Cross-talk between NKT and regulatory T cells (Tregs) in modulation of immune response in patients with colorectal cancer following different pain management techniques

Natural killer T (NKT) and regulatory T cells (Tregs) play an important role in innate immune response. Natural killer (NK) and NKT cells are indispensable factors in the body's ongoing defense against tumor development, as well as viral infection. NKT cells are a subset of T cells that shares properties of natural killer cells and conventional T cells. They are involved in innate immune responses, tumor rejection, post transplantation immunotherapy, immune surveillance and control of autoimmune diseases. They may also play both protective and harmful roles in the progression of certain autoimmune diseases, such as diabetes, lupus, atherosclerosis, and allergen-induced asthma. Immune surveillance involves the process whereby precancerous and malignant cells are recognized by the host immune system as damaged and are consequently targeted for elimination. The pharmacological management of postoperative pain in patients with malignancies uses very different techniques whose possible cytotoxic functions we still known very poor. The present study compared effects of two different postoperative pain management techniques in patients undergoing colorectal cancer surgery on the innate immunity. Our data indicate that the patients with colorectal cancer have significantly increased the percentage of Tregs and NKT cells. The values were statistically higher during epidural analgesia in comparison with intravenous analgesia, indicating that epidural pain management technique ameliorate the immune suppression after surgery.     

NK and NKT cell functions in immunosenescence

Immunosenescence is defined as the state of dysregulated immune function that contributes to the increased susceptibility to infection, cancer and autoimmune diseases observed in old organisms, including humans. However, dysregulations in the immune functions are normally counterbalanced by continuous adaptation of the body to the deteriorations that occur over time. These adaptive changes are likely to occur in healthy human centenarians. Both innate (natural) and adaptive (acquired) immune responses decline with advancing age. Natural killer (NK) and natural killer T (NKT) cells represent the best model to describe innate and adaptive immune response in aging. NK and NKT cell cytotoxicity decreases in aging as well as interferon-gamma (IFN-gamma) production by both activated cell types. Their innate and acquired immune responses are preserved in very old age. However, NKT cells bearing T-cell receptor (TCR) gammadelta also display an increased cytotoxicity and IFN-gamma production in very old age. This fact suggests that NKT cells bearing TCRgammadelta are more involved in maintaining innate and adaptive immune response in aging leading to successful aging. The role played by the neuroendocrine-immune network and by nutritional factors, such as zinc, in maintaining NK and NKT cell functions in aging is discussed.     

Cross-regulation between distinct natural killer T cell subsets influences immune response to self and foreign antigens

Natural killer T (NKT) cells generally recognize lipid-antigens presented in the context of the MHC class I-like molecule CD1d. CD1d-restricted NKT cells consist of two broad subsets: Type I, which express an invariant T cell receptor (TCR) and type II, which utilize diverse TCR gene segments. A major type II NKT subset has been shown to recognize a self-glycolipid, sulfatide. Both subsets play important roles in autoimmune diseases, tumor surveillance, and infectious diseases. While type I NKT cells protect from tumor growth by enhancing tumor surveillance, type II NKT cells may suppress anti-tumor immune responses. In a murine autoimmune hepatitis model, type I NKT cells contribute to pathogenesis, whereas activation of sulfatide-reactive type II NKT cells protects from disease. Sulfatide-mediated activation of type II NKT cells results in modification of dendritic cells and induction of anergy in type I NKT cells. Elucidation of this novel pathway of cross-regulation among NKT cell subsets will provide tools for intervention in autoimmune diseases and for designing strategies for effective anti-tumor immunity.     

Natural killer lymphocytes: biology,development, and function

Natural killer (NK) lymphocytes represent the first line of defense against virally infected cells and tumor cells. The role of NK cells in immune responses has been markedly explored, mainly due to the identification of NK cell receptors and their ligands, but also through the analysis of mechanisms underlying the effects of various cytokines on NK cell development and function. A population of lymphocytes that shares function and receptors with NK cells is represented by natural killer T (NKT) cells. NKT lymphocytes are regulators of both innate and adaptive immune responses, but have also been reported to function as effector antitumor cells. The marked progress in our understanding of the biology, development, and function of NK/NKT cells has provided the basis for their potential application in tumor clinical trials.This work was presented at the first Cancer Immunology and Immunotherapy Summer School, 8–13 September 2003, Ionian Village, Bartholomeio, Peloponnese, Greece.     

