast Cells and the Adaptive Immune Response

Background  The idea that the innate and adaptive immune systems are not separate entities is no longer new. In fact, it is surprising that this paradigm was accepted without question for so long. Many innate cells express cell surface molecules and soluble mediators that are essential for the development and activation of T cells and B cells. Yet among the innate cell populations, mast cells may play the major role in regulating adaptive immune cell function. Discussion  This role first came to light in studies of mast cells and their involvement in the autoimmune disease experimental allergic encephalomyelitis, the major rodent model of multiple sclerosis and has subsequently been verified in many in vitro and in vivo model systems.     

Natural killer cells remember: An evolutionary bridge between innate and adaptive immunity?

Since their discovery three decades ago, NK cells have been classified as cells of the innate immune system. NK cells were shown to respond rapidly and non‐specifically to infection, and were thought to act as a functional “bridge” to sustain the early innate immune response until the later adaptive immune responses could be mounted. In light of new findings showing how NK cells possess nearly all of the features of adaptive immunity including memory, we propose the placement of NK cells as an “evolutionary bridge” between innate and adaptive immunity.     

Mast cells in allergic asthma and beyond

Mast cells have been regarded for a long time as effector cells in IgE mediated type I reactions and in host defence against parasites. However, they are resident in all environmental exposed tissues and express a wide variety of receptors, suggesting that these cells can also function as sentinels in innate immune responses. Indeed, studies have demonstrated an important role of mast cells during the induction of life-saving antibacterial responses. Furthermore, recent findings have shown that mast cells promote and modulate the development of adaptive immune responses, making them an important hinge of innate and acquired immunity. In addition, mast cells and several mast cell-produced mediators have been shown to be important during the development of allergic airway diseases. In the present review, we will summarize findings on the role of mast cells during the development of adaptive immune responses and highlight their function, especially during the development of allergic asthma.     

The role of platelet CD154 in the modulation in adaptive immunity

Platelets’ primary role is hemostasis. However, a growing body of research has demonstrated that platelets are integral to the initiation of an inflammatory response and are potent effector cells of the innate immune response. Activated platelets express CD154, a molecule critical to adaptive immune responses, which has been implicated in platelet-mediated modulation of innate immune responses and inflammation. Recent studies utilizing CD154 knockout mice extend the role of platelet-derived CD154 to the modulation of adaptive immune response by enhancing antigen presentation, improving CD8⁺ T cell responses, and playing a critical function in T-dependent humoral immunity under physiological conditions. Together these data provide a basis for the expansion of the current paradigm of B cell activation and germinal center formation to include a role for platelets.     

Evolutionary implication of B-1 lineage cells from innate to adaptive immunity

The paradigm that B cells mainly play a central role in adaptive immunity may have to be reevaluated because B-1 lineage cells have been found to exhibit innate-like functions, such as phagocytic and bactericidal activities. Therefore, the evolutionary connection of B-1 lineage cells between innate and adaptive immunities have received much attention. In this review, we summarized various innate-like characteristics of B-1 lineage cells, such as natural antibody production, antigen-presenting function in primary adaptive immunity, and T cell-independent immune responses. These characteristics seem highly conserved between fish B cells and mammalian B-1 cells during vertebrate evolution. We proposed an evolutionary outline of B cells by comparing biological features, including morphology, phenotype, ontogeny, and functional activity between B-1 lineage cells and macrophages or B-2 cells. The B-1 lineage may be a transitional cell type between phagocytic cells (e.g., macrophages) and B-2 cells that functionally connects innate and adaptive immunities. Our discussion would contribute to the understanding on the origination of B cells specialized in adaptive immunity from innate immunity. The results might provide further insight into the evolution of the immune system as a whole.     

