NK细胞免疫负性调节分子及其抗肿瘤作用

目前已发现多种表达于自然杀伤(NK)细胞上的免疫负性调节分子,主要包括杀伤抑制受体(KIR)、自然杀伤细胞2组成员A(NKG2A)以及同样表达在T细胞上的程序性死亡蛋白1(PD-1)、T细胞免疫球蛋白和黏蛋白结构域3(TIM-3)、带有免疫球蛋白和免疫受体酪氨酸抑制基序结构域的T细胞免疫受体(TIGIT)和淋巴细胞活化...     

中国汉族群体KIR基因多样性的研究进展

人杀伤细胞免疫球蛋白样受体分子(killer cell immnoglobulin-like receptor,KIR)主要表达于NK细胞和部分T细胞表面.KIR分子的配体是表达于靶细胞上的某些HLA Ⅰ类分子,两者可形成配体/受体复合物.HLA-Ⅰ/KIR分子相互识别,通过传导活化或抑制信号调节NK细胞的杀伤功能,这是NK细胞参与适应性免疫应答的重要机制之一.在免疫应答过程中,HLA-Ⅰ/KIR分子的相互作用,可保护机体抵御各种各样病原体的侵袭.本文就我国汉族群体KIR基因多样性的研究进展作一综述.     

阻断KIR2DL4(CD158d)增强NK细胞的杀伤功能

目的利用抗体阻断人原代培养的自然杀伤(NK)细胞表面的杀伤细胞免疫球蛋白样受体2DL4(KIR2DL4),抑制其与配体人白细胞抗原G(HLA-G)的结合,观察对NK细胞杀伤功能的影响。方法用免疫磁珠法分离人NK细胞并培养,流式细胞术检测所得NK细胞的纯度;流式细胞术检测NK细胞表面KIR2DL4的表达水平和人乳腺癌SK-BR-3细胞表面HLA-G的表达水平;将NK细胞与SK-BR-3细胞共培养,并加入KIR2DL4的阻断抗体,ELISA检测NK细胞分泌γ干扰素(IFN-γ)的水平,利用流式细胞术检测NK细胞表面CD107a的表达水平,以检测其脱颗粒情况。结果分离得到的人原代NK细胞纯度可达90%以上;共培养实验发现,KIR2DL4的阻断抗体可促进NK细胞分泌IFN-γ,且NK细胞表面CD107a的表达水平也明显提高,提示其脱颗粒能力增强。结论阻断KIR2DL4信号可明显促进NK细胞的杀伤功能,KIR2DL4在NK细胞杀伤靶细胞的过程中发挥抑制性作用。     

KIR基因的进化、表达与功能

KIR基因位于人染色体19q34,呈共显性表达.编码蛋白主要分布于NK细胞和T细胞,特异性识别HLA分子,传导活化或抑制信号,调控杀伤功能.观察表明,骨髓移植时供者KIR表型与受者HLA表型可影响骨髓移植的预后.不同种族的KIR表达有着明显的差异,因此有必要研究中国人的KIR遗传背景.本文对杀伤免疫球蛋白样受体(KIR)的进化、遗传、表达规律和功能进行综述.     

杀伤细胞KIR与造血干细胞移植

NK细胞的杀伤细胞免疫球蛋白样受体(killercellimmunoglobulin-likereceptor,KIR)是属于免疫球蛋白样超家族的一系列分子,表达于自然杀伤(naturekiller,NK)细胞和部分T细胞的表面,能识别HLAI类分子。它们可通过与靶细胞表面的HLAI类分子结合,传导激活或抑制信号,从而调节NK细胞和T细胞的活性。造血干细胞移植(hematopoieticstemcelltransplantation,HSCT)过程中,当供者KIR与受者HLAI类分子不匹配时,供者NK细胞功能不被抑制,从而对受者抗原提呈细胞(antigen-presentingcell,APC)和残留肿瘤细胞产生较强的异源反应。研究也已证实供者NK细胞的异源反应活性可提高移植物植入率、促进移植物抗白血病细胞(graft-versus-leukemia,GvL)作用并降低移植物抗宿主病(graft-versus-hostdisease,GvHD)。     

KIR研究进展

NK细胞能够识别“自己”和“非己”的特性 ,主要通过其表面的激活性受体和抑制性受体来执行。杀伤细胞免疫球蛋白样受体是表达在NK细胞和部分T细胞的表面的一类受体 ,本文拟从KIR的基因结构、多态性、KIR与MHCⅠ类分子的相互作用、胞内信号传导及其功能等方面作一综述。     

NK细胞受体KIR2DL4的结构与功能

KIR2DL4分子是NK细胞受体(NKR)的一种,属于免疫球蛋白样(IgSF)受体家族成员,主要分布在自然杀伤(Natural killer,NK)细胞上。KIR2DL4是HLA-G分子的特异性受体,结构上具备激活性和抑制性受体的双重特点,能够通过不同途径影响NK细胞的活性,具有重要的免疫调节功能。     

032 KIR研究进展

NK细胞能够识别"自己"和"非已"的特性,主要通过其表面的激活性受体和抑制性受体来执行.杀伤细胞免疫球蛋白样受体是表达在NK细胞和部分T细胞的表面的一类受体,本文拟从KIR的基因结构、多态性、KIR与MHCⅠ类分子的相互作用、胞内信号传导及其功能等方面作一综述.     

