Current Immunology Reviews (Discontinued) - Volume 6, Issue 2, 2010

The NKT cells represent an intriguing subset of T lymphocytes co-expressing NKR-P1B/C (NK1.1)(CD161), which are clearly distinct from conventional T cells. The majority of NKT cells express an invariant (i) T cell receptor (TCR), typically comprising Vα14/Jα18 combined with a highly skewed TCRVβ towards Vβ8.2 in the mouse, and homologous chain Vα24/Jα18 paired with Vβ11 in the human (iNKT cells). Unlike conventional T cells which are selected by polymorphic major histocompatibility complex (MHC) class I or class II expressed on the surface of thymic stromal cells, iNKT cells develop dependently on nonpolymorphic MHC class I-like antigen presentation molecule CD1d expressed on CD4+CD8+ cortical thymocytes. In contrast to conventional T cells, which recognize peptide antigens presented by MHC class I or class II, iNKT cells recognize glycolipid antigens such as α-galactosylceramide (α-GalCer), a synthetic glycolipid originally isolated from marine sponge in CD1d-dependent fashion. Upon activation (e.g. TCR ligation), iNKT cells promptly secrete large quantities of both type 1 and type 2 cytokines, and express cytolytic activity. The iNKT cells have been shown to participate in the regulation of various immune responses. Administration of α-GalCer into mice causes rapid release of various cytokines from iNKT cells, which participate in the prevention of various diseases (e.g. tumor rejection, prevention of the development of autoimmune diseases and protection against microbial pathogens). Indeed, clinical trial has just started for the treatment of patients suffering from cancer. Thus, it appears that iNKT cells are crucial target cells in the control of various diseases and that their ligands are highly expected as a new preventive/therapeutic medicine. In this issue, Drs. Kazuya Iwabuchi, Luc van Kaer, Hiroshi Wakao, Shin-ichiro Fujii and Yuki Kinjo, leading scientists in the field of iNKT cells, review whether and how iNKT cells can control autoimmune diseases, infectious diseases and cancer. Dendritic cells are essential for iNKT cell activation because they express CD1d on their surface at bright intensity and have a great potential to present glycolipid antigens to iNKT cells. Dr. Iwabuchi et al. describe an immunotherapy by manipulating iNKT cells with cytokine-pretreated dendritic cells. They provide us information on a unique method to potentiate a biased response by iNKT cells to enhance selectively type 1- (e.g. IFN-γ) or type 2-cytokine (e.g. IL-4) production with IL-4- or IFN- γ-pre-treated dendritic cells, respectively, and discuss possible mechanisms shared by these pre-treatments and therapeutic applications to tumor immunity, infectious diseases and autoimmune diseases. A prominent antigen for iNKT cells is α-GalCer. α-glucuronosylceramide from Sphingomonas sp. and Ehrlichia sp., α- galactosyldiacylglycerol from Borrelia sp., phosphatidylinositol mannoside from Mycobacterium sp. and phosphoethanolamine have been identified as possible ligands for iNKT cells, although all of these activate iNKT cells to a lesser degree than α- GalCer. Numerous investigators have been trying to identify a natural ligand for iNKT cells and some synthetic glycolipids have been identified as a ligand for iNKT cells. Dr. van Kaer et al. describes iNKT cell ligands and focus on the therapy of autoimmune diseases such as type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis, myasthenia gravis, autoimmune uveritis, Graves' disease, etc. by controlling iNKT cell activation. Although iNKT cells are abundant in the liver and the bone marrow as compared to other organs and peripheral blood, these cells are far less abundant in the total body as compared to conventional T cells. The rarity of iNKT cells has not only hindered deciphering the molecular mechanisms underlying their immunomodulatory functions, but also prevented the direct use in cell therapy/regenerative medicine. Dr. Wakao gives a picture of induction of immunocompetent iNKT cells from embryonic stem cells, which may open the avenue for the future cell therapy/regenerative medicine using iNKT cells. On the one hand, iNKT cells play a major role in induction of immune responses, but on the other hand, they also participate in induction of immunological tolerance. Yet, an approach to manipulate the dual nature of iNKT cell function has not apparently been established. Dr. Fujii et al. describe two strategies inducing the opposite immune responses. In addition, they show several types of α-GalCer-pulsed antigen presenting cells (APCs) that generate stimulatory iNKT cells capable of releasing proinflammatory cytokines and leading to adaptive immune responses. Moreover, they give us information on immune modulation approach using liposomal α-GalCer, which generates regulatory iNKT cells. These regulatory iNKT cells induce regulatory T cells (Treg) and hence, this approach can be applied for diminution of excessive immune responses as is seen in autoimmune diseases as well as allergic diseases.