Role of NKT cells in the digestive system. IV. The role of canonical natural killer T cells in mucosal immunity and inflammation

Lymphocytes that combine features of T cells and natural killer (NK) cells are named natural killer T (NKT) cells. The majority of NKT cells in mice bear highly conserved invariant Valpha chains, and to date two populations of such canonical NKT cells are known in mice: those that express Valpha14 and those that express Valpha7.2. Both populations are selected by nonpolymorphic major histocompatibility complex class I-like antigen-presenting molecules expressed by hematopoietic cells in the thymus: CD1d for Valpha14-expressing NKT cells and MR1 for those cells expressing Valpha7.2. The more intensely studied Valpha14 NKT cells have been implicated in diverse immune reactions, including immune regulation and inflammation in the intestine; the Valpha7.2 expressing cells are most frequently found in the lamina propria. In humans, populations of canonical NKT cells are found to be highly similar in terms of the expression of homologous, invariant T cell antigen-receptor alpha-chains, specificity, and function, although their frequency differs from those in the mouse. In this review, we will focus on the role of both of these canonical NKT cell populations in the mucosal tissues of the intestine.     

Participatory role of natural killer and natural killer T cells in atherosclerosis: lessons learned from in vivo mouse studies

Atherosclerosis is a multifactor, highly complex disease with numerous aetiologies that work synergistically to promote lesion development. One of the emerging components that drive the development of both early- and late-stage atherosclerotic lesions is the participation of both the innate and acquired immune systems. In both humans and animal models of atherosclerosis, the most prominent cells that infiltrate evolving lesions are macrophages and T lymphocytes. The functional loss of either of these cell types reduces the extent of atherosclerosis in mice that were rendered susceptible to the disease by deficiency of either apolipoprotein E or the LDL (low density lipoprotein) receptor. In addition to these major immune cell participants, a number of less prominent leukocyte populations that can modulate the atherogenic process are also involved. This review will focus on the participatory role of two "less prominent" immune components, namely natural killer (NK) cells and natural killer T (NKT) cells. Although this review will highlight the fact that both NK and NKT cells are not sufficient for causing the disease, the roles played by both these cells types are becoming increasingly important in understanding the complexity of this disease process.     

Invariant NKT Cells: Regulation and Function during Viral Infection

Natural killer T cells (NKT cells) represent a subset of T lymphocytes that express natural killer (NK) cell surface markers. A subset of NKT cells, termed invariant NKT cells (iNKT), express a highly restricted T cell receptor (TCR) and respond to CD1d-restricted lipid ligands. iNKT cells are now appreciated to play an important role in linking innate and adaptive immune responses and have been implicated in infectious disease, allergy, asthma, autoimmunity, and tumor surveillance. Advances in iNKT identification and purification have allowed for the detailed study of iNKT activity in both humans and mice during a variety of chronic and acute infections. Comparison of iNKT function between non-pathogenic simian immunodeficiency virus (SIV) infection models and chronic HIV-infected patients implies a role for iNKT activity in controlling immune activation. In vitro studies of influenza infection have revealed novel effector functions of iNKT cells including IL-22 production and modulation of myeloid-derived suppressor cells, but ex vivo characterization of human iNKT cells during influenza infection are lacking. Similarly, as recent evidence suggests iNKT involvement in dengue virus pathogenesis, iNKT cells may modulate responses to a number of emerging pathogens. This Review will summarize current knowledge of iNKT involvement in responses to viral infections in both human and mouse models and will identify critical gaps in knowledge and opportunities for future study. We will also highlight recent efforts to harness iNKT ligands as vaccine adjuvants capable of improving vaccination-induced cellular immune responses.     