KIR2DL分子的研究进展

KIR2DL分子是NK细胞受体(NKR)的一种,属免疫球蛋白样受体家族成员,分布在NK细胞和部分细胞毒性T淋巴细胞上。KIR2DL与相应的配体HLA-C结合后传递抑制信号,使NK细胞对靶细胞的杀伤作用被抑制。本文对此受体的结构及其识别与信号转导机制的研究进展作一综述。     

KIR研究进展

NK细胞能够识别“自己”和“非己”的特性。主要通过其表面的激活性受体和抑制性受体来执行。杀伤细胞免疫球蛋白样受体是表达在NK细胞和部分T细胞的表面的一类受体，本文拟从KIR的基因结构。多态性，KIR与MHCⅠ类分子的相互作用，胞内信号传导及其功能等方面作一综述。     

Killer immunoglobulin-like receptors

Killer Ig-like receptors (KIRs) are surface inhibitory receptors specific for allelic forms of human leukocyte antigen (HLA) class I molecules, which are expressed by natural killer (NK) cells and a subset of T lymphocytes. Upon engagement with HLA class I molecules, KIRs block NK cell activation and function. Cells lacking HLA class I molecules are promptly killed by NK cells because of the predominant effect of several activating NK receptors. The NK-mediated killing of these cells might represent an important defence mechanism, antagonizing spreading of pathogens and tumours. Evidence has been accumulated that KIR-encoding genes have evolved and diversified rapidly in primates and in humans. Similar to HLA loci, KIR sequences are highly polymorphic and, moreover, KIR haplotypes greatly vary in the number of the type of genes they contain. KIR gene expression is regulated by mechanisms of DNA methylation. As recently shown, the HLA class I regulated control of NK cell function can be exploited in an allogeneic bone marrow transplantation setting to eradicate acute myeloid leukaemias.     

NK cell MHC class I specific receptors (KIR): from biology to clinical intervention

The natural killer (NK) cell effector response towards infected cells or tumoural cells is guided by the integration of activating and inhibitory signals sensed by NK cell surface receptors. Major histocompatibility complex class I specific inhibitory receptors expressed by NK cells have two distinct roles: while allowing self tolerance, they are also needed for the acquisition of NK cell functional competence, a process termed education. In the context of allotransplantation, NK cell alloreactivity, arising from the expression on donor NK cells of inhibitory killer Ig-like receptors (KIRs) that do not recognize human leukocyte antigen from the patient, has shown clinical benefit for leukaemia patients. Based on these genetic studies, a blocking antibody directed against KIRs, as well as allogeneic NK cell infusions are now tested in clinical trials in various oncology indications. They offer promising immunotherapeutic approaches for the treatment of cancer patients.     

Regulation of KIR expression in human T cells: a safety mechanism that may impair protective T-cell responses

Killer-cell inhibitory receptors (KIRs) are a new family of major histocompatibility complex (MHC) class I-specific receptors. KIRs allow natural killer cells to identify and lyse self cells that do not express sufficient amounts of MHC class I molecules. Here, Maria Cristina Mingari and colleagues view the expression of KIRs by cytolytic T lymphocytes and their regulation by certain cytokines as a double-edged sword.     

Human Lymphocytes Obtained from Decidual Tissue Express Killer Activatory Receptors as Well as Killer Inhibitory Receptors: Analysis Using a Single Strand Conformation Polymorphism Method

PROBLEM: The objective was to clarify whether lymphocytes in decidual tissue express only killer inhibitory receptors (KIRs) or both KIRs and killer activatory receptors (KARs). METHOD OF STUDY: A polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis method, using cDNA as a template, was applied to detect as many natural killer receptors (NKRs) expressed on natural killer (NK) cells as possible and to distinguish between KIRs and KARs. Using this method, we analyzed NKRs on lymphocytes in decidual tissue and maternal peripheral blood mononuclear cells (PBMCs) (n = 10) from the same individuals. RESULTS: More than 20 SSCP bands were detected for NKRs on both the lymphocytes in decidual tissue and the maternal PBMCs. The SSCP band patterns were different for each individual. KARs mRNA was detected in lymphocytes in decidual tissue according to the SSCP analysis results. CONCLUSION: Lymphocytes in decidual tissue express not only KIRs but also KARs; this finding suggests their roles in placentation and the maintenance of pregnancy.     

