KIR in adaptive immunity: in vivo relevance for human disease

背景这个项目利用了我们最近在杀伤细胞免疫球蛋白样受体(KIRS)方面的工作。KIR主要表达在自然杀伤细胞上，在先天免疫中发挥重要作用。很少有研究阐明KIRS对人类疾病中T细胞反应的影响。我们的研究揭示了一种新的、意想不到的增强免疫力的方法。我们发现，在两种慢性病毒感染(丙型肝炎病毒和人类T淋巴细胞白血病病毒)中，特定的KIR(KIR2DL2)增强了保护性和破坏性的HLAI类疾病的相关性，并且是临床结果的重要决定因素。值得注意的是，尽管KIR主要与先天免疫有关，但我们认为我们的观察表明，它们也对适应性免疫反应有重大影响。KIR的新角色？据报道，KIR-人类白细胞抗原基因对与疾病转归之间存在许多关联。在每一种情况下，KIR-HLA对都由KIR及其结合的HLA分子组成，其作用归因于直接的NK杀伤；即NK细胞表达KIR，KIR与其HLA配体结合，从而调节病毒感染细胞的NK杀伤，从而影响疾病转归。我们观察到的情况截然不同。我们报道，在没有KIR2DL2的情况下，人类白细胞抗原I类分子与疾病预后之间的关联很弱，但在存在KIRDL2的情况下，这种关联会增强，如果有两个KIR2DL2基因的拷贝，情况会更好。对于多个HLA-A、B和C等位基因来说也是如此，其中大多数不结合KIR2DL2。我们在两种不同的病毒感染以及保护性和有害的人类白细胞抗原关联中看到了这种影响。临床结果和病毒负担都会受到影响。此外，KIR2DL2还增强了许多不同病毒多肽与人类白细胞抗原结合的保护作用。相比之下，KIR2DL2及其C1配体(不是在保护性或有害的人类白细胞抗原分子的背景下)对这两种病毒的任何指标都绝对没有可检测到的影响。我们认为，这种KIR2DL2增强的人类白细胞抗原I类关联不能用NK杀伤病毒感染的细胞来解释。相反，我们假设KIRS和获得性免疫之间存在一种新的相互作用，这对临床结果产生了重大影响。我们认为KIR2DL2通过增加慢性感染期间T细胞的存活来增强获得性免疫，从而增强CD8+T细胞的反应强度。如果CD8+T细胞受到保护性的HLAI类分子的限制，那么在KIR2DL2+的人中，CD8+T细胞的反应将会更强，保护性关联将会增强，但同样地，如果CD8+T细胞受到有害的HLA分子的限制，那么有害的关联将会增强。目的我们将检验KIR2DL2增强获得性免疫的假设，并调查这种效应有多普遍。具体地说，我们将测试患有KIR2DL2的患者CD8+T细胞对丙型肝炎病毒和人类T淋巴细胞趋化病毒的反应是否更强，我们将调查KIR2DL2是否也会影响发生病毒相关性白血病的风险。重要的是，我们的数据与先天免疫和获得性免疫之间意外的、重要的临床相互作用是一致的。了解如何增强CD8+T细胞反应将代表着我们基础知识的重大进步，并将是对抗与免疫减弱相关的功能障碍的重要一步。方法我们采用多学科系统方法，将寄主和病原体基因组的数学建模和测序与更“传统”的细胞免疫学结合起来。研究人类免疫反应是具有挑战性的；通过使用这种结合的方法，我们获得了独特的见解。

BACKGROUNDThis project capitalises on our recent work on killer cell immunoglobulin-like receptors (KIRs). KIRs are expressed predominantly on natural killer cells where they play an important role in innate immunity. There are few studies elucidating the impact of KIRs on the T cell response in human disease.WORK WHICH HAS LED UP TO THIS PROJECT Our research has revealed a novel and unexpected way in which immunity can be enhanced. We have found that a particular KIR (KIR2DL2) enhances both protective and detrimental HLA class I disease associations in two chronic virus infections (hepatitis C virus and human T lymphotropic virus) and is an important determinant of clinical outcome. Strikingly, although KIRs are primarily associated with innate immunity, we believe our observations suggest that they also have a major impact on the adaptive immune response. A NEW ROLE FOR KIR? Many associations between disease outcome and pairs of KIR-HLA genes have been reported. In every case the KIR-HLA pair consisted of a KIR and the HLA molecule that it binds and the effect was attributed to direct NK killing; i.e. NK cells express the KIR which binds its HLA ligand, this modulates the NK killing of virus-infected cells and thus affects disease outcome. What we have observed is quite different. We report that associations between HLA class I molecules and disease outcome are weak in the absence of KIR2DL2 but are enhanced in the presence of KIRDL2, more so if there are two copies of the KIR2DL2 gene. This is true for multiple HLA-A, B and C alleles, most of which do not bind KIR2DL2. We see this effect for two different virus infections and for both protective and detrimental HLA associations. Both clinical outcome and, independently, viral burden are affected. Additionally, the protective effect of HLA binding of many different viral peptides is also enhanced by KIR2DL2. In contrast KIR2DL2 with its C1 ligand (not in the context of protective or detrimental HLA molecules) has absolutely no detectable impact on any measure for either virus. We think that this KIR2DL2-enhancement of HLA class I associations cannot be explained by NK killing of virus-infected cells. Instead we postulate a novel interaction between KIRs and adaptive immunity that is having a significant impact on clinical outcome.HYPOTHESIS We suggest KIR2DL2 enhances adaptive immunity by increasing T cell survival during chronic infection and thus enhances the strength of the CD8+ T cell response. If the CD8+ T cell is restricted by a protective HLA class I molecule then, in a KIR2DL2+ person, the CD8+ T cell response will be stronger and protective associations will be enhanced, but equally if CD8+ T cells are restricted by a detrimental HLA molecule then the detrimental associations will be enhanced. OBJECTIVESWe will test the hypothesis that KIR2DL2 enhances adaptive immunity and investigate how general this effect is. Specifically, we will test if the CD8+ T cell response to hepatitis C virus and human T lymphotropic virus is stronger in individuals with KIR2DL2 and we will investigate if KIR2DL2 also impacts on the risk of developing virus-associated leukemia.IMPORTANCEOur data are consistent with an unexpected and clinically important interaction between innate and adaptive immunity. Understanding how the CD8+ T cell response can be enhanced would represent a significant advance in our basic knowledge and would be a major step towards combating the dysfunctions associated with weakened immunity. APPROACH We take a multidisciplinary systems approach in which we combine mathematical modelling and sequencing of the host and pathogen genomes with more "traditional" cellular immunology. Investigating the human immune response is challenging; by using this combined approach we gain unique insight.