Invariant natural killer T cells: innate-like T cells with potent immunomodulatory activities

Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that react with glycolipid antigens presented by the major histocompatibility complex class I-related glycoprotein CD1d. Although iNKT cells express an antigen-specific receptor of the adaptive immune system, they behave more like cells of the innate immune system. A hallmark of iNKT cells is their capacity to produce copious amounts of immunoregulatory cytokines quickly after activation. The cytokines produced by iNKT cells can influence the level of activation of many cell types of the innate and adaptive immune systems as well as the quality of an adaptive immune response. As such, iNKT cells have emerged as important regulators of immune responses, playing a role in microbial immunity, autoimmunity, tumor immunity, and a variety of inflammatory conditions. Although several endogenous and exogenous glycolipid antigens of iNKT cells have been identified, how these glycolipids orchestrate iNKT-cell functions remains poorly understood. Nevertheless, iNKT cells hold substantial promise as targets for development of vaccine adjuvants and immunotherapies. These properties of iNKT cells have been investigated most extensively in mouse models of human disease using the marine sponge-derived agent α-galactosylceramide (α-GalCer) and related iNKT-cell antigens. While these preclinical studies have raised enthusiasm for developing iNKT-cell-based immunotherapies, they also showed potential health risks associated with iNKT cell activation. Although α-GalCer treatment in humans was shown to be safe in the short term, further studies are needed to develop safe and effective iNKT-cell-based therapies.     

The contribution of mast cells to bacterial and fungal infection immunity

Mast cells are hematopoietic progenitor-derived, granule-containing immune cells that are widely distributed in tissues that interact with the external environment, such as the skin and mucosal tissues. It is well-known that mast cells are significantly involved in IgE-mediated allergic reactions, but because of their location, it has also been long hypothesized that mast cells can act as sentinel cells that sense pathogens and initiate protective immune responses. Using mast cell or mast cell protease-deficient murine models, recent studies by our groups and others indicate that mast cells have pleiotropic regulatory roles in immunological responses against pathogens. In this review, we discuss studies that demonstrate that mast cells can either promote host resistance to infections caused by bacteria and fungi or contribute to dysregulated immune responses that can increase host morbidity and mortality. Overall, these studies indicate that mast cells can influence innate immune responses against bacterial and fungal infections via multiple mechanisms. Importantly, the contribution of mast cells to infection outcomes depends in part on the infection model, including the genetic approach used to assess the influence of mast cells on host immunity, hence highlighting the complexity of mast cell biology in the context of innate immune responses.     

Regulatory T cells inhibit Fas ligand-induced innate and adaptive tumour immunity

CD4+CD25+ regulatory T cells (Treg) are known to influence T cell responses to tumours. Here we have explored the role of Treg in inhibiting not only adaptive, but also innate immune responses to tumours. To this end we used a Fas ligand (FasL)-expressing melanoma cell line in a mouse model. In this system, innate immunity is sufficient to reject the tumour. All mice depleted of Treg and challenged with FasL-expressing melanoma remained tumour-free. Investigation of the underlying cellular effector mechanisms revealed that depletion of Treg enhanced an NK cell response capable of tumour lysis. Furthermore, this initial innate immune response primed mice to make an effective adaptive immune response leading to complete rejection of challenge with the parental melanoma. Both antigen-specific antibody and CD4+ T cells were implicated in protection via adaptive immunity. We conclude that removal of Treg and vaccination with whole tumour cells expressing FasL activates multiple arms of the immune system, leading to efficient tumour rejection. These findings highlight a novel role for FasL in inducing innate immune responses that are normally inhibited by Treg and uncover an adjuvant effect of FasL that can be used to stimulate tumour immunity after depletion of Treg.     

中波紫外线对皮肤免疫细胞的作用研究

紫外线诱导皮肤免疫抑制一直是光学免疫领域的研究热点,而中波紫外线(UVB)是引起皮肤免疫抑制作用的主要光谱,其对皮肤免疫细胞的作用是紫外线诱导皮肤免疫抑制的关键,皮肤中主要的免疫细胞大致也可分为固有免疫细胞和非固有免疫细胞,固有免疫细胞包括皮肤朗格汉斯细胞(LC)、肥大细胞、单核巨噬细胞、角质形成细胞(KC)、NK细胞;非固有免疫细胞主要包括T淋巴细胞、B淋巴细胞.研究UVB对皮肤固有免疫细胞和非固有免疫细胞的影响很有意义.     

Insights from the worm: The C. elegans model for innate immunity

The nematode worm Caenorhabditis elegans comprises an ancestral immune system. C. elegans recognizes and responds to viral, bacterial, and fungal infections. Components of the RNA interference machinery respond to viral infection, while highly conserved MAPK signaling pathways activate the innate immune response to bacterial infection. C. elegans has been particularly important for exploring the role of innate immunity in organismal stress resistance and the regulation of longevity. Also functions of neuronal sensing of infectious bacteria have recently been uncovered. Studies on nematode immunity can be instructive in exploring innate immune signaling in the absence of specialized immune cells and adaptive immunity.     