Immunotherapy with ligands of natural killer T cells

Natural killer T (NKT) cells are innate lymphocytes that share receptor structures and functions with conventional T cells and natural killer cells. NKT cells are specific for glycolipid antigens bound by the major histocompatibility complex class I-like protein CD1d. One striking property of NKT cells is their capacity to rapidly produce large amounts of cytokines in response to T-cell receptor engagement, suggesting that activated NKT cells can modulate adaptive immune responses. Recent pre-clinical studies have revealed significant efficacy of NKT-cell ligands such as the glycolipid alpha-galactosylceramide for treatment of metastatic cancers and infections, and for prevention of autoimmune diseases. These findings suggest that appropriate stimulation of NKT cells could be exploited for prevention or treatment of human diseases.     

NKT细胞在抗肿瘤免疫中的作用及其机制

NKT细胞是免疫细胞中一类具有NK细胞特定标志的T细胞亚群,经活化,既可直接作为抗肿瘤效应细胞发挥杀伤作用,又能通过激活其他免疫效应细胞,如NK细胞,间接实现抗肿瘤作用。NKT细胞在抗肿瘤免疫、获得性免疫应答及免疫调节中起着重要作用。     

CD4(-)CD8alphaalpha subset of CD1d-restricted NKT cells controls T cell expansion

Valpha24 invariant (Valpha24i) CD1d-restricted NKT cells are widely regarded to have immune regulatory properties. They are known to have a role in preventing autoimmune diseases and are involved in optimally mounted immune responses to pathogens and tumor cells. We were interested in understanding how these cells provide protection in autoimmune diseases. We first observed, using EBV/MHC I tetrameric complexes, that expansion of Ag-specific cells in human PBMCs was reduced when CD1d-restricted NKT cells were concomitantly activated. This was accompanied by an increase in a CD4(-)CD8alphaalpha(+) subset of Valpha24i NKT cells. To delineate if a specific subset of NKT cells was responsible for this effect, we generated different subsets of human CD4(-) and CD4(+) Valpha24i NKT clones and demonstrate that a CD4(-)CD8alphaalpha(+) subset with highly efficient cytolytic ability was unique among the clones in being able to suppress the proliferation and expansion of activated T cells in vitro. Activated clones were able to kill CD1d-bearing dendritic or target cells. We suggest that one mechanism by which CD1d-restricted NKT cells can exert a regulatory role is by containing the proliferation of activated T cells, possibly through timely lysis of APCs or activated T cells bearing CD1d.     

A novel immunoregulatory axis of NKT cell subsets regulating tumor immunity

There are many mechanisms that regulate and dampen the immune response to cancers, including several types of regulatory T cells. Besides the T reg cell, we have identified another immunoregulatory circuit initiated by NKT cells that produce IL-13 in response to tumor growth and this IL-13 then induces myeloid cells to make TGF-beta that inhibits cytotoxic T cell-mediated tumor immunosurveillance in several mouse tumor models. This finding created a paradox in the role of NKT cells in tumor immunity, in that they can also contribute to protection. We resolve this paradox by the finding that the suppressive NKT cell is a type II NKT cell that lacks the canonical invariant T cell receptor, whereas the protective cell is a type I NKT cell that expresses the invariant receptor. Further, we see that these two subsets of NKT cells counter-regulate each other, defining a new immunoregulatory axis. The balance along this axis may determine the outcome of tumor immunosurveillance as well as influence the efficacy of anti-cancer vaccines and immunotherapy.     

