Immune characterization of an individual with an exceptionally high natural killer T cell frequency and her immediate family

Natural killer T cells (NKT) are a regulatory subset of T lymphocytes whose frequency in peripheral blood is highly variable within the human population. Lower than normal NKT frequencies are associated with increased predisposition to a number of diseases, including type 1 diabetes and some forms of cancer, raising the possibility that an increased frequency may be protective. However, there is little or no understanding of how high NKT frequencies arise or, most importantly, whether the potential exists to boost and maintain NKT levels for therapeutic advantage. Here, we provide a detailed functional and phenotypic characterization of the NKT compartment of a human donor with NKT levels approximately 50 times greater than normal, including an analysis of NKT in her immediate family members. The study focuses upon the characteristics of this donor and her family, but demonstrates more broadly that the size and flexibility of the NKT niche is far greater than envisioned previously. This has important implications for understanding how the human NKT compartment is regulated, and supports the concept that the human NKT compartment might be expanded successfully for therapeutic benefit.     

中国东北地区成年人外周血自然杀伤细胞和自然杀伤T细胞绝对计数研究

目的 研究中国东北地区成人NK、NKT和T淋巴细胞绝对计数。方法 用流式细胞术单平台法检测130例健康成人外周血NK、NKT、CD3^＋T、CD3^＋CD4T、CD3^＋CD8^＋T细胞绝对计数及百分数。结果建立了中国东北地区成人外周血NK、NKT、CD3^＋T、CD，CD4^＋T、CD3^＋CD8T细胞绝对计数及百分数等参考范围；男性NK细胞数量和NK％高于女性，其余各指标男女无明显差别。35岁以下成人CD8^＋T细胞数量高于60岁以上成人（P〈0．05），CD8^＋T细胞数量与年龄呈负相关，r=-0．201，P〈0．05。结论 中国东北地区成年人NK细胞数量明显高于西方人群，且NK细胞数量和百分数与性别相关，而CD4^＋T细胞数量与国外参考范围相近。     

Preserved IFN-alpha production of circulating Valpha24 NKT cells in primary lung cancer patients

Human Valpha24 NKT cells bearing an invariant Valpha24JalphaQ antigen receptor, the counterpart of murine Valpha14 NKT cells, are activated by a specific ligand, alpha-GalCer, in a CD1d-dependent manner. Here, we demonstrate decreased numbers of circulating Valpha24 NKT cells in patients with primary lung cancer compared to healthy volunteers. However, Valpha24 NKT cells and DCs from lung cancer patients were functionally normal, even in the presence of tumor. Furthermore, levels of Valpha24 NKT cells in surgically resected lung tissue appeared to be equivalent to those of Valpha14 NKT cells in the mouse lung. Levels of Valpha24 NKT cells in the tumor tissue itself were increased about 2.5 times. Administration of alpha-GalCer-pulsed DCs expanded Valpha14 NKT cells in the lung more than 10 times, and the increased levels were sustained for 1 week. This may explain the previous finding that alpha-GalCer-pulsed DCs exerted strong antitumor activity in mouse lung tumor metastatic models. The potential use of alpha-GalCer-pulsed DCs for immunotherapy aimed at activating endogenous Valpha24 NKT cells in the lung of cancer patients is discussed.     

Expansion of Lung Vα14 NKT Cells by Administration of α-Galactosylceramide-pulsed Dendritic Cells

NKT cells, a novel murine lymphoid lineage bearing an invariant T cell receptor encoded by Vα14 and Jα281 gene segments, recognize a specific ligand glycolipid, α-galactosylceramide (α-GalCer) in a CDld-dependent manner. Recent research has revealed that activated Vα14 NKT cells have dramatic antitumor effects against a wide variety of tumor cell lines in vivo and in vitro. Here, we demonstrate strong in vivo antitumor effects brought about by treatment with α-GalCer-pulsed dendritic cells in comparison with in vitro -activated Vα14 NKT cells. Furthermore, we show a significant expansion of endogenous Vα14 NKT cells in the lung following the administration of α-GalCer-pulsed dendritic cells. The feasibility of immunotherapy with α-GalCer-pulsed dendritic cells is discussed.     

乙型肝炎病毒感染对机体免疫功能影响的研究进展

机体免疫功能的紊乱是乙型肝炎发病的重要因素.HBV感染可以引起多种免疫细胞(如DC、淋巴细胞、NK/NKT细胞)的功能障碍,包括表面分子表达的异常,分泌细胞因子的异常和亚型比例失调等.凋亡也是肝组织损伤和淋巴细胞功能障碍的原因之一.     