NKT cell can modulate the immune response through the production of type 1 T helper (Th1), Th2, or even Th17 cytokines and serve as a good target for immunotherapy. Selective enhancement of either Th1- or Th2-cytokine production upon stimulation may better control immune-mediated diseases according to the respective immunopathology. By employing a co-culture of NKT cells with differently treated dendritic cells (DC) and quantifying cytokines in the culture supernatants, we have developed novel methods to enhance either IFN-γ or IL-4 production by NKT cells. When α-galactosylceramide-loaded DCs were pre-treated with IL-4 or IFN-γ and then co-cultured with NKT cells, the enhanced production of IFN-γ or IL-4 by NKT cells was respectively induced, implying that NKT cells could produce a cytokine of the opposite response to the cytokine used for pre-treatment of the DCs. Dynamics of inhibitory ligand expression on DCs appear to be involved in this phenomenon. Utilization of negative feedback regulation may expand the utility of NKT cells for therapy for tumors, infectious diseases, and autoimmunity.

Invariant natural killer T (iNKT) cells are a unique subset of T lymphocytes that share characteristics with both innate and adaptive immune cells. The iNKT cell receptor recognizes glycolipid antigens presented in the context of CD1d, an analogue of the major histocompatibility complex class I molecule. These cells rapidly produce a variety of cytokines in response to stimuli, providing them with the capacity to regulate the activities of other cells in the immune system. These regulatory properties of iNKT cells play critical roles in a variety of disease models for infection, autoimmunity, inflammation and cancer. Here, we review the role of iNKT cells in modulating the immune response in autoimmune diseases and we discuss prospects and limitations for targeting iNKT cells during immunotherapy for these diseases.

Natural killer T (NKT) cells are considered to be a good therapeutic target in diseases wherein the maintenance of immune balance is dysfunctional. Regardless of their nature as an immunomodulatory cell, realization of their clinical use has been hampered owing to the rarity of NKT cells and poor knowledge about the molecular mechanism underlying their dual nature in the immune system. The successful induction of NKT cells from embryonic stem cells prepared by somatic cell nuclear transfer and their autonomous maturation followed by an antigen-specific adjuvant effect upon adoptive transfer will open a novel avenue for the realization of cell therapy.

Invariant natural killer T (iNKT) cells are a conserved T cell sublineage and an important component of the innate immune system. The invariant T cell antigen receptor (TCR) α chain on iNKT cells interacts with glycolipid presented via CD1d on antigen-presenting cells (APCs), resulting in the production of a variety of cytokines, and thus bridging the innate and adaptive immune systems. In this review, we discuss two strategies of immune modulation that target iNKT cells using either liposomal α-galactosylceramide (α-GalCer) or α-GalCer-loaded APCs. Liposomal α- GalCer generates regulatory iNKT cells, which serve to induce regulatory T cells (Treg) and can be used to diminish immune responses as is seen in autoimmunity and allergic diseases. In contrast, α-GalCer-pulsed APCs generate stimulatory iNKT cells capable of releasing pro-inflammatory cytokines and leading to adaptive immune responses that can be used for treating malignancies. Here, we summarize the modalities used to manipulate the dual nature of iNKT cell function and their tremendous potential in treating both allergic and malignant disease.

Natural killer T (NKT) cells are T lymphocytes that express T cell antigen receptor (TCR) and NK receptors. NKT cells expressing invariant TCRs (iNKT cells) participate in the response to various microbial pathogens. In many cases, these cells respond to pathogens during the early phase of infection and affect the outcome of disease. iNKT cells respond to microorganisms by recognizing microbial glycolipid antigens, or by inflammatory cytokines produced by dendritic cells (DCs), with or without recognition of endogenous antigen. Recent studies show that iNKT cell antigen has a potent adjuvant activity that enhances the antigen-specific CD4 and CD8 T cell response and antibody production by B cells when a glycolipid antigen and a peptide or a DNA vaccine were co-administered. Therefore, glycolipid antigen- mediated iNKT cell activation could be applied to the design of a new type of combined vaccination.