NKT cells mediate organ-specific resistance against Leishmania major infection

Whereas the acquired T cell-mediated protection against intracellular pathogens such as Leishmania major has been well studied in the past, the cells and mechanisms involved in their innate control are still poorly understood. Here, we investigated the role of natural killer T (NKT) cells in a high dose L. major mouse infection model. In vitro, L. major only weakly stimulated NKT cells and antagonized their response to the prototypic NKT cell ligand alpha-galactosylceramide, indicating that L. major partially escapes the activation of NKT cells. NKT cell deficiency as analyzed by subcutaneous infection of Jalpha281-/- mice (lacking invariant CD1d-restricted NKT cells) and CD1-/- mice (lacking all CD1d-restricted NKT cells) led to a transient increase in skin lesions, but did not impair the clinical cure of the infection, NK cell cytotoxicity, the production of IFN-gamma, the expression of inducible nitric oxide synthase, and the control of the parasites in the lymph node. In the spleen, however, NKT cells were required for NK cell cytotoxicity and early IFN-gamma production, they lowered the parasite burden, and exerted bystander effects on Leishmania antigen-specific T cell responses, most notably after systemic infection. Thus, NKT cells fulfill organ-specific protective functions during infection with L. major, but are not essential for parasite control.     

NK细胞和NKT细胞发育的转录调控

自然杀伤（natural killer,NK）细胞和自然杀伤T（natural killer T,NKT）细胞是参与机体抗病毒免疫和肿瘤免疫的两群淋巴细胞亚群,是介导先天性免疫（innate immunity）应答和调节适应性免疫（adaptive immunity）应答的重要效应细胞。近年来,随着对NK细胞和NKT细胞及其转录调控因子研究的不断深入,NK细胞和NKT细胞的发育机制逐步被阐明,这将为提高NK细胞和NKT细胞的抗病毒和肿瘤免疫疗效提供新的策略。     

NKT 细胞在动脉粥样硬化中的作用*

然杀伤T细胞(natural killer T cell,NKT细胞)是一种特殊的淋巴细胞亚群,具有部分T细胞和NK细胞的特征。与这些细胞不同的是,NKT细胞不仅能够识别醣脂类抗原,还在激活后产生促炎症因子和抗炎症因子。由于这些特性,NKT细胞在炎症和免疫方面的研究越来越热。动脉粥样硬化是一种受免疫调节的炎性疾病,因此对NKT细胞在该疾病中作用的研究也逐渐开展起来。     

Genetic background influences natural killer cell activation during bacterial peritonitis in mice, and is interleukin 12 and interleukin 18 independent

Some mouse strains produce strong pro-inflammatory, T-helper (Th)1 responses (e.g. C57BL/6), or strong anti-inflammatory, Th2 responses (e.g. BALB/c). The exact mechanisms for development of distinct immune responses to infection are not completely understood, although cytokines such as interleukin (IL)-12, IL-18 and IL-4 are known to play roles. Natural killer T (NKT)/natural killer (NK) cells are important regulators of immune responses in infection and non-infection models, and NKT/NK activation is also regulated by IL-12 and IL-18 in many models. We investigated the role of IL-12/IL-18 in NKT/NK activation in murine bacterial peritonitis, as well as differential NKT and NK cell activation in C57BL/6 and BALB/c mice. No differences in NKT or NK cell activation or intracellular interferon (IFN)-gamma were determined between mice given control, anti-IL-12 or anti-IL-18 antibodies or in NKT/NK cell activation in STAT4-/- mice (deficient in IL-12 signaling) or wild type controls. However, there were significant differences in the activation of NKT and NK cells between C57BL/6 mice and BALB/c mice, with NKT/NK cytokine production following Th1 or Th2 lines dependent on strain. This suggests a role for NKT and NK cell activation in the development of Th1 and Th2 responses during bacterial infection independently of IL-12 or IL-18.     

Role of natural killer T lymphocytes during helminthic infection

Natural killer (NK)T cells are innate lymphocytes that release important amount of immunoregulatory cytokines (IFN-gamma and/or IL-4) shortly after T cell receptor engagement by (glyco)lipid antigens presented by the CD1d molecules. Through this property, NKT cells play pivotal role in many physiopathologic situations. Here, we review the current knowledge of the functions and mechanisms of activation of NKT cells during infection, with a particular emphasis on helminthic infections. Recent findings suggest that, although dispensable for host resistance, NKT cells play part in the development of the acquired immune response and in the control of the pathology during murine schistosomiasis.     

