Natural killer T cells: rapid responders controlling immunity and disease

Natural killer T (NKT) cells are a subset of T cells that share properties of natural killer cells and conventional T cells. They are involved in immediate immune responses, tumor rejection, immune surveillance and control of autoimmune diseases. Most NKT cells express both an invariant T cell antigen receptor and the NK cell receptor NK1.1, and are referred to as invariant NKT cells. This invariant T cell receptor is restricted to interactions with glycolipids presented by the non-classical MHC, CD1d. These NKT cells rapidly produce high levels of interleukin (IL)-2, IFN-gamma, TNF-alpha, and IL-4 upon stimulation through their TCR. Most also have cytotoxic activity similar to NK cells. NKT cells are involved in a number of pathological conditions, and have been shown to regulate viral infections in vivo, and control tumor growth. 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.     

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.     

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。     

肿瘤对自然杀伤细胞的杀伤敏感性研究

自然杀伤细胞（NK细胞）是机体抗肿瘤的第一道防线,是机体天然免疫的主要承担者,也是获得性细胞免疫的核心调节细胞。NK细胞对肿瘤的杀伤活性与其细胞表面受体和肿瘤细胞表面的配体密切相关,由于肿瘤细胞表面配体表达不同致使对NK细胞杀伤的敏感性有很大差异,临床疗效不一。我们简要介绍了影响肿瘤细胞对NK细胞杀伤敏感性的机制,对目前提高肿瘤细胞敏感性的策略和方法进行了总结。     

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.     

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。     

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.     

Investigating the morphology, function and genetics of cytotoxic cells in bony fish

Bony fish (teleosts) possess multiple cytotoxic cell lineages that recognize and destroy virally infected and transformed cells. In general, these lineages parallel their functional equivalents in mammals and include neutrophilic granulocytes, macrophages, cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. These four cell types have been morphologically identified in multiple fish species but only limited information is available about their function. In contrast, much work has gone into examining the function of a fifth cytotoxic cell lineage, termed nonspecific cytotoxic cells (NCC), that has been referred to as the bony fish equivalent of NK cells. However, evidence suggesting that NCC do not represent the NK lineage has come through the development of multiple cytotoxic catfish cell lines that are morphologically and functionally similar to human NK cells and are distinct from NCC. In addition to characterizing cytotoxic cells from fish, recent work has identified the novel immune-type receptors (NITR) and cichlid killer leukocyte receptors (cKLR) that are structurally related to mammalian NK receptors and likely play a role in cytotoxic function in fish. This review summarizes the morphological and functional evidence for cytotoxic cells within bony fish and discusses future directions for examining cytotoxicity through genomics and transgenics.     

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.