Natural type I interferon-producing cells as a link between innate and adaptive immunity

Type I interferons (IFNs) are promptly produced upon invasion of pathogens, and activate a broad range of effector cells in the innate and adaptive immune system. Lin⁻CD4⁺CD11c⁻ plasmacytoid dendritic cell precursors (plasmacytoid pre-DCs) produce enormous amounts of type I IFNs in response to viruses and CpG DNA, thus corresponding to the previously described but not fully defined natural type I IFN-producing cells (IPCs). Plasmacytoid pre-DCs strongly express toll-like receptor (TLR) 7 and TLR9, in contrast to monocytes, which mainly express TLR1, 2, 4, 5, and 8, suggesting that these two DC precursors recognize different microbial molecules and that they may have developed through different evolutionary trails. Three different stimuli, CpG DNA plus CD40 ligand, interleukin-3 (IL-3), and herpes simplex virus, stimulate plasmacytoid pre-DCs to differentiate into DCs that induce distinct types of T helper cells, i.e., Th1, Th2, and IFN-γ- and IL-10-producing T cells, respectively. The remarkable versatility of plasmacytoid pre-DCs distinguishes them from other cell types in the immune system that have only limited functions, and suggests that these cells may play a key role in integrating the innate and adaptive aspects of various immune responses.     

From plasmacytoid to dendritic cell: morphological and functional switches during plasmacytoid pre-dendritic cell differentiation

Plasmacytoid dendritic cell precursors (pDC/IPC) are the major producers of type I interferon and have the unique ability to link innate and adaptive immunity. After producing large amounts of type I IFN in response to microbial stimulation, they can differentiate into DC capable of stimulating naive T cells and modulate the adaptive immune response. In this review, we focus on the transition between these two highly specialized cell types, which is accompanied by major morphological, structural and functional changes, many of which remain to be fully characterized. We propose that the plasmacytoid and dendritic morphologies correspond to distinct differentiation states and effector functions.     

Mast cells as sources of cytokines,chemokines, and growth factors

Mast cells are hematopoietic cells that reside in virtually all vascularized tissues and that represent potential sources of a wide variety of biologically active secreted products, including diverse cytokines and growth factors. There is strong evidence for important non-redundant roles of mast cells in many types of innate or adaptive immune responses, including making important contributions to immediate and chronic IgE-associated allergic disorders and enhancing host resistance to certain venoms and parasites. However, mast cells have been proposed to influence many other biological processes, including responses to bacteria and virus, angiogenesis, wound healing, fibrosis, autoimmune and metabolic disorders, and cancer. The potential functions of mast cells in many of these settings is thought to reflect their ability to secrete, upon appropriate activation by a range of immune or non-immune stimuli, a broad spectrum of cytokines (including many chemokines) and growth factors, with potential autocrine, paracrine, local, and systemic effects. In this review, we summarize the evidence indicating which cytokines and growth factors can be produced by various populations of rodent and human mast cells in response to particular immune or non-immune stimuli, and comment on the proven or potential roles of such mast cell products in health and disease.     

Mast cell functions in the innate skin immune system

Mast cells are not only potent effector cells in allergy, but are also important players in protective immune responses against pathogens. Most of our knowledge about mast cells in innate immunity is derived from models of sepsis, whereas their role in innate immune responses of the skin has largely been neglected in the past. Their particular pattern of distribution in the skin and their ability to sense and react to pathogens and other danger signals indicate that mast cells can be important sentinels and effector cells in skin immune responses. The recent findings reviewed here have confirmed this hypothesis and have established a prominent role for skin mast cells in innate immunity.     

The underdeveloped innate immunity in embryonic stem cells: The molecular basis and biological perspectives from early embryogenesis

Embryonic stem cells (ESCs) have been intensively studied as a promising cell source for regenerative medicine. The rapid advancements in the field have not only proven the feasibility of ESC‐based cell therapy, but also led to a better understanding of pluripotent stem cells (PSCs) as a unique cell population at an early stage of embryogenesis. Recent studies have revealed that both human and mouse ESCs have attenuated innate immune responses to infectious agents and inflammatory cytokines. These findings raise interesting questions about the rationale for ESCs, the PSCs experimentally derived from preimplantation stage embryos, to not have an innate defense mechanism that has been adapted so well in somatic cells. All somatic cells have innate immune systems that can be activated by pathogen‐associated molecular patterns (PAMPs) or cellular damage‐associated molecular patterns (DAMPs), leading to production of cytokines. The underdeveloped innate immunity represents a unique property of PSCs that may have important implications. This review discusses the immunological properties of PSCs, the molecular basis underlying their diminished innate immune responses, and the hypothesis that the attenuated innate immune responses could be an adaptive mechanism that allows PSCs to avoid cytotoxicity associated with inflammation and immune responses during early embryogenesis.     

99th Dahlem Conference on Infection,Inflammation and Chronic Inflammatory Disorders: Evolution of adaptive immunity in vertebrates

Adaptive immunity has been defined, principally through studies of avian and mammalian species, as the ability to mount specific immune responses to a virtually unlimited variety of antigens. A key feature of an adaptive immune system is the ability to remember previous encounters with antigens and to achieve a more rapid, heightened response on secondary encounter. Adaptive immune systems featuring an enormous anticipatory receptor diversity and specific memory have been defined only in vertebrates. Surprisingly, the adaptive immune systems in jawless and jawed vertebrates employ very different types of antigen receptors. This evolutionary inventiveness suggests that adaptive immunity provided additional fitness value over the previously existing innate immune mechanisms.     

Human Dendritic Cell Subsets for Vaccination

TProtective immunity results from the interplay of antigen (Ag)-nonspecific innate immunity and Ag-specific adaptive immunity. The cells and molecules of the innate system employ non-clonal recognition pathways such as lectins and TLRs. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing Ag or peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). As a component of the innate immunc system, DC organize and transfer information from the outside world to the cells of the adaptive immune system. DC can induce such contrasting states as active immune responsiveness or immunological tolerance. Recent years have brought a wealth of information regarding DC biology and pathophysiology that shows the complexity of this cell system. Thus, presentation of antigen by immature (non-activated) DCs leads to tolerance, whereas mature, antigen-loaded DCs are geared towards the launching of antigen-specific immunity. Furthermore, DCs are composed of multiple subsets with distinct functions at the interface of the innate and adaptive immunity. Our increased understanding of DC pathophysiologywill permit their rational manipulation for therapy such as vaccination to improve immunity.     

Widespread immunological functions of mast cells: fact or fiction?

Immunological functions of mast cells are currently considered to be much broader than the original role of mast cells in IgE-driven allergic disease. The spectrum of proposed mast cell functions includes areas as diverse as the regulation of innate and adaptive immune responses, protective immunity against viral, microbial, and parasitic pathogens, autoimmunity, tolerance to graft rejection, promotion of or protection from cancer, wound healing, angiogenesis, cardiovascular diseases, diabetes, obesity, and others. The vast majority of in?vivo mast cell data have been based on mast cell-deficient Kit mutant mice. However, work in new mouse mutants with unperturbed Kit function, which have a surprisingly normal immune system, has failed to corroborate some key immunological aspects, formerly attributed to mast cells. Here, we consider the implications of these recent developments for the state of the field as well as for future work, aiming at deciphering the physiological functions of mast cells.     

NKG2D ligands: unconventional MHC class I-like molecules exploited by viruses and cancer

Our best teachers in revealing the importance of immune pathways are viruses and cancers that have subverted the most prominent pathways to escape from immune recognition. Viruses and cancer impair antigen presentation by classical MHC class I to escape adaptive immunity. The activating receptor NKG2D and its MHC class I-like ligands are other recently defined innate and adaptive immune pathways exploited by viruses and cancer. This review discusses recent advances in the understanding of how NKG2D, expressed on innate immune cells including natural killer cells, gammadelta+ T cells and macrophages, and adaptive immune cells such as CD8+ T cells, recognize stress-induced, MHC class I-like, self-ligands. Moreover, we describe how viruses and cancer have developed strategies to evade this recognition pathway.