Inhibitory and activatory KIR gene frequencies in the Polish population

Killer cell immunoglobulin-like receptors (KIRs) present on natural killer cells and minor subpopulations of T cells recognize class I human leukocyte antigen (HLA) molecules on the surface of target cells. Human individuals differ by the presence or absence of some KIR genes on their chromosomes (haplotypic polymorphism). As KIRs (especially two-immunoglobulin-domain-like containing, or KIR2D, molecules) are important for the outcome of tissue (particularly for haematopoietic stem cell) transplantation and possibly for pregnancy, the knowledge of KIR gene distribution in a given human population is of practical value. Therefore, we tested 175 healthy individuals from Poland for the presence or absence of these KIR genes which show haplotypic polymorphism and are expressed. Results were compared with those published for other human populations, showing close relations with other Caucasoids.     

Involvement of inhibitory NKRs in the survival of a subset of memory-phenotype CD8+ T cells

Inhibitory natural killer receptors (NKRs) such as killer cell immunoglobulin-like receptors (KIRs) in humans and Ly49 molecules in mice are expressed on NK cells and recognize multiple major histocompatibility (MHC) class I proteins. In humans and mice, a subset of CD8+ T cells also expresses NKRs and harbors a memory phenotype. Using mice that are transgenic for KIR2DL3 and its cognate HLA-Cw3 ligand, we show that engagement of inhibitory NKRs selectively drives the in vivo accumulation of a subset of memory-phenotype CD8+ T cells that express the beta chain of the interleukin 2 receptor. In vitro, recognition of MHC class I molecules by inhibitory NKRs on T cells down-regulated activation-induced cell death. These results unveil an MHC class I-dependent pathway that promotes the survival of a subset of memory-phenotype CD8+ T cells and also reveal an unexpected biological function for inhibitory NKRs on T cells.     

Natural killer cell receptors for major histocompatibility complex class I and related molecules in cytomegalovirus infection

Downmodulation of major histocompatibility complex (MHC) class I molecules by cytomegalovirus (CMV) impairs the engagement of specific leucocyte-inhibitory receptors, rendering infected cells vulnerable to natural killer (NK) cells. Members of the murine Ly49 and human KIR families, CD85j (ILT2 or leucocyte Ig-like receptor-1), as well as the CD94/NKG2A-inhibitory killer lectin-like receptor (KLR) fulfil this surveillance role. On the other hand, NK-activating receptors specific to ligands expressed on virus-infected cells may overcome the control by inhibitory receptors. In this regard, NKG2D and Ly49H lectin-like molecules trigger NK-cell functions recognizing, respectively class I-related stress-inducible molecules and the m157 murine CMV glycoprotein. Among a variety of immune evasion strategies, CMV promotes the synthesis of class I surrogates and selectively preserves the expression of some class I molecules in infected cells; moreover, CMV interferes with the expression of ligands for NKG2D. We herein review these aspects of the host-pathogen interaction, discussing a number of open issues.     

NK cell receptor gene of the KIR family with two IG domains but highest homology to KIR receptors with three IG domains

The killer cell inhibitory receptors (KIRs) are surface glycoproteins expressed by natural killer (NK) cells and some T cells. They recognize polymorphic human HLA class I molecules. Two families of KIRs have been identified and named p58 and p70. The p58 family of genes encode type I membrane proteins with two extracellular immunoglobulin (Ig) domains, while the p70 genes have three Ig domains. We here report the cloning and characterization of a novel KIR cDNA obtained from tumor cell lines with NK reactivity (YT and NK-92). This gene is also expressed in the normal cell line NK 3.3 and in NK cells obtained from some but not all normal donors. The clone, KIR103AS, has an open reading frame consistent with a KIR with two extracellular Ig domains, a transmembrane region and a 114 amino acid long cytoplasmic domain containing a single src homology 2 (SH2) binding motif. The membrane distal Ig domain of KIR 103AS has highest homology with the first Ig domain of p70 KIRs and differs significantly from the first Ig domain of p58 KIRs. The second, membrane proximal Ig domain of KIR103AS has similar and high homology with the membrane proximal Ig domains of both p70 and p58 KIRs. The extracellular domains of KIR 103AS therefore share characteristic features with both p70 and p58 genes: the domain structure is identical to p58 KIRs but the sequence homology matches closely with p70 KIRs. The putative transmembrane and cytoplasmic domains are distinctly different from all previously reported KIR cDNAs.