The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation

Dendritic cell (DC) maturation is an innate response that leads to adaptive immunity to coadministered proteins. To begin to identify underlying mechanisms in intact lymphoid tissues, we studied alpha-galactosylceramide. This glycolipid activates innate Valpha14(+) natural killer T cell (NKT) lymphocytes, which drive DC maturation and T cell responses to ovalbumin antigen. Hours after giving glycolipid i.v., tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were released primarily by DCs. These cytokines induced rapid surface remodeling of DCs, including increased CD80/86 costimulatory molecules. Surprisingly, DCs from CD40(-/-) and CD40L(-/-) mice did not elicit CD4(+) and CD8(+) T cell immunity, even though the DCs exhibited presented ovalbumin on major histocompatibility complex class I and II products and expressed high levels of CD80/86. Likewise, an injection of TNF-alpha up-regulated CD80/86 on DCs, but CD40 was required for immunity. CD40 was needed for DC interleukin (IL)-12 production, but IL-12p40(-/-) mice generated normal ovalbumin-specific responses. Therefore, the link between innate and adaptive immunity via splenic DCs and innate NKT cells has several components under distinct controls: antigen presentation in the steady state, increases in costimulatory molecules dependent on inflammatory cytokines, and a distinct CD40/CD40L signal that functions together with antigen presentation ("signal one") and costimulation ("signal two") to generate functioning CD4(+) T helper cell 1 and CD8(+) cytolytic T lymphocytes.     

Immunomodulation of experimental colitis: the role of NK1.1 liver lymphocytes and surrogate antigens--bystander effect.

The imbalance between Th1 pro-inflammatory and Th2 anti-inflammatory cytokine-producing cells plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Induction of oral tolerance to colitis-extracted proteins was previously shown to down-regulate the anti-colon immune response, thereby alleviating experimental colitis. Immune bystander effect and liver-associated lymphocytes expressing the NK1.1 marker (NK1.1(+) LAL) have been suggested as being important in tolerance induction. The aims of the present study were to determine whether oral administration of inflammatory and non-inflammatory colon-extracted proteins of different species can induce peripheral immune tolerance and alleviate experimental colitis; and to examine the role of NK1.1(+) LAL in oral tolerance induction. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted from TNBS-colitis colonic wall, or normal colonic wall, from four different species. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFNgamma) and interleukin 10 (IL10) levels were measured by ELISA. To evaluate the role of NK1.1(+) LAL in maintaining the balance between immunogenic and tolerogenic subsets of cells, their cytotoxicity functions were tested in tolerized and non-tolerized-mice. The administration of mouse-derived colitis-extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or human inflammatory colons, was found to alleviate experimental colitis. Tolerized mice had less diarrhoea; showed a marked reduction of colonic ulceration, intestinal and peritoneal adhesions, wall thickness, and oedema; and demonstrated a significant improvement of all microscopic parameters for colitis. Induction of tolerance led to an increase in IL10 and a decrease in IFNgamma serum levels. NK1.1(+) LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from normal rat, rabbit, and human colon, or from rabbit inflammatory colon, developed severe colitis, with a marked increase in IFNgamma and a decrease in IL10 serum levels, and down-regulation of NK1.1(+) LAL function. This study has shown that oral tolerance can be induced in experimental colitis by means of the feeding of surrogate antigens; this alleviates experimental colitis. NK1.1(+) LAL cytotoxicity function is associated with peripheral tolerance induction and may help to maintain the Th1/Th2 immune balance.     

Immunopathogenesis of psoriasis: focus on natural killer T cells

Psoriasis is a common inflammatory skin disease triggered by dysregulated immune response and characterized by hyperproliferation and altered differentiation of keratinocytes. Formation of psoriatic lesions is thought to be elicited by the complex cellular and cytokine network arising from the pathogenic interactions between keratinocytes and components of innate and acquired immune system. Natural killer T (NKT) cells are a heterogenous T-cell lineage that has been implicated in the pathogenesis of various autoimmune diseases including psoriasis. Due to the numerous functions of NKT cells that link innate and adaptive immunity, their role in psoriasis is complex and still elusive. We summarize the currently available literature data on this issue and discuss the possible role of NKT cells in the immunopathogenesis of this autoimmune disease.     

中药九节茶提取物对应激负荷小鼠免疫功能的改善作用

目的:研究中药九节茶对束缚应激小鼠免疫功能的改善作用.方法:实验将雄性C_(57)BL/6小鼠分为正常对照组,应激对照组,125,500 mg·kg~(-1)九节茶提取物给药组,制备脾脏淋巴细胞悬液,流式细胞术分析T淋巴细胞亚群、NK细胞和NKT细胞比例及数目.结果:与应激对照组相比,中药九节茶可以提高束缚应激小鼠脾脏淋巴细胞总数,改善T淋巴细胞亚群比例,同时增加脾脏NK细胞和NKT细胞比例及数目.结论:中药九节茶可以改善应激负荷小鼠淋巴细胞数目及淋巴细胞亚群比例.