NK cells and innate immunity to malaria

Innate immune response against Plasmodium falciparum (Pf), a causative agent of human malaria, is the result of several thousand years of co-evolution between the parasite and his host. An early IFN-gamma production during infection is associated with a better evolution of the disease. Natural killer (NK) cells are among the first cells in peripheral blood to produce IFN-gamma in response to Pf-infected erythrocytes (Pf-E). NK cells are found in blood, in secondary lymphoid organs as well as in peripheral non-lymphoid tissues. They participate in host innate responses that occur upon viral and intracytoplasmic bacterial infections, but also during the course of tumor development and allogeneic transplantation. These lymphocytes are not only important players of innate effector responses, but also participate in the initiation and development of adaptive immune responses. In addition, direct sensing of Pf infection by NK cells induces their production of the proinflammatory chemokine IL-8, suggesting a role for NK cells in the recruitment and the activation of other cells during malaria infection. Several other cell subsets are involved in the innate immune response to Pf. Dendritic cells, macrophages, gamma delta T cells, NKT cells are able to sense the presence of the parasite. Along this line, the presence of IL-12 is necessary to NK cell IFN-gamma production and a functional cooperation takes place between macrophages and NK cells in the context of this parasitic infection. In particular, IL-18 produced by macrophages is a key factor for this NK response. However, the molecular basis of Pf-E recognition by NK cells as well as the functional role of NK cell responses during the course of the disease remain to be adressed.     

TLR4 and NKT Cell Synergy in Immunotherapy against Visceral Leishmaniasis

NKT cells play an important role in autoimmune diseases, tumor surveillance, and infectious diseases, providing in most cases protection against infection. NKT cells are reactive to CD1d presented glycolipid antigens. They can modulate immune responses by promoting the secretion of type 1, type 2, or immune regulatory cytokines. Pathogen-derived signals to dendritic cells mediated via Toll like Receptors (TLR) can be modulated by activated invariant Natural Killer T (iNKT) cells. The terminal β-(1–4)-galactose residues of glycans can modulate host responsiveness in a T helper type-1 direction via IFN-γ and TLRs. We have attempted to develop a defined immunotherapeutic, based on the cooperative action of a TLR ligand and iNKT cell using a mouse model of visceral leishmaniasis. We evaluated the anti-Leishmania immune responses and the protective efficacy of the β-(1–4)-galactose terminal NKT cell ligand glycosphingophospholipid (GSPL) antigen of L. donovani parasites. Our results suggest that TLR4 can function as an upstream sensor for GSPL and provoke intracellular inflammatory signaling necessary for parasite killing. Treatment with GSPL was able to induce a strong effective T cell response that contributed to effective control of acute parasite burden and led to undetectable parasite persistence in the infected animals. These studies for the first time demonstrate the interactions between a TLR ligand and iNKT cell activation in visceral leishmaniasis immunotherapeutic.     

Human invariant NKT cells display alloreactivity instructed by invariant TCR-CD1d interaction and killer Ig receptors

Invariant NKT (iNKT) cells are a subset of highly conserved immunoregulatory T cells that modify a variety of immune responses, including alloreactivity. Central to their function is the interaction of the invariant TCR with glycosphingolipid (GSL) ligands presented by the nonpolymorphic MHC class I molecule CD1d and their ability to secrete rapidly large amounts of immunomodulatory cytokines when activated. Whether iNKT cells, like NK and conventional T cells, can directly display alloreactivity is not known. We show in this study that human iNKT cells and APC can establish a direct cross-talk leading to preferential maturation of allogeneic APC and a considerably higher reactivity of iNKT cells cultured with allogeneic rather that autologous APC. Although the allogeneic activation of iNKT cells is invariant TCR-CD1d interaction-dependent, GSL profiling suggests it does not involve the recognition of disparate CD1d/GSL complexes. Instead, we show that contrary to previous reports, iNKT cells, like NK and T cells, express killer Ig receptors at a frequency similar to that of conventional T cells and that iNKT cell allogeneic activation requires up-regulation and function of activating killer Ig receptors. Thus, iNKT cells can display alloreactivity, for which they use mechanisms characteristic of both NK and conventional T cells.