Neutrophils are one of the first cells to arrive at a site of infection or inflammation. Approximately 2-5% of the dry weight of the neutrophil is made up of myeloperoxidase (MPO). In addition to neutrophils, monocytes are transiently positive for this enzyme. During differentiation into a macrophage (MØ), these cells become negative for MPO. For years the principal function of MPO was viewed as being a participant in the cytotoxic triad. This triad composed of MPO, H2O2, and a halide, usually chloride, is toxic for micro-organisms as well as aberrant mammalian cells. Certainly, MPO in this role is beneficial to the host. Recently, however, the malevolent side of MPO has been exposed. This enzyme is associated with “classical” inflammatory responses such as those found in rheumatoid arthritic joints, Crohn's disease, asthma, and coronary vascular disease. In addition to its participation in inflammatory responses, MPO can function as an antigen and induce the formation of MPO-anti-nuclear cytoplasmic antibody (MPO-ANCA). These antibodies promote acute inflammation and are biological markers for systemic vasculitis, glomerulonephritis, etc. However, the truly ugly aspect of MPO, is its association with the “a-typical” inflammatory responses of neurodegenerative diseases such as, Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS). Although the above view of MPO may seem quite varied, in reality, it is myopic. Missing from the above, are the unrecognized functions of this enzyme. During the ingestion of cells, particles, and/or cellular debris by neutrophils, MPO is released into the microenvironment where ∼ 40% of the enzyme is inactivated (iMPO). From studies done by the present investigators, it appears that there is a dichotomy of function between MPO and iMPO. MPO functions primarily in situations involving cell killing by the cytotoxic triad and reactive oxygen species (ROS). Conversely, iMPO is more efficient in the induction of cytokines with minimal ROS production and is, therefore, highly immunoregulatory. It is the authors' intention to relate “the good, the bad and the ugly” of an enzyme that plays many known, as well as, unrecognized roles in the immune response.

CD40 is a member of the TNF receptor super family (tnfrsf) that's role in autoimmunity has been long established. Predominantly studies focus on CD40 as an antigen presenting cell receptor. We and others determined that CD40 acts as a functional receptor on T cells. In fact CD40 is a co-stimulus for T cells potentially precluding the CD28 - B7 costimulation axis. CD40+ T cells (Th40) are highly pathogenic - transferring type 1 diabetes (T1D) to SCID mice. The number and percentage of Th40 cells increases concurrently with insulitits through diabetes onset. An important finding was that blocking CD40 - CD154 interactions prevents T1D onset, and reestablishes homeostatic balance between Th40 cells and traditional, naturally occurring regulatory T cells (Tregs). We discovered a distinct dysregulation between Th40 cells and Tregs during autoimmunity. The actual number and function of Tregs in NOD mice, the model of T1D, is in fact normal. The percentage of Tregs is skewed to appear abnormally low. We determined that Th40 cells over time in NOD mice radically outpace Tregs in number and percentage. Mechanistically Th40 cells have lower levels of the death inducing Fas molecule and are highly resistant to cell death. Th40 cells are capable of producing Th1 cytokines including IFNγ and TNFα but also can produce IL-17A, demonstrating a pro-inflammatory phenotype.

Mesenchymal stem cells (MSCs) represent a promising new approach to the treatment of several diseases that are associated with dismal outcomes. These include myocardial damage, graft versus host disease, and possibly cancer. Although the potential therapeutic aspects of MSCs continue to be well-researched, the possible hazards of MSCs, and in particular their oncogenic capacity are poorly understood. This review addresses the oncogenic and tumor-supporting potential of MSCs within the context of cancer treatment. The risk for malignant transformation is discussed for each stage of the clinical lifecycle of MSCs. This includes malignant transformation in vitro during production phases, during insertion of potentially therapeutic transgenes, and finally in vivo via interactions with tumor stroma. The immunosuppressive qualities of MSCs, which may facilitate evasion of the immune system by a tumor, are also addressed. Limitations of the methods employed in clinical trials to date are reviewed, including the absence of long term follow-up and lack of adequate screening methods to detect formation of new tumors. Through discussions of the possible oncogenic and tumor-supporting mechanisms of MSCs, directions for future research are identified which may eventually facilitate the future clinical translation of MSCs for the treatment of cancer